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The paired box 6 (Pax6) gene encodes a highly conserved transcription factor, involved in the development of eyes, brain, and endocrine glands. Homozygous loss of Pax6 resulted in neonatal death in mice, plus loss of eyes and malformation of cerebral cortex. In patients with heterozygous Pax6 mutations, a reduction in thickness of the frontoparietal cortex was detected, which was also observed in small eye mice. In this study, we found that Pax6 overexpression increased the cortical thickness, especially in the intermediate zone of the cortex, which conflicts with the report of Manuel et al. Pax6 overexpression appears to detain neurons in the intermediate zone while promoting cell proliferation. It is worth noting that the impact of Pax6 overexpression on cortical thickness and neuronal migration was temporal, explaining the differences with other reports. We postulated that the alteration of Pax6 isoform ratio by autoregulation might be responsible for this. JASPAR analysis together with the results of qPCR, Western blot, CUT&Tag, and rescue experiments revealed that Pax6 regulates neuronal migration and cell proliferation by indirectly mediating Wnt3a expression. Therefore, we propose that Pax6 participates in corticogenesis via interaction with Wnt3a in regulating neuronal migration and cell proliferation., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Platelet-rich plasma (PRP) has emerged as a promising therapy in a variety of medical fields. However, it is crucial to go beyond simple platelet concentration and examine the complex molecular composition both inside and outside platelets. The present work studies the effectiveness of a novel type of PRP named 'balanced protein-concentrate plasma' (BPCP). Different growth factor (GF) levels were measured using Enzyme Linked Immunosorbent Assay (ELISA), and in addition to the increase in intra-platelet GFs found in standard PRP (sPRP), BPCP also showed a higher concentration of plasmatic protein. Furthermore, extracellular vesicle (EV) concentration was significantly higher in BPCP. Cell proliferation was higher in cells incubated with lysates derived from BPCP compared to those cultured with sPRP. Regarding cell migration capacity, it was found that the process is platelet-dependent. Finally, the anti-inflammatory effect of BPCP was evaluated by inducing an inflammatory environment in M1-type macrophages. Cytokine levels were measured by ELISA following BPCP administration, showing a significant decrease in pro-inflammatory IL-1β, IL-6 and TNF-α. In summary, although further preclinical and clinical studies are needed in order to determine the therapeutic potential of BPCP, this PRP with unique characteristics demonstrates encouraging in vitro results that could potentially enhance tissue regeneration capacity., Competing Interests: Declarations. Competing interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MS has a patent pending with the title “PLASMA ENRICHED IN PLATELETS AND PLASMA MOLECULES” and reference code “PCT/EP2024/059994”. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2025. The Author(s).)

Background: Renal cell carcinoma (RCC) is a frequent and aggressive type of kidney cancer with limited therapeutic options. Although phosphatase and tensin homolog (PTEN) have been recognized as a potential tumor suppressor in all kinds of cancers, its function in RCC remains to be thoroughly elucidated., Objective: This article was recruited to examine the PTEN's role in managing the PI3K/AKT pathway and its impact on the RCC cell proliferation and migration., Methods: This study collected renal cancer and adjacent non-cancerous tissue samples from our hospital. HK-2 and 786-O cells were used, with 786-O cells divided into control, vector, and oe-PTEN groups. PTEN and related protein levels were detected using RT-qPCR and Western blot. Statistical analyses were performed using the Mann-Whitney U test and Kruskal-Wallis H test. Cell viability and migration were assessed using the CCK-8 assay and wound healing assay. All analyses were conducted with SPSS 22.0 software, with statistical significance defined as p < 0.05., Results: RT-qPCR results showed that PTEN expression was significantly increased in RCC tumor tissues compared to normal tissues (p < 0.01). However, PTEN mRNA levels were significantly reduced in 786-O cells compared to HK-2 cells (p < 0.01). In 786-O cells with low PTEN expression, further induction of PTEN overexpression significantly inhibited PI3K/AKT signaling activity (p < 0.01), accompanied by decreased cell viability and migration ability. These results indicate that the expression pattern of PTEN in RCC is complex, but its overexpression can exert tumor-suppressive effects by inhibiting the PI3K/AKT signaling pathway., Conclusion: Our findings demonstrate that PTEN overexpression in RCC cells leads to decreased PI3K/AKT signaling, decreasing cell viability and migration. This study highlights the critical role of PTEN in RCC progression and suggests potential therapeutic targets for intervention., Competing Interests: Declarations. Ethics approval and consent to participate: The study protocol was approved by the Institutional Review Board of The First Affiliated Hospital of Naval Medical University. Informed consent was obtained from all patients participating in the study. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Mucosal healing is the primary goal for inflammatory bowel disease (IBD) treatment. We previously showed the direct beneficial effects of rhamnogalacturonan (RGal) on intestinal epithelial barrier function. Here, we aimed to evaluate the effect of RGal in intestinal epithelial wound healing. Confluent cancer cell lines and colonoid monolayers were wounded, treated with RGal for 48 h, and assessed using a live cell imaging system. Proliferation and apoptosis of cells were evaluated using 5-ethynyl-2'-deoxyuridine (EdU) and TUNEL assays, respectively. Inhibitors were used to determine the receptor and signaling pathways involved. Female and male mice with DSS-induced colitis were treated orally with RGal for 7 days during the recovery phase. RGal enhanced wound healing in Caco-2, T84, and primary cells by increasing cell migration. Inhibition of pretranscriptional signaling pathways FAK, Src, PI3K, Rho family, and JNK reversed the RGal-induced wound healing. RNAseq data from Caco-2 and primary cells treated with RGal showed the upregulation of the NF-κB pathway at 12 h. Actinomycin D, Bay 11-7082 or JSH-23, and NS-398 treatment significantly reversed the effect of RGal on wound healing, confirming that the response was also transcriptionally dependent and involved NF-κB signaling and downstream COX-2 protein activity. RGal treatment of male mice enhanced recovery from DSS colitis. RGal promoted wound healing in cancer and primary cells by increasing cell migration and accelerated epithelial mucosal healing in male mice. Our findings show a novel mechanism of action of RGal in wound healing that could help in mucosal healing and the resolution of intestinal inflammation. NEW & NOTEWORTHY RGal increases wound healing in colon cancer cell lines and primary cells through increased cell migration and participation of important pretranscriptional signaling pathways and the transcription factor NF-κB. In addition, RGal also accelerates intestinal mucosal healing of male mice with DSS-induced colitis.

AKAPs (A-kinase-anchoring proteins) act as scaffold proteins that anchor the regulatory subunits of the cAMP-dependent PKA (protein kinase A) to coordinate and compartmentalize signaling elements and signals downstream of Gs-coupled GPCRs (G protein-coupled receptors). The β 2 AR (β-2-adrenoceptor), as well as the Gs-coupled EP2 and EP4 (E-prostanoid) receptor subtypes of the EP receptor subfamily, are effective regulators of multiple airway smooth muscle (ASM) cell functions whose dysregulation contributes to asthma pathobiology. Here, we identify specific roles of the AKAPs Ezrin and Gravin in differentially regulating PKA substrates downstream of the β 2 AR, EP2R (EP2 receptor) and EP4R. Knockdown of Ezrin, Gravin, or both in primary human ASM cells caused differential phosphorylation of the PKA substrates VASP (vasodilator-stimulated phosphoprotein) and HSP20 (heat shock protein 20). Ezrin knockdown, as well as combined Ezrin and Gravin knockdown, significantly reduced the induction of phospho-VASP and phospho-HSP20 by β 2 AR, EP2R, and EP4R agonists. Gravin knockdown inhibited the induction of phospho-HSP20 by β 2 AR, EP2R, and EP4R agonists. Knockdown of Ezrin, Gravin, or both also attenuated histamine-induced phosphorylation of MLC20. Moreover, knockdown of Ezrin, Gravin, or both suppressed the inhibitory effects of Gs-coupled receptor agonists on cell migration in ASM cells. These findings demonstrate the role of AKAPs in regulating Gs-coupled GPCR signaling and function in ASM and suggest the therapeutic utility of targeting specific AKAP family members in the management of asthma.

Obesity increases the risk and mortality of breast cancer through dysregulated secretion of proinflammatory cytokines and tumor adipokines that induce an inflammatory breast microenvironment. Resistin is an adipokine secreted by adipocytes, immune cells, and predominantly macrophages, which contributes to cancer progression, but its molecular mechanism in cancer is not completely described. In this study, we analyzed the relationship of resistin on breast cancer prognosis and tumor progression and the effect in vitro of resistin on p38 and ERK1/2 activation in breast cancer cell lines. By bioinformatic analysis, we found that resistin is overexpressed in the basal subtype triple-negative breast cancer and is related to poor prognosis. In addition, we demonstrated a positive correlation between RETN and MAPK3 expression in basal triple-negative breast cancer. Importantly, we found amplifications of the RETN gene in at least 20 % of metastatic samples from patients with breast cancer. Most samples with RETN amplifications metastasized to bone and showed high expression of IL-8 (CXCL8) and IL-6 (IL6). Finally, resistin could be considered a prognostic marker for basal triple-negative breast cancer, and we also proposed the possibility that resistin-induced cell migration involves the activation of MAPK in breast cancer cells., Competing Interests: Declaration of competing interest Please check the following as appropriate: X All authors have participated in (a) conception and design, or analysis and interpretation of the data; (b) drafting the article or revising it critically for important intellectual content; and (c) approval of the final version. X This manuscript has not been submitted to, nor is under review at, another journal or other publishing venue. X The authors have no affiliation with any organization with a direct or indirect financial interest in the subject matter discussed in the manuscript The following authors have affiliations with organizations with direct or indirect financial interest in the subject matter discussed in the manuscript., (Copyright © 2024 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

The role of the integrin family in malignancy has received increasing attention. Many studies have confirmed that ITGB4 could activate multiple signal pathways and promote cell migration in various cancers. However, the regulatory role of integrin β4 (ITGB4) in lung adenocarcinoma (LUAD) is still unclear. Examination of the expression or survival analysis of ITGB4 in cells, pathological samples, and bioinformatics lung adenocarcinoma databases showed ITGB4 was highly expressed in LUAD and significantly associated with poor prognosis. Small interfering RNA and plasmids were performed to investigate the effect of changes in ITGB4 expression on lung adenocarcinoma. Focal adhesion kinase (FAK) inhibitor defactinib was used to further explore the molecular mechanism of ITGB4. The results showed depletion of ITGB4 inhibited migration and activation of FAK signaling pathways in lung adenocarcinoma cells. Moreover, increased ITGB4 expression activated FAK signaling and promoted cell migration, which can be reversed by defactinib. In addition, ITGB4 could interact with FAK in lung adenocarcinoma cells. ITGB4 may promote cell migration of lung adenocarcinoma through FAK signaling pathway and has the potential to be a biomarker for lung adenocarcinoma., Competing Interests: Declarations. Conflict of interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Ethical Approval: The study was approved by the Ethics Committee of affiliated Xing Tai People Hospital of Hebei Medical University. All methods in this study were performed in accordance with the relevant guidelines and regulations. The study is reported in accordance with ARRIVE guidelines., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Canonical transient receptor potential isoform 3 (TRPC3), a calcium-permeable non-selective cation channel, has been reported to be upregulated in breast cancers and a modulator of cell migration. Calcium-sensitive transcription factor NFATc1, which is important for cell migration, was shown to be frequently activated in triple negative breast cancer (TNBC) biopsy tissues. However, whether TRPC3-mediated calcium influx would activate NFATc1 and affect the migration of TNBC cells, and, if yes, the underlying mechanisms involved, remain to be investigated. By immunostaining followed by confocal microscopy, TNBC lines MDA-MB-231 and BT-549 were both found to express TRPC3 on their plasma membrane while ER + line MCF-7 and HER2 + line SK-BR3 do not. Blockade of TRPC3 by pharmacological inhibitor Pyr3 or stable knockdown of TRPC3 by lentiviral vector both inhibited cell migration as measured by wound healing assay. Importantly, blocking TRPC3 by Pyr3 or knockdown of TRPC3 both caused the translocation of NFATc1 from the nucleus to the cytosol as revealed by confocal microscopy. Interestingly, NFATc1 was found to bind to the promoter of glypican 6 (GPC6) as determined by chromatin immunoprecipitation assay. Consistently, knockdown of TRPC3 decreased the expression of GPC6 as revealed by western blotting. Moreover, long-term knockdown of GPC6 by lentiviral vector also consistently decreased the migration of TNBC cells. Intriguingly, GPC6 proteins physically interact with vinculin in MDA-MB-231 as determined by co-immunoprecipitation. Blockade of TRPC3, knockdown of TRPC3 or knockdown of GPC6 all induced larger, stabilized actin-bound peripheral focal adhesion (FA) formations in TNBC cells as determined by co-staining of actin and vinculin followed by confocal microscopy. These large, stabilized actin-bound peripheral FAs indicated a defective FA turnover, and were reported to be responsible for impairing directed cell migration. Our results suggest that, in TNBC cells, calcium influx through TRPC3 channel positively regulates NFATc1 nuclear translocation and GPC6 expression, which maintains the dynamics of FA turnover and optimal cell migration. Our study reveals a novel TRPC3-NFATc1-GPC6-vinculin signaling cascade in maintaining the migration of TNBC cells., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Breast cancer is a heterogeneous disease and is one of the most prevalent cancers in women. Triple-negative breast cancer (TNBC) is a relatively aggressive subtype of breast cancer, which is difficult to treat. Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane protein that is overexpressed in various types of cancers, including breast cancer, especially TNBC. In this study, bioinformatic analyses revealed enhanced fibroblast growth factor receptor 1 (FGFR1) signaling in patients with invasive breast cancer, and the GPNMB high /FGFR1 high group exhibited a lower probability of relapse-free survival (RFS) than the GPNMB low /FGFR1 low group. Additionally, we observed that GPNMB and FGFR1 were essential for sphere formation, cellular migration, and epithelial-mesenchymal transition (EMT)-like changes in TNBC cells. To explore the mutual interaction between these two molecules, we conducted in silico protein-protein docking studies and molecular dynamics simulations. The results revealed that GPNMB isoform b exhibits high binding affinity for FGFR1 isoform c (FGFR1c), which correlates with cancer aggressiveness. We also confirmed the interaction between GPNMB and FGFR1 in TNBC cells. Furthermore, our study demonstrated that GPNMB is essential for AKT phosphorylation at T308 following FGF2 stimulation, resulting in high affinity for FGFR1c. Inhibition of AKT phosphorylation substantially reduces the tumorigenic potential of TNBC cells., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The subcellular localization of mRNAs plays a pivotal role in biological processes, including cell migration. For instance, β-actin mRNA and its associated RNA-binding protein (RBP), ZBP1/IGF2BP1, are recruited to focal adhesions (FAs) to support localized β-actin synthesis, crucial for cell migration. However, whether other mRNAs and RBPs also localize at FAs remains unclear. Here, we identify hundreds of mRNAs that are enriched at FAs (FA-mRNAs). FA-mRNAs share characteristics with stress granule (SG) mRNAs and are found in ribonucleoprotein (RNP) complexes with the SG RBP. Mechanistically, G3BP1 binds to FA proteins in an RNA-dependent manner, and its RNA-binding and dimerization domains, essential for G3BP1 to form RNPs in SG, are required for FA localization and cell migration. We find that G3BP1 RNPs promote cell speed by enhancing FA protein mobility and FA size. These findings suggest a previously unappreciated role for G3BP1 RNPs in regulating FA function under non-stress conditions., Competing Interests: Declaration of interests S.W. is a co-inventor on a patent applied for by Harvard University related to the MERFISH technology. S.W. is a shareholder and consultant of Translura, Inc. M.H. is a current employee of Merck Research Laboratories., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

During the postpartum and lactation period, the involuted thymus, affected by pregnancy hormones, initiates its morphophysiological recovery with the positive regulation of the hormone prolactin (PRL), present at high levels during lactation. PRL has pleiotropic effects on thymic epithelial cells, thymocytes, as well as on elements of the extracellular matrix. In this study, we evaluated the production of the chemokine CXCL12 by the thymic microenvironment and its receptor, CXCR4, by thymocytes from lactating female mice. To achieve this objective, we used C57BL/6 female mice that were nulliparous or on the 15th day of lactation. After euthanasia, their thymi were collected, weighed, and processed for histological analyses and PRL quantitation. In other experiments, the thymus was mechanically disrupted to obtain fresh thymocytes, which were subsequently subjected to in vitro assays and flow cytometry analyses. Also, the plasma serum of the females was collected to measure PRL levels. It was observed that there was lower cellularity and thymic weight on the 15th day of lactation, along with histological alterations that this organ normally exhibits during this period. It was found that the thymic supernatant presented higher levels of PRL than the animals' serum. Additionally, the thymic medulla exhibited higher quantities of CXCL12, and thymocytes displayed elevated levels of CXCR4, making them more adept at migrating in response to this chemotactic stimulus. Remarkably, this is the first report, to the best of our knowledge, indicating the action of the CXCL12/CXCR4 pair in the thymus during the physiological lactation period., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

The mushroom Pleurotus ostreatus is widely produced in Brazil and its stipes are discarded before commercialization. In the present study, this agricultural fungal waste (mushroom stipes), was analyzed by preparing an aqueous extract and obtaining the polysaccharides by ethanol precipitation (POS-extract). The fraction presented 37 % of carbohydrates and small amounts of proteins and phenolic compounds. Rheological analyses showed a high viscosity and a gel-like behavior depending on temperature and concentration. The main polysaccharides present were β-glucans and mannogalactans, which were confirmed by the enzymatic method, monosaccharide composition, and NMR. Methylation analyses showed a high content of 1,6-linkages for both polysaccharides. The POS-extract was tested on Caco-2 cells to observe cytotoxicity and cell migration ability. Incubation with different concentrations of POS-extract showed no significant cytotoxic effects (p ≥ 0.05) and promoted wound closure of the injured monolayer by 95 % after 72 h (at 300 μg/mL). The preliminary results indicate a promising application of mushroom by-products, containing easily extractable bioactive compounds., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2025 Elsevier B.V. All rights reserved.)

The role of immune cells is crucial in nerve regeneration following spinal cord injury. Kif15, a member of the kinesin family, has been shown to enhance macrophage phagocytosis. This study investigates the impact of Kif15 deficiency on immune cells in zebrafish with spinal cord injury. Using kif15 morphants in Tg(coro1a:EGFP) zebrafish, we observed increased recruitment of Coro1a + cells to the injury site, followed by a rapid decline in kif15 morphants. Transcriptome analysis revealed that inflammatory and phagocytic signals were significantly enhanced at 1-hour post-injury (hpi), while MAPK pathways indicated growth at 24 hpi. Enhanced phagocytosis was confirmed using neutral red particles, and the Kif15 inhibitor GW406108X further supported increased migration and phagocytosis in macrophages. Activation of Cdc42 and RhoA was significantly increased, contributing to cell motility and phagocytosis. Additionally, the number of apoptotic cells was reduced in kif15 morphants, suggesting that Kif15 depletion could activate immune cells and efficiently remove apoptotic cells. Our study provides in vivo evidence that Kif15 is involved in immune cell migration and phagocytosis and suggests potential therapeutic roles for Kif15 inhibitors in spinal cord injury treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Despite accounting for only ~0.001% of all neurons in the human brain, midbrain dopaminergic neurons control numerous behaviors and are associated with many neuropsychiatric disorders that affect our physical and mental health. Dopaminergic neurons form various anatomically and functionally segregated pathways. Having such defined dopaminergic pathways is key to controlling varied sets of brain functions; therefore, segregated dopaminergic pathways must be properly and uniquely formed during development. How are these segregated pathways established? The three key developmental stages that dopaminergic neurons go through are cell migration, axon guidance, and synapse formation. In each stage, dopaminergic neurons and their processes receive unique molecular cues to guide the formation of specific dopaminergic pathways. Here, we outline the molecular mechanisms underlying the establishment of segregated dopaminergic pathways during each developmental stage in the mouse brain, focusing on the formation of the three major dopaminergic pathways: the nigrostriatal, mesolimbic, and mesocortical pathways. We propose that multiple stage-specific molecular gradients cooperate to establish functionally segregated dopaminergic circuits., Competing Interests: Declaration of interests We declare no competing interests in relation to this work., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Focal adhesions (FAs), multi-protein complexes that link the extracellular matrix to the intracellular cytoskeleton, are key mediators of cell adhesion, migration, and proliferation. These dynamic structures act as mechanical sensors, transmitting stimuli from the extracellular to intracellular environment activating in this way signaling pathways and enabling cells to adapt to environmental changes. As such, FAs are critical for tissue organization and serve as hubs governing cell spatial arrangement within the organism. The assembly, reactivity, and functional regulation of FAs are tightly controlled by post-translational modifications, including redox modulation by reactive oxygen and nitrogen species. Increasing evidence suggests that redox signaling plays a pivotal role in both the physiological and pathological functions of FAs and their downstream processes. Redox regulation affects various components of the FA complex, including integrins, focal adhesion kinase 1 (FAK1), SRC, adapter proteins, and cytoskeletal elements. In this review, we provide an updated overview of the complex interplay between redox signaling and post-translational modifications in FAs. We explore how redox reactions influence the structure, dynamics, and function of FAs, shedding light on their broader implications in health and disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Long non-coding RNAs (lncRNAs) have emerged as pivotal regulatory molecules in cancer biology. Among these, long intergenic non-protein coding RNA 02418 (LINC02418), a recently identified lncRNA, has been linked to endometrial cancer (EC), although its function and operational mechanisms are largely unclear. The present investigation aims to elucidate the molecular mechanism through which LINC02418 influences EC pathogenesis. We employed Western blotting and quantitative real-time PCR to analyze Ras protein specific guanine nucleotide releasing factor 1 (RASGRF1) and LINC02418 expression profiles in EC tissues and cell lines. Functional analyses, including cell proliferation, migration, and invasion assays, were conducted to evaluate the impact of LINC02418 overexpression on EC cells. Xenograft mouse models were established for in vivo validation. The molecular interactions between LINC02418, miR-494-3p, and RASGRF1 were characterized using luciferase reporter and RNA pull-down assays. LINC02418 expression was significantly downregulated in EC tissues and cell lines compared to their normal counterparts. Forced expression of LINC02418 significantly suppressed EC cell proliferation, migration, and invasion in vitro. In xenograft models, LINC02418 overexpression resulted in reduced tumor burden and enhanced cell death. Mechanistically, LINC02418 enhanced RASGRF1 expression by sequestering miR-494-3p, a finding substantiated by RNA pull-down assays. The tumor-suppressive effects of LINC02418 were partially reversed by RASGRF1 silencing and miR-494-3p overexpression. Clinical analyses revealed that reduced RASGRF1 expression correlated with poor histological differentiation, advanced tumor stages, and decreased overall survival in EC patients. Our findings establish LINC02418 as a tumor suppressor that regulates EC progression through modulation of the miR-494-3p/RASGRF1 axis, highlighting its potential as a therapeutic target in EC treatment., Competing Interests: Declarations. Conflicts of interest: The authors declared that there was no conflicts of interest associated with the manuscript. Ethical approval: The study was approved by the Institutional Review Board at the Affiliated People’s Hospital of Ningbo University following the ethical guidelines of the 1964 Declaration of Helsinki and its amendments. Written informed consent was obtained from all participants or their legal representatives prior to sample collection. Research involving animal participants: The procedures involving animals were approved by the Animal Care and Use Committee at the Affiliated People’s Hospital of Ningbo University, and were meticulously carried out in accordance with the established protocols and statutes governing the management of experimental animals within the institution. Consent for publication: Not applicable., (© 2025. The Author(s), under exclusive licence to Springer Nature B.V.)

Regenerating skin tissue remains a major challenge in medical science, especially due to the risk of scarring and prolonged healing, which becomes even more complicated in people with diabetes. Recent advancements have led to the creation of therapeutic dressings incorporating drug-delivery systems to tackle these issues. Exosomes (Exos) derived from mesenchymal stem cells (MSCs) have gained significant attention for mediating therapy without directly using cells, thanks to their natural anti-inflammatory and tissue repair properties mirroring those of MSCs. In this study, an advanced wound dressing combines chitosan (CS) and polyethylene glycol (PEG) hydrogel with adipose MSCs-derived Exos (ADMSCs-Exos). This composite, formed using a straightforward blending technique, is engineered to improve the healing process of severe skin injuries by steadily releasing Exos as the hydrogel degrades. The in vitro studies demonstrate that this hydrogel-exosome dressing greatly enhances endothelial cell migration, reduces oxidative stress, and promotes angiogenesis, crucial for effective wound healing. Additionally, real time-polymerase chain reaction (RT-PCR) analysis revealed significant upregulation of key genes involved in these processes, supporting the therapeutic potential of the hydrogel-Exo combination. These findings emphasize the potential of this hydrogel-Exos combination as an innovative and promising solution for advanced wound care., (© 2025 The Author(s). Macromolecular Bioscience published by Wiley‐VCH GmbH.)

Glioblastoma (GBM), the most malignant primary brain tumor in adults, has poor prognosis irrespective of therapeutic advances due to its radio-resistance and infiltrative growth into brain tissue. The present study assessed functions and putative druggability of BRCA1-associated ATM activator 1 (BRAT1) as a crucial factor driving key aspects of GBM, including enhanced DNA damage response and tumor migration. By a stable depletion of BRAT1 in GBM and glioma stem-like (GSC) cell lines, we observed a delay in DNA double-strand break repair and increased sensitivity to radiation treatment, corroborated by in vitro and in vivo studies demonstrating impaired tumor growth and invasion. Proteomic and phosphoproteomic analyses further emphasize the role of BRAT1's cell migration and invasion capacity, with a notable proportion of downregulated proteins associated with these processes. In line with the genetic manipulation, we found that treatment with the BRAT1 inhibitor Curcusone D (CurD) significantly reduced GSC migration and invasion in an ex vivo slice culture model, particularly when combined with irradiation, resulting in a synergistic inhibition of tumor growth and infiltration. Our results reveal that BRAT1 contributes to GBM growth and invasion and suggest that therapeutic inhibition of BRAT1 with CurD or similar compounds might constitute a novel approach for anti-GBM directed treatments., Competing Interests: Declarations. Ethical approval: All animal procedures were conducted in accordance with a valid approval (FK-1116) by the Regierungspräsidium Darmstadt. Conflict of interest: The authors declare no conflict of interest., (© 2024. The Author(s).)

Colorectal cancer (CRC) ranks second in mortality worldwide while metastasis accounts for most CRC-related deaths. Thus, understanding cell migration, a crucial step in metastasis, is imperative for developing new therapies. Growth Differentiation Factor-15 (GDF15), a member of the Transforming Growth Factor β superfamily, is overexpressed in CRC and promotes metastasis with a so far unknown mechanism. LIMS1 is a cell-matrix adhesion prosurvival protein that is also overexpressed in CRC and localized at the tumor invasive front, while bioinformatics analysis shows that both genes exhibit the same expression pattern in metastatic CRC samples. In the present study, treatment of low-aggressiveness HT29 CRC cells with human recombinant GDF15 (hrGDF15) led to increased LIMS1 expression, increased mRNA level of RhoGTPases RAC1 and RHOA but not CDC42, and increased migration. Conversely, GDF15 or LIMS1-siRNA-mediated silencing in invasive HCT116 cells resulted in downregulation of LIMS1 and GDF15 respectively, decreased RAC1, and RHOA as well as reduced cell migration, which were fully restored by hrGDF15 treatment both in GDF15 and LIMS1-siRNA-treated cells. Our findings indicate that GDF15 and LIMS1 have an interdependent role in the migration process which renders them potent targets for the development of novel therapeutic strategies to inhibit metastatic spread., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier B.V.)

Using a combined top-down (i.e., operator-directed) and bottom-up (i.e., cell-directed) strategy, an Under-oil Open Microfluidic System (UOMS)-based microtumor model is presented for investigating tumor cell migration and anti-metastasis drug test. Compared to the mainstream closed microfluidics-based microtumor models, the UOMS microtumor model features: i) micrometer-scale lateral resolution of surface patterning with open microfluidic design for flexible spatiotemporal sample manipulation (i.e., top-down); ii) self-organized extracellular matrix (ECM) structures and tumor cell-ECM spontaneous remodeling (i.e., bottom-up); and iii) free physical access to the samples on a device with minimized system disturbance. The UOMS microtumor model - allowing a controlled but also self-organized, cell-directed tumor-ECM microenvironment in an open microfluidic configuration - is used to test an anti-metastasis drug (incyclinide, aka CMT-3) with a triple-negative breast cancer cell line (MDA-MB-231). The in vitro results show a suppression of tumor cell migration and ECM remodeling echoing the in vivo mice metastasis results., (© 2025 The Author(s). Small published by Wiley‐VCH GmbH.)

Teleost fish, such as Poecilia latipinna, exhibit remarkable regenerative capabilities, making them excellent models for studying tissue regrowth. They regenerate body parts like the tail fin through epimorphic regeneration, involving wound healing, blastema formation (a pool of proliferative cells), and tissue differentiation. Bone Morphogenetic Protein (BMP) and Fibroblast Growth Factor (FGF) signaling pathways play crucial roles in this process, but their specific functions during blastema formation remain unclear. To explore this, BMP and FGF signaling were inhibited using targeted drug treatments prior to blastema formation in amputated tail fins. The treatment group of P. latipinna received drugs at set intervals, and analyses were conducted using skeletal staining, gene expression via quantitative real-time PCR, and protein analysis with Western blotting to assess blastema formation, extracellular matrix (ECM) remodeling, and skeletal patterning. Dual inhibition of BMP and FGF pathways led to significant regenerative defects, including bent blastema and disrupted bone structure, along with downregulation of essential patterning genes like sonic hedgehog (Shh) and bmp2b. Additionally, ECM remodeling and epithelial-to-mesenchymal transition (EMT) were impaired, as shown by reduced matrix metalloproteinases (MMP2 and MMP9), hindering cell migration and blastema stability. Cell proliferation was markedly decreased, as evidenced by reduced proliferating cell nuclear antigen (PCNA) expression and bromodeoxyuridine (BrdU) incorporation, while apoptosis increased, with elevated markers like caspase 3 (casp3) and higher DNA fragmentation. These findings indicate that BMP and FGF signaling are essential for blastema formation and skeletal patterning, with their inhibition causing major regenerative abnormalities., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof. Suresh Balakrishnan reports financial support was provided by India Ministry of Science & Technology Department of Biotechnology. Prof. Suresh Balakrishnan reports financial support was provided by Science and Engineering Research Board. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier GmbH. All rights reserved.)

The efficacy of available treatments for melanoma is limited by side effects and the rapidly emerging resistance to treatment. In this context, the decavanadate compounds represent promising tools to design efficient therapeutic agents. In our study, we synthesized a dimagnesium disodium decavanadate icosahydrate compound (Mg 2 Na 2 V 10 O 28 ·20H 2 O) and investigated its structure stability as well as its antimelanoma effects. Results showed that the Mg 2 Na 2 V 10 O 28 ·20H 2 O compound is structured in a monoclinic system with the space group C2/c, stabilized by oxygen vertices, hydrogen bonds, and van der Waals interactions. Interestingly, we found that this newly synthesized compound reduced the viability of human (IGR39, IGR37, and SKMEL28) and murine (B16-F10) melanoma cells in a dose-dependent manner. The IC 50 values ranged from 7.3 to 18 μM after 24 h and decreased to 1.4 μM after 72 h of treatment. Notably, this effect was more important than that of cisplatin (IC 50  = 3 μM after 72 h of treatment), a chemotherapeutic agent, commonly used in the treatment of malignant melanoma. Furthermore, the cytotoxicity of the decavanadate compound was relatively weak on normal human keratinocytes (HaCaT), with a light effect (IC 50 >> 70 μM) observed after 24 h of treatment. Thus, the Mg 2 Na 2 V 10 O 28 ·20H 2 O compound displayed an advantage over cisplatin, which was reported to be much more aggressive to the keratinocyte cell line (IC 50  = 23.9 μM). Moreover, it inhibited dose-dependently the adhesion of IGR39 cells to collagen (IC 50  = 2.67 μM) and fibronectin, as well as their migration with an IC 50 value of 2.23 μM. More interestingly, its in vivo administration to B16-F10 allografted mice, at the nontoxic dose of 50 μg (2.5 mg/kg), prevented and suppressed by 70% the tumor growth, compared to the nontreated mice. Moreover, this compound has also allowed a recovery against inflammation induced in mice by a mixture of DMBA and croton oil. Thus, all our results showed the potential of the Mg 2 Na 2 V 10 O 28 ·20H 2 O compound to prevent and efficiently treat the growth and metastasis of melanoma., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2025 Amine Essid et al. Bioinorganic Chemistry and Applications published by John Wiley & Sons Ltd.)

Background: Inadequate treatment responses, chemotherapy resistance, significant heterogeneity, and lengthy treatment durations create an urgent need for new pancreatic cancer therapies. This study aims to investigate the effectiveness of gemcitabine-loaded nanoparticles enclosed in an organo-metallic framework under ketogenic conditions in inhibiting the growth of MIA-PaCa-2 cells., Methods: Gemcitabine was encapsulated in Metal-organic frameworks (MOFs) and its morphology and size distribution were examined using transmission electron microscopy (TEM) and Dynamic light scattering (DLS) with further characterization including FTIR analysis. Various drug groups were established to evaluate their influences on cell cytotoxicity, apoptosis rate, cell cycle distribution, levels of superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA), and cell migration., Results: The gemcitabine-MOF was thoroughly analyzed to determine its size, morphology, and chemical composition, confirming its successful preparation. The treatment results showed an increase in the number of apoptotic cells following gemcitabine-MOF treatment, which was found to be associated with cell cycle arrest in the sub-G1 phase. Moreover, these treatments also resulted in reduced cell migration, decreased activity of antioxidant enzymes (SOD, GPx), and increased accumulation of MDA. Additionally, when exposed to ketogenic conditions (where beta-hydroxybutyrate is present in a glucose-limited medium), there was a further increase in cell cycle arrest, accompanied by a more pronounced decrease in SOD and GPx activity, as well as decreased migration., Conclusion: The use of metal-organic framework to encapsulate gemcitabine yielded notable pro-apoptotic effects in MIA-PaCa-2 cells with which ketogenic conditions had a synergistic effect that can hold promise for improving therapeutic options., Competing Interests: Declarations. Ethics approval and consent to participate: The project underwent an ethical evaluation and received approval from the ethics committee of the Vice President of Research at Iran University of Medical Sciences. The project code assigned by the ethics committee is IR.IUMS.FMD.REC.1401.206. The project solely utilized a commercially available cell line, specifically the MIA-PaCa-2 cells, which were procured from the cell stock center and possess an authentic certificate. As a result, there was no requirement to obtain consent from any patients. This research involved in vitro experimentation using commercially purchased cells from a cell bank, and did not involve any human samples or data from patients or healthy subjects. Therefore, no “participant consent” was required. Consent for publication: Since the manuscript and supplementary materials do not contain any personal or identifying information of participants, the consent for publication is unnecessary. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Abundant research indicates that increased extracellular matrix (ECM) stiffness significantly enhances the malignant characteristics of hepatocellular carcinoma (HCC) cells. Plectin, an essential cytoskeletal linker protein, has recently emerged as a promoter of cancer progression, particularly in the context of cancer cell invasion and metastasis. However, the responsiveness of plectin to changes in ECM stiffness and its impact on HCC progression remain unclear. In this study, we aimed to investigate whether plectin responds to variations in ECM stiffness and to explore its involved molecular mechanisms in regulating HCC cell migration., Results: Our results showed that, when compared with control group (7 kPa), high ECM stiffness (53 kPa) boosts HCC cell migration by upregulating plectin and integrin β1 expression and increasing F-actin polymerization. Knockdown of integrin β1 negated the high stiffness-upregulated plectin expression. Furthermore, reducing either plectin or integrin β1 levels, or using latrunculin A, effectively prevented the high ECM stiffness-induced F-actin polymerization and HCC cell migration., Conclusions: These findings demonstrate that integrin β1-plectin-F-actin axis is necessary for high matrix stiffness-driven migration of HCC cells, and provide evidence for the critical role of plectin in mechanotransduction in HCC cells., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: All authors read and approved the paper for publication. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Proper adhesion of cells to their environment is essential for the normal functioning of single cells and multicellular organisms. To attach to the extracellular matrix (ECM), mammalian cells form integrin adhesion complexes consisting of many proteins that together link the ECM and the actin cytoskeleton. Similar to mammalian cells, the amoeboid cells of the protist Dictyostelium discoideum also use multiprotein adhesion complexes to control their attachment to the underlying surface. However, the exact composition of the multiprotein complexes and the signaling pathways involved in the regulation of adhesion in D. discoideum have not yet been elucidated. Here, we show that the IQGAP-related protein IqgC is important for normal attachment of D. discoideum cells to the substratum. Mutant iqgC-null cells have impaired adhesion, whereas overexpression of IqgC promotes directional migration. A RasGAP C-terminal (RGCt) domain of IqgC is sufficient for its localization in the ventral adhesion focal complexes, while RasGAP activity of a GAP-related domain (GRD) is additionally required for the proper function of IqgC in adhesion. We identify the small GTPase RapA as a novel direct IqgC interactor and show that IqgC participates in a RapA-regulated signaling pathway targeting the adhesion complexes that include talin A, myosin VII, and paxillin B. On the basis of our results, we propose that IqgC is a positive regulator of adhesion, responsible for the strengthening of ventral adhesion structures and for the temporal control of their subsequent degradation., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors have no relevant financial or nonfinancial interests to disclose., (© 2025. The Author(s).)

Gastric cancer is the fifth most common cancer and the fourth leading cause of cancer-related deaths worldwide, accounting for nearly 800,000 fatalities annually. ITGAX (Integrin alpha X) is closely associated with immune cells, such as macrophages and dendritic cells. Its involvement in gastric cancer was identified through an analysis of The Gene Expression Omnibus (GEO) database, which highlighted ITGAX as one of four key gastric cancer-related genes. Our study demonstrates that ITGAX expression is significantly elevated in tumor tissues compared to normal tissues and is positively correlated with clinical prognosis in gastric cancer patients from the GEO database. Moreover, ITGAX enhanced cell proliferation, invasion, and tumorigenic capacity in mouse models. Furthermore, we explored the underlying role of ITGAX using Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction networks (PPI) analysis. Our findings reveal that ITGAX promotes gastric cancer progression by driving epithelial-mesenchymal transition pathway (EMT), suggesting its potential as a biomarker for early diagnosis and prognosis in gastric cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Hu, Cao, Huang and Chen.)

Introduction: Artificial vascular scaffolds can mimic the structure of natural blood vessels and replace the damaged vessels by implanting them at the injury site to perform the corresponding functions. Electrospinning technology can perfectly combine biological signals and topographical cues to synergistically induce directed cell migration and growth., Methods: In this study, poly (caprolactone) (PCL) nanofibers, PCL nanofibers uniformly coated with the extracellular matrix derived from endothelial cells (ECd), and bi-directional linear gradient ECd-coated PCL nanofibers were prepared by electrospinning and electrospray techniques to evaluate their effects on the proliferation and migration of Human umbilical vein endothelial cells (HUVECs) and rapid endothelialization., Results: The results showed that HUVECs could successfully adhere to the surface of these three nanofibers and maintain high viability. The migration results indicated that the bidirectional linear gradient coating could accelerate the migration of HUVECs and the endothelialization process. On this basis, three types of bionic vascular scaffolds, including PCL vascular scaffold, uniform ECd-coated PCL vascular scaffold, and bi-directional linear gradient ECd-coated PCL vascular scaffold, were further prepared. The results showed that the topology and biological signal of the bi-directional linear gradient ECd-coated PCL vascular scaffold synergistically promoted the migration of HUVECs more effectively., Discussion: This provides a new way to clinically promote the structural and functional recovery of damaged vessels and develop personalized or universal artificial vascular scaffolds, which is of great importance in cardiovascular regenerative medicine., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer (BS) declared a past co-authorship with the author(s) (YW) to the handling editor., (Copyright © 2025 Zhou, Lin, Liu, Zhang, Li and Wang.)

Angiopoietin-1 (Ang-1) and its receptor Tie-2 promote vascular integrity and angiogenesis. MicroRNAs (miRNAs) are involved in the regulation of many cellular functions, including endothelial cell (EC) survival, proliferation, and differentiation. Several reports indicate that these effects of miRNAs on EC functions are mediated through the modulation of angiogenesis factor signaling including that of vascular endothelial growth factor (VEGF). To date, very little is known about the roles played by miRNAs in the signaling and angiogenesis promoted by the Ang-1-Tie-2 receptor axis. Our high-throughput screening of miRNAs regulated by Ang-1 exposure in human umbilical vein endothelial cells (HUVECs) has identified miR-1233-3p as a mature miRNA whose cellular levels are significantly downregulated in response to Ang-1 exposure. The expression of miR-1233-3p in these cells is also downregulated by other angiogenesis factors including VEGF, fibroblast growth factor 2 (FGF-2), transforming growth factor β (TGFβ), and angiopoietin-2 (Ang-2). The overexpression of miR-1233-3p in HUVECs using specific mimics significantly attenuated cell survival, migration, and capillary-like tube formation, and promoted apoptosis. Moreover, miR-1233-3p overexpression resulted in reversal of the anti-apoptotic, pro-migration, and pro-differentiation effects of Ang-1. Biotinylated miRNA pull-down assays showed that p53 and DNA damage-regulated 1 (PDRG1) is a direct target of miR-1233-3p in HUVECs. The exposure of HUVECs to Ang-1, angiopoietin-2 (Ang-2), fibroblast growth factor 2 (FGF2), vascular endothelial growth factor (VEGF), or transforming growth factor β (TGFβ) triggers the regulation of PDRG1 expression. This study highlights that miR-1233-3p exerts inhibitory effects on Ang-1-induced survival, migration, and the differentiation of cultured ECs.

The epithelial-mesenchymal transition (EMT) is a biological process in which epithelial cells change into mesenchymal cells with fibroblast-like characteristics. EMT plays a crucial role in the progression of fibrosis. Classical inducers associated with the maintenance of EMT, such as TGF-β1, have become targets of several anti-EMT therapeutic strategies. Natural products from the pentacyclic triterpene class have emerged as promising elements in inhibiting EMT. Uvaol is a pentacyclic triterpene found in olive trees ( Olea europaea L.) known for its anti-inflammatory, antioxidant, and antiproliferative properties. Yet, its effect on the TGF-β1-induced EMT in alveolar epithelial cells is unknown. The present study aimed to investigate the impact of uvaol upon TGF-β1-induced EMT in a cultured A549 human alveolar epithelial cell line, a classic in vitro model for studies of EMT. Changes in cell shape were measured using phase-contrast and confocal microscopy, whereas protein expression levels were measured using immunofluorescence, flow cytometry, and Western blotting. We also performed wound scratch experiments to explore its effects on cell migration. Uvaol had no significant cytotoxic effects on A549 cells. By contrast, the changes in the cell morphology consistent with TGF-β1-induced EMT were largely suppressed by treatment with uvaol. In addition, increased contents of mesenchymal markers, namely, vimentin, N-cadherin, and fibronectin in TGF-β1-induced A549 cells, were downregulated by uvaol treatment. Furthermore, the TGF-β1-induced migration of A549 cells was significantly suppressed by uvaol. Mechanistically, uvaol prevented the nuclear translocation of β-catenin and reduced the TGF-β1-induced levels of ZEB1 in A549 cells. These results provide compelling evidence that uvaol inhibits EMT by regulating proteins related to the mesenchymal profile in human alveolar epithelial cells, likely by modulating β-catenin and ZEB1 levels., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Patrícia Gonçalves Tenório, Xavier, Silveira Wagner, Moreira Bagri, Alves Ferreira, Galvani, Mermelstein, Bonomo, Savino and Barreto.)

Introduction: Endoplasmic reticulum aminopeptidases 1 (ERAP1) and 2 (ERAP2) modulate a plethora of physiological processes for the maintenance of homeostasis in different cellular subsets at both intra and extracellular level., Materials and Methods: In this frame, the extracellular supplementation of recombinant human (rh) ERAP1 and ERAP2 (300 ng/ml) was used to mimic the effect of stressor-induced secretion of ERAPs on neutrophils isolated from 5 healthy subjects. In these cells following 3 h or 24 h rhERAP stimulation by Western Blot, RT-qPCR, Elisa, Confocal microscopy, transwell migration assay, Oxygraphy and Flow Cytometry we assessed: i) rhERAP internalization; ii) activation; iii) migration; iv) oxygen consumption rate; v) reactive oxygen species (ROS) accumulation; granule release; vi) phagocytosis; and vii) autophagy., Results: We observed that following stimulation rhERAPs: i) were internalized by neutrophils; ii) triggered their activation as witnessed by increased percentage of MAC-1 + CD66b + expressing neutrophils, cytokine expression/release (IL-1β, IL-8, CCL2, TNFα, IFNγ, MIP-1β) and granule enzyme secretion (myeloperoxidase, Elastase); iii) increased neutrophil migration capacity; iv) increased autophagy and phagocytosis activity; v) reduced ROS accumulation and did not influence oxygen consumption rate., Conclusion: Our study provides novel insights into the biological role of ERAPs, and indicates that extracellular ERAPs, contribute to shaping neutrophil homeostasis by promoting survival and tolerance in response to stress-related inflammation. This information could contribute to a better understanding of the biological bases governing immune responses, and to designing ERAP-based therapeutic protocols to control neutrophil-associated human diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Saulle, Limanaqi, Garziano, Murno, Artusa, Strizzi, Giovarelli, Schulte, Aiello, Clerici, Vanetti and Biasin.)

Hepatocellular carcinoma (HCC) is the most common and highly aggressive tumor in the world. Although immunotherapy, surgical resection, targeted therapy and HCC transplantation could improve the prognosis for HCC patients, the tumor recurrence rate of the tumor remains high due to its insidious and invasive nature. Therefore, the development of new HCC therapeutic agents has become particularly important. Quinoa is abundant in bioactive peptides, proteins, and other functional ingredients that confer various health benefits to humans. Quinoa bran, the outer seed coat of quinoa, like quinoa, has extremely high nutritional value and rich protein content. This study firstly found that hydrolysate from quinoa bran protein (QBPP) exhibited targeting anti-HCC effect on the proliferation of HepG2 and Bel-7402 HCC cells in a concentration dependent manner, without significant toxic side effects on normal human liver cells L02. Further, QBPP exerted anti-HCC effect through mitochondria-mediated apoptosis and inhibition of HCC cells migration. Collectively, QBPP shows potential as a next-generation dietary supplement for the prevention and treatment of HCC., Competing Interests: Declarations. Ethical Approval: Not applicable. Informed Consent: Not applicable. Conflict of Interest: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The Neural Crest cells are multipotent progenitor cells formed at the neural plate border that differentiate and give rise to a wide range of cell types and organs. Directional migration of NC cells and their correct positioning at target sites are essential during embryonic development, and defects in these processes results in congenital diseases. The NC migration begins with the epithelial-mesenchymal transition and extracellular matrix remodeling. The main cellular mechanisms that sustain this migration include contact inhibition of locomotion, co-attraction, chemotaxis and mechanical cues from the surrounding environment, all regulated by proteins that orchestrate cell polarity and motility. In this review we highlight the molecular mechanisms involved in neural crest cell migration and polarity, focusing on the role of small GTPases, Heterotrimeric G proteins and planar cell polarity complex. Here, we also discuss different congenital diseases caused by altered NC cell migration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Salinas, Ruano-Rivadeneira, Leal, Caprile, Torrejón and Arriagada.)

Radiation therapy (RT) is fundamental to the fight against cancer because of its exceptional ability to target and destroy cancer cells. However, conventional radiation therapy can significantly affect the adjacent normal tissues, leading to fibrosis, inflammation, and decreased organ function. This tissue damage not only reduces the quality of life but also prevents the total elimination of cancer. The transformation of epithelial cells into mesenchymal-like cells, termed epithelial-mesenchymal transition (EMT), is essential for processes such as fibrosis, embryogenesis, and wound healing. Conventional radiation therapy increases the asymmetric activation of fibrotic and inflammatory pathways, and the resulting chronic fibrotic changes and organ dysfunction are linked to radiation-induced epithelial-mesenchymal transition. Recent advances in radiation therapy, namely flash radiation therapy (FLASH-RT), have the potential to widen the therapeutic index. Radiation delivered by FLASH-RT at very high dose rates (exceeding 40 Gy/s) can protect normal tissue from radiation-induced damage, a phenomenon referred to as the "FLASH effect". Preclinical studies have demonstrated that FLASH-RT successfully inhibits processes associated with fibrosis and epithelial-mesenchymal transition, mitigates damage to normal tissue, and enhances regeneration. Three distinct types of EMT have been identified: type-1, associated with embryogenesis; Type-2, associated with injury potential; and type-3, related with cancer spread. The regulation of EMT via pathways, including TGF-β/SMAD, WNT/β-catenin, and NF-κB, is essential for radiation-induced tissue remodelling. This study examined radiation-induced EMT, TGF-β activity, multiple signalling pathways in fibrosis, and the potential of FLASH-RT to reduce tissue damage. FLASH-RT is a novel approach to treat chronic tissue injury and fibrosis post-irradiation by maintaining epithelial properties and regulating mesenchymal markers including vimentin and N-cadherin. Understanding these pathways will facilitate the development of future therapies that can alleviate fibrosis, improve the efficacy of cancer therapy, and improve the quality of life of patients., Competing Interests: Declarations. Conflict of interest: The authors declare no financial relationships with any commercial associations, ensuring no conflicts of interest. The material is original, unpublished elsewhere, and has been submitted only to Radiation and Environmental Biophysics. Ethical approval: Not applicable. Consent participation: Not applicable. Consent for publication: Not applicable., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The risk of breast cancer (BC) recurrence is high in postmenopausal women, though the underlying molecular mechanisms are not yet fully understood. We developed a long-term estrogen-deprived (LTED) cell line from MCF-7 cells, which we used as an in vitro model for aromatase inhibitor (AI)-resistant estrogen receptor α (ERα)-positive postmenopausal BC. We also describe the involvement of fatty acid 2-hydroxylase (FA2H) in the modulation of LTED cell migration. Small interfering RNA specific to FA2H (siFA2H) could reduce cell migration, whereas the introduction of plasmid expressing FA2H, but not its inactive mutant, resulted in enhanced migration. Moreover, proliferation of the LTED cells was not affected by modulation of FA2H expression. Fulvestrant (FUL), a selective estrogen receptor degrader used to treat AI-resistant ERα-positive postmenopausal BC, was found to induce degradation of ERα together with a decrease in ER-mediated transcription; however, FA2H protein expression and migration remained unchanged. Overall, the findings of this study suggest that FA2H is one of the drivers of LTED cell migration, and that LTED cells resistant to FUL therapy may be involved in malignancy and metastatic mechanisms., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

The extracellular matrix (ECM) is a complex structure involved in many biological processes with collagen being the most abundant protein. Density of collagen fibers in the matrix is a factor influencing cell motility and migration speed. In cancer, this affects the ability of cells to migrate and invade distant tissues which is relevant for designing new therapies. Furthermore, increased cancer cell migration and invasion have been observed in hypoxic conditions. Interestingly, it has been revealed that the Hypoxia Inducible Factor (HIF) can not only impact the levels of metabolic genes but several collagen remodeling genes as well. The goal of this paper is to explore the impact of the HIF protein on both the tumour metabolism and the cancer cell migration with a focus on the Warburg effect and collagen remodelling processes. Therefore, we present an agent-based model (ABM) of tumour growth combining genetic regulations with metabolic and collagen-related processes involved in HIF pathways. Cancer cell migration is influenced by the extra-cellular collagen through a biphasic response dependant on collagen density. Results of the model showed that extra-cellular collagen within the tumour was mainly influenced by the local cellular density while collagen also influenced the shape of the tumour. In our simulations, proliferation was reduced with higher extra-cellular collagen levels or with lower oxygen levels but reached a maximum in the absence of cell-cell adhesion. Interestingly, combining lower levels of oxygen with higher levels of collagen further reduced the proliferation of the tumour. Since HIF impacts the metabolism and may affect the appearance of the Warburg Effect, we investigated whether different collagen conditions could lead to the adoption of the Warburg phenotype. We found that this was not the case, results suggested that adoption of the Warburg phenotype seemed mainly controlled by inhibition of oxidative metabolism by HIF combined with oscillations of oxygen., Competing Interests: Declarations. Conflict of interest: The authors declare no conflict of interest., (© 2024. The Author(s).)

Niches are often found in specific positions in tissues relative to the stem cells they support. Consistency of niche position suggests that placement is important for niche function. However, the complexity of most niches has precluded a thorough understanding of how their proper placement is established. To address this, we investigated the formation of a genetically tractable niche, the Drosophila Posterior Signaling Center (PSC), the assembly of which had not been previously explored. This niche controls hematopoietic progenitors of the lymph gland (LG). PSC cells were previously shown to be specified laterally in the embryo, but ultimately reside dorsally, at the LG posterior. Here, using live-imaging, we show that PSC cells migrate as a tight collective and associate with multiple tissues during their trajectory to the LG posterior. We find that Slit emanating from two extrinsic sources, visceral mesoderm and cardioblasts, is required for the PSC to remain a collective, and for its attachment to cardioblasts during migration. Without proper Slit-Robo signaling, PSC cells disperse, form aberrant contacts, and ultimately fail to reach their stereotypical position near progenitors. Our work characterizes a novel example of niche formation and identifies an extrinsic signaling relay that controls precise niche positioning., Competing Interests: KN, KL, LA, SD No competing interests declared, (© 2024, Nelson et al.)

Long noncoding RNAs (lncRNAs) have been recognized as essential regulators in various human malignancies. Hundreds of lncRNAs were known to be abnormally expressed in renal cell carcinoma (RCC) through a lncRNA expression microarray, among which lncRNA OSTM1 antisense RNA 1(OSTM1-AS1) was revealed as one of the most abundant lncRNAs. However, the function of OSTM1-AS1 in RCC remains unknown. Here, we examined OSTM1-AS1 functional roles and mechanism in RCC development. OSTM1-AS1 expression was significantly highly expressed among RCC tissue specimens and cell lines. Functionally, OSTM1-AS1 knockdown significantly suppressed cell proliferation, migration along with metastasis of RCC cells. Mechanistically, miR-491-5p was targeted via OSTM1-AS1, and down-regulation of miR-491-5p reversed OSTM1-AS1 knockdown impact on RCC migration and invasion. MMP-9 was targeted via miR-491-5p, and MMP-9 overexpression reversed miR-491-5p or OSTM1-AS1 knockdown impact on cell migration and invasion. MMP-9 abundance was decreased by OSTM1-AS1 silence, that was reduced by miR-491-5p deficiency. Importantly, our investigation revealed that OSTM1-AS1 has the ability to interact with miR-491-5p, thereby increasing the MMP-9 expression. The in vivo trial demonstrated that OSTM1-AS1 suppression resulted in tumor growth inhibition among nude mice. In summary, our findings indicate, for the first time, at least to the best of our knowledge, that OSTM1-AS1 serves as an oncogene among RCC by promoting proliferation, invasion, and metastasis through its targeting of the miR-491-5p/MMP9 axis. Therefore, this axis could represent a promising alternative therapeutic target for RCC treatment., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics declarations: The present study was approved (approval no. 2016-R007) by the Ethics Committee of The First Affiliated Hospital of Ningbo University (Ningbo, China) following the Helsinki Declaration’s ethical principles. Written informed consent was obtained from all patients. The animal experiments were conducted out in Ningbo, all animal methods were carried out in accordance with ARRIVE principles and were approved by the Animal Experiment Ethics Committee of Ningbo University (approval no. 10994)., (© 2025. The Author(s).)

Cells use traction forces to sense mechanical cues in their environment. While the molecular clutch model effectively explains how cells exert more forces on stiffer substrates, it falls short in addressing their adaptation to dynamic mechanical fluctuations prevalent in tissues and organs. Here, using hydrogel with photo-responsive rigidity, we show that cells' response to rigidity changes is frequency dependent. Strikingly, at certain frequencies, cellular traction forces exceed those on static substrates 4-fold stiffer, challenging the established molecular clutch model. We discover that the discrepancy between the rapid adaptation of traction forces and the slower deactivation of mechanotransduction signaling proteins results in their accumulation, thereby enhancing long-term cellular traction in dynamic settings. Consequently, we propose a new model that melds immediate mechanosensing with extended mechanical signaling. Our study underscores the significance of dynamic rigidity in the development of synthetic biomaterials, emphasizing the importance of considering both immediate and prolonged cellular responses., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Using metallic/polymeric orthopedic screws causes cavities in bone trauma after the attachment of broken bones, which prolongs the healing. Yet, it remains unknown how to overcome such a challenge. The main aim of this research was to use both polymers and gels to fabricate and study a new PCL/chitosan/hydroxyapatite scaffold-like orthopedic screw for cancellous bone trauma. This screw, because of its low stiffness and its scaffold-based matrix (due to the gel part), can facilitate bone healing. Different concentrations of PCL (60-95% w/v ) and chitosan (0-5% w/v ) were blended according to the Response Surface Methodology using the Central Composite Design. The screws were fabricated using the freeze-drying technique. The screws were assessed mechanically, physically, and biologically (cell viability, cell attachment, DAPI, ALP staining, and Alizarin Red staining), and in vivo (a rat subcutaneous implantation model). Based on the results, screws depending on the PCL and gel content depicted different but notable mechanical behavior (10-60 MPa of compressive strength and 100-600 N force). The gel part could affect the physical properties of screws including water uptake (120%), degradation (18% after 21 days), porosities (23%), and mechanical strength (elastic modulus = 59.47 Mpa). The results also demonstrated no cytotoxicity towards MC3T3 cells (>80% cell viability) with good cell attachment, cell concentration, and mineralization (>90%) that was justified by the gel content. The results also showed good in vivo biocompatibility. To sum up, fabricated scaffold-like screws with gel content can be a good candidate for cancellous-bone-based orthopedic purposes. However, more in vitro and in vivo studies are required to optimize the PCL:gel ratio.

Natural killer (NK) cells are pivotal in immunotherapy due to their potent tumor-targeting capabilities. However, accessible in vitro 3D dynamic models for evaluating Tumor Infiltrating Natural Killer Cells (TINKs) remain scarce. This study addresses this gap by developing a novel pump-free microfluidic chip to investigate the interactions between NK-92 cells and prostate DU 145 tumor spheroids. The platform facilitates the separation of free NKs and TINKs for subtype characterization. The design integrates multiple planes with a multi-layer paper scaffold to accommodate tumor spheroids, allowing NK-92 cells to traverse Matrigel-coated barriers that mimic the extracellular matrix. The dual-channel pump-free device enables unidirectional circulation of NK-92 cells, allowing analysis of tumor spheroid movement and NK-92 cell interactions under flow conditions. Results demonstrate continuous fluid circulation in the dual-channel device by rocking the platform at tilt angles of 21° and 15°. Tumor spheroids show- enhanced migration under flow conditions compared to static culture. Although spheroids recruit slightly more NK-92 cells under flow conditions, CD56 and CD16 receptor expression on IL-2-activated free NK-92 cells and tumor-infiltrating NK-92 cells matches in vivo patterns in dynamic cultures. These findings suggest that tumor cells and fluid dynamics significantly influence NK cell subtypes. This pump-free microfluidic platform is a functional tool for simulating and studying immune cell-tumor interactions, providing valuable insights into NK cell dynamics with tumor spheroids in physiologically relevant environments., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Study of cell migration in cancer is crucial to the comprehension of the processes and factors that govern tumor spread. Cancer cells migrate invading tissues, causing alterations in cell adhesion, cytoskeleton, and signaling pathways. Little is known about the physical attributes of cancer cells that change when interacting with microenvironments. In this work, the local topography of the ECM has been mimicked through micropillar array substrates. MDA-MB-231 and MCF-7 breast cancer cells, exhibiting high and low metastatic potential, respectively, were analyzed. Differences in morphology and migration of the cells were investigated by examining the cell spreading area, circularity, aspect ratio, migration speed, and migration path. This work encountered that none of the studied cell lines have preferential orientation migrating on uniform patterns. In contrast, cell migration on graded patterns shows preferential orientation along the longitudinal direction from sparser to denser zones which is significantly influenced by substrate stiffness and indicates that both cell lines can sense the spacing gradient and respond to this topographical cue. The migration speed of the breast cancer cell lines significantly decreases from the sparse to medium to dense zones, registering higher values for the MDA-MB-231., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Although humans are frequently exposed to multiple pollutants simultaneously, research on their harmful effects on health has typically focused on studying each pollutant individually. Inorganic arsenic (As) and benzo[a]pyrene (BaP) are well-known pollutants with carcinogenic potential, but their co-exposure effects on breast cancer cell progression remain incompletely understood. This study aimed to assess the combined impact of BaP and As on the viability and migration of MDA-MB-231 cells. The results indicated that even at low levels, both inorganic As (0.01 μM, 0.1 μM, and 1 μM) and BaP (1 μM, 2.5 μM), individually or in combination, enhanced the viability and migration of the cells. However, the cell cycle analysis revealed no significant differences between the control group and the cells exposed to BaP and As. Specifically, exposure to BaP alone or in combination with As (As 0.01 μM + BaP 1 μM) for 24 h led to a significant increase in vimentin gene expression. Interestingly, short-term exposure to As not only did not induce EMT but also modulated the effects of BaP on vimentin gene expression. However, there were no observable changes in the expression of E-cadherin mRNA. Consequently, additional research is required to evaluate the prolonged effects of co-exposure to As and BaP on the initiation of EMT and the progression of breast cancer., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Tissue factor (TF) and protease-activated receptor 2 (PAR2) have been associated with the progression of cancer, while integrins are essential for the adhesion and migration of cancer cells. This study aimed to explore the cross-talk between the TF:FVIIa complex, PAR2 signaling, and the expression of integrin α1 in cervical cancer cells. Utilizing data from The Cancer Genome Atlas (TCGA), the research examined the relationship between the TF and PAR2 genes and the integrin α1 gene (ITGA1) in reproductive cancers, revealing a positive correlation between integrin α1 expression and both TF and PAR2 genes. Analyses through Western blotting and RT-PCR demonstrated that TF:FVIIa complex transactivates PAR2, which significantly increases the phosphorylation of MEK1/2 and subsequently elevates integrin α1 expression. Inhibition of either PAR2 or MEK1/2 resulted in a decrease in the FVIIa-induced increase in integrin α1 expression. Additionally, cell migration studies indicated that elevated expression of integrin α1, mediated by the TF:FVIIa/PAR2 pathway, was linked to enhanced cell migration, which could be inhibited by blocking integrin α1. This investigation uncovers a novel signaling pathway in HeLa cells, highlighting the significance of the TF:FVIIa:PAR2 axis in modulating integrins that are vital for cancer progression, thereby offering insights for potential targeted therapeutic approaches in cancer treatment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Paranitharan Nagarajan reports financial support was provided by Council of Scientific & Industrial Research (CSIR). Velayuthaprabhu Shanmugam reports financial support was provided by Rashtriya Uchchatar Shiksha Abhiyan (RUSA 2.0 BEICH). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The α L β 2 integrin LFA-1 plays a key role in T-cell adhesion to the endothelial vasculature and migration into both secondary lymphoid organs and peripheral tissues via interactions with its target protein ICAM-1, but the pathways that regulate LFA-1-mediated T-cell polarity and migration are not fully understood. In this study we screened two RNAi libraries targeting G protein-coupled receptors (GPCR)/GPCR-associated proteins and kinases in a HuT 78 T cell line model of LFA-1-stimulated T-cell migration. Based on staining of the actin cytoskeleton, multiple parameters to measure cell morphology were used to assess the contribution of 1109 genes to LFA-1-mediated T-cell polarity and migration. These RNAi screens identified a number of both novel and previously identified genes that either increased or decreased the polarity and migratory capacity of these cells. Following multiparametric analysis, hierarchical clustering and pathway analysis, three of these genes were characterized in further detail using primary human T cells, revealing novel roles for the heterotrimeric G protein subunit Gβ1 and Casein Kinase 2 in LFA-1-mediated T-cell polarity and migration in vitro. Our studies also highlighted a new role for ICAP-1, an adaptor protein previously described to be associated with β1 integrins, in β2 integrin LFA-1-directed migration in T cells. Knockdown of ICAP-1 expression in primary T cells revealed a role in cell polarity, cell velocity and transmigration towards SDF-1 for this adaptor protein. This study therefore uncovers new roles for GPCR/GPCR-associated proteins and kinases in T-cell migration and provides potential novel targets for modulation of the T-cell immune response., (© 2024 The Author(s). Immunology & Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of the Australian and New Zealand Society for Immunology, Inc.)

In native tissues, cells encounter a diverse range of stiffness, which can significantly affect their behavior and function. The ability of cells to sense and respond to these mechanical cues is essential for various physiological processes, including cell migration. Cell migration is a complex process influenced by multiple factors, with substrate stiffness emerging as a critical determinant. This study developed a technique to edit the stiffness of polyacrylamide (PAA) hydrogel substrates by adjusting the grayscale level of a photomask during photopolymerization. By analyzing cell morphologies on the hydrogel, we confirmed the development of a single PAA hydrogel substrate with continuous stiffness gradients. This method was used to explore the correlation between substrate stiffness and cell migration dynamics. The study found that cells typically migrated from softer to stiffer surfaces. When the cells initially located on stiffer surfaces, they were able to travel longer distances. Additionally, a continuous 2D stiffness gradient surface was fabricated to explore how cells migrate on smoother versus steeper stiffness gradients. The results showed that cells tended to migrate more readily on smoother stiffness gradient surfaces compared to steeper ones. This study provides valuable insights into cell migration dynamics on substrates with varying stiffness gradients. The results underscore the importance of the mechanical environment in cancer cell migration and offer promising directions for developing interventions to prevent cancer spread., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Brain vasculature formation begins with vessel invasion from the perineural vascular plexus, which expands through vessel sprouting and growth. Recent studies have indicated the existence of oligodendrocyte-vascular crosstalk during development. However, the relationship between oligodendrocyte progenitor cells (OPCs) and the ordered spatiotemporal vascularization of the neocortex has not been elucidated. Our findings suggest that OPCs play a complex role in the vessel density of the embryonic and postnatal neocortex. Analyses of normal human and mouse embryonic cerebral cortex show that vascularization and OPC distribution are tightly controlled in a spatially and temporally restricted manner, exhibiting a positive correlation. Loss of OPCs at both embryonic and postnatal stages led to a reduction in vascular density, suggesting that OPC populations play a role in vascular density. Nonetheless, dynamic observation on cultured brain slices and staining of tissue sections indicate that OPC migration is unassociated with the proximity to blood vessels, primarily occurring along radial glial cell processes. Additionally, in vitro experiments demonstrate that OPC secretions promote vascular endothelial cell (VEC) growth. Together, these observations suggest that vessel density is influenced by OPC secretions., (© 2024 Wiley Periodicals LLC.)

Seaweeds are natural sources of sulfated polysaccharides (SPs), biopolymers with remarkable pharmacological properties, including biological actions capable of attenuating components of the inflammatory process such as edema, cytokines, cell migration and pain. Our results confirm that SPs obtained from Gracilaria domingensis (SP-GD) are agarans, primarily composed of residues of β-d-galactopyranose 6-sulfate and 3,6-anhydro-α-l-galactopyranose. Specifically, SP-GD at a dose of 10 mg/kg was effective in significantly reducing paw edema induced by carrageenan or histamine, serotonin, bradykinin, 48/80 and prostaglandin E2. SP-GD (10 mg/kg) was also able to reduce neutrophil migration and the activity of the myeloperoxidase enzyme in carrageenan-induced peritonitis, as well as conserve glutathione concentration and reduce malondialdehyde levels in the animals' peritoneal fluid. Furthermore, it showed antinociceptive action in the abdominal writhing test induced by acetic acid and in the paw licking test induced by formalin. Thus, the results obtained allow us to infer that SPs extracted from G. domingensis at a dose of 10 mg/kg have anti-inflammatory effects by reducing neutrophil migration and modulating the activity of vasoactive mediators and antinociceptive effects by acting, at least in part, through a peripheral mechanism dependent on the negative modulation of inflammatory mediators., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The prognosis for many pediatric brain tumors, including cerebellar medulloblastoma (MB), remains dismal but there is promise in new therapies. We have previously generated a mouse model developing spontaneous MB at high frequency, Ptch1 +/- /Tis21 -/- . In this model, reproducing human tumorigenesis, we identified the decline of the Cxcl3 chemokine in cerebellar granule cell precursors (GCPs) as responsible for a migration defect, which causes GCPs to stay longer in the proliferative area rather than differentiate and migrate internally, making them targets of transforming insults. We demonstrated that 4-week Cxcl3 infusion in cerebella of 1-month-old mice, at the initial stage of MB formation, forces preneoplastic GCPs (pGCPs) to leave lesions and differentiate, with a complete suppression of MB development. In this study, we sought to verify the effect of 4-week Cxcl3 treatment in 3-month-old Ptch1 +/- /Tis21 -/- mice, when MB lesions are at an advanced, irreversible stage. We found that Cxcl3 treatment reduces tumor volumes by sevenfold and stimulates the migration and differentiation of pGCPs from the lesion to the internal cerebellar layers. We also tested whether the pro-migratory action of Cxcl3 favors metastases formation, by xenografting DAOY human MB cells in the cerebellum of immunosuppressed mice. We showed that DAOY cells express the Cxcl3 receptor, Cxcr2, and that Cxcl3 triggers their migration. However, Cxcl3 did not significantly affect the frequency of metastases or the growth of DAOY-generated MBs. Finally, we mapped the expression of the Cxcr2 receptor in human MBs, by evaluating a well-characterized series of 52 human MBs belonging to different MB molecular subgroups. We found that Cxcr2 was variably expressed in all MB subgroups, suggesting that Cxcl3 could be used for therapy of different MBs., (© 2024 The Author(s). Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)