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Background: Chemoresistance presents a significant obstacle in the treatment of colorectal cancer (CRC), yet the molecular basis underlying CRC chemoresistance remains poorly understood, impeding the development of new therapeutic interventions. Elongation factor Tu GTP binding domain containing 2 (EFTUD2) has emerged as a potential oncogenic factor implicated in various cancer types, where it fosters tumor growth and survival. However, its specific role in modulating the sensitivity of CRC cells to chemotherapy is still unclear. Methods: Public dataset analysis and in-house sample validation were conducted to assess the expression of EFTUD2 in 5-fluorouracil (5-FU) chemotherapy-resistant CRC cells and the potential of EFTUD2 as a prognostic indicator for CRC. Experiments both in vitro, including MTT assay, EdU cell proliferation assay, TUNEL assay, and clone formation assay and in vivo, using cell-derived xenograft models, were performed to elucidate the function of EFTUD2 in sensitivity of CRC cells to 5-FU treatment. The molecular mechanism on the reciprocal regulation between EFTUD2 and the oncogenic transcription factor c-MYC was investigated through molecular docking, ubiquitination assay, chromatin immunoprecipitation (ChIP), dual luciferase reporter assay, and co-immunoprecipitation (Co-IP). Results: We found that EFTUD2 expression was positively correlated with 5-FU resistance, higher pathological grade, and poor prognosis in CRC patients. We also demonstrated both in vitro and in vivo that knockdown of EFTUD2 sensitized CRC cells to 5-FU treatment, whereas overexpression of EFTUD2 impaired such sensitivity. Mechanistically, we uncovered that EFTUD2 physically interacted with and stabilized c-MYC protein by preventing its ubiquitin-mediated proteasomal degradation. Intriguingly, we found that c-MYC directly bound to the promoter region of EFTUD2 gene, activating its transcription. Leveraging rescue experiments, we further confirmed that the effect of EFTUD2 on 5-FU resistance was dependent on c-MYC stabilization. Conclusion: Our findings revealed a positive feedback loop involving an EFTUD2/c-MYC axis that hampers the efficacy of 5-FU chemotherapy in CRC cells by increasing EFTUD2 transcription and stabilizing c-MYC oncoprotein. This study highlights the potential of EFTUD2 as a promising therapeutic target to surmount chemotherapy resistance in CRC patients. [ABSTRACT FROM AUTHOR]

Isocitrate dehydrogenase (IDH) mutation, a known pathologic classifier, initiates metabolic reprogramming in glioma cells and has been linked to the reaction status of glioma‐associated microglia/macrophages (GAMs). However, it remains unclear how IDH genotypes contribute to GAM phenotypes. Here, it is demonstrated that gliomas expressing mutant IDH determine M1‐like polarization of GAMs, while archetypal IDH induces M2‐like polarization. Intriguingly, IDH‐mutant gliomas secrete excess cholesterol, resulting in cholesterol‐rich, pro‐inflammatory GAMs without altering their cholesterol biosynthesis, and simultaneously exhibiting low levels of tumoral cholesterol due to expression remodeling of cholesterol transport molecules, particularly upregulation of ABCA1 and downregulation of LDLR. Mechanistically, a miR‐19a/LDLR axis‐mediated novel post‐transcriptional regulation of cholesterol uptake is identified, modulated by IDH mutation, and influencing tumor cell proliferation and invasion. IDH mutation‐induced PERK activation enhances cholesterol export from glioma cells via the miR‐19a/LDLR axis and ABCA1/APOE upregulation. Further, a synthetic PERK activator, CCT020312 is introduced, which markedly stimulates cholesterol efflux from IDH wild‐type glioma cells, induces M1‐like polarization of GAMs, and consequently suppresses glioma cell invasion. The findings reveal an essential role of the PERK/miR‐19a/LDLR signaling pathway in orchestrating gliomal cholesterol transport and the subsequent phenotypes of GAMs, thereby highlighting a novel potential target pathway for glioma therapy. [ABSTRACT FROM AUTHOR]

Cancer cell survival, function and fate strongly depend on endoplasmic reticulum (ER) proteostasis. Although previous studies have implicated the ER stress signaling network in all stages of cancer development, its role in cancer metastasis remains to be elucidated. In this study, we investigated the role of Gremlin-1 (GREM1), a secreted protein, in the invasion and metastasis of colorectal cancer (CRC) cells in vitro and in vivo. Firstly, public datasets showed a positive correlation between high expression of GREM1 and a poor prognosis for CRC. Secondly, GREM1 enhanced motility and invasion of CRC cells by epithelial–mesenchymal transition (EMT). Thirdly, GREM1 upregulated expression of activating transcription factor 6 (ATF6) and downregulated that of ATF4, and modulation of the two key players of the unfolded protein response (UPR) was possibly through activation of PI3K/AKT/mTOR and antagonization of BMP2 signaling pathways, respectively. Taken together, our results demonstrate that GREM1 is an invasion-promoting factor via regulation of ATF6 and ATF4 expression in CRC cells, suggesting GREM1 may be a potential pharmacological target for colorectal cancer treatment. [ABSTRACT FROM AUTHOR]

GREMLIN1 (GREM1) is a secreted protein that antagonizes bone morphogenetic proteins (BMPs). While abnormal GREM1 expression has been reported to cause behavioral defects in postpartum mice, the spatial and cellular distribution of GREM1 in the brain and the influence of the GREM1-secreting cells on brain function and behavior remain unclear. To address this, we designed a genetic cassette incorporating a 3×Flag-TeV-HA-T2A-tdTomato sequence, resulting in the creation of a novel Grem1Tag mouse model, expressing an epitope tag (3×Flag-TeV-HA-T2A) followed by a fluorescent reporter (tdTomato) under the control of the endogenous Grem1 promoter. This design facilitated precise tracking of the cell origin and distribution of GREM1 in the brain using tdTomato and Flag (or HA) markers, respectively. We confirmed that the Grem1Tag mouse exhibited normal motor, cognitive, and social behaviors at postnatal 60 days (P60), compared with C57BL/6J controls. Through immunofluorescence staining, we comprehensively mapped the distribution of GREM1-secreting cells across the central nervous system. Pervasive GREM1 expression was observed in the cerebral cortex (Cx), medulla, pons, and cerebellum, with the highest levels in the Cx region. Notably, within the Cx, GREM1 was predominantly secreted by excitatory neurons, particularly those expressing calcium/calmodulin-dependent protein kinase II alpha (Camk2a), while inhibitory neurons (parvalbumin-positive, PV+) and glial cells (oligodendrocytes, astrocytes, and microglia) showed little or no GREM1 expression. To delineate the functional significance of GREM1-secreting cells, a selective ablation at P42 using a diphtheria toxin A (DTA) system resulted in increased anxiety-like behavior and impaired memory in mice. Altogether, our study harnessing the Grem1Tag mouse model reveals the spatial and cellular localization of GREM1 in the mouse brain, shedding light on the involvement of GREM1-secreting cells in modulating brain function and behavior. Our Grem1Tag mouse serves as a valuable tool for further exploring the precise role of GREM1 in brain development and disease. • Construction of a Grem1Tag mouse for tracking GREM1 molecules and the cell of origin. • The distribution pattern and intensity of GREM1 molecules in various brain regions using the Grem1Tag mouse. • GREM1 is secreted mainly by excitatory neurons, and to a much lesser extent by microglia. • Partial removal of GREM1-secreting-cells induced phenomenal behavioral abnormalities in Grem1-CreERT2 : DTA mouse. [ABSTRACT FROM AUTHOR]

B Tumor Microenvironment b Cholesterol is the essential structural and functional component for glioma cells to maintain their biological aggressiveness. PERK-Mediated Cholesterol Excretion from IDH Mutant Glioma Determines Anti-Tumoral Polarization of Microglia (Adv. Sci. 20/2023) In article number 2205949, Yulong He, Yonggao Mou, Ningning Li, and co-workers identify that excessive cholesterol excreted from IDH-mutant glioma cells, as a metabolic messenger, determines M1-like polarization of glioma-associated microglia/macrophage (GAMs). [Extracted from the article]