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The article presents a letter to the editor regarding the role of the p53 family inhibitor in cellular differentiation and embryogenesis.

Cell Death and Differentiation (2003) 10, 612-614. doi:10.1038/sj.cdd.4401205 [ABSTRACT FROM AUTHOR]

Abstract Background Cancer arises from normal cells through the stepwise accumulation of genetic alterations. Cancer development can be studied by direct genetic manipulation within experimental models of tumorigenesis. Thereby, confusion by the genetic heterogeneity of patients can be circumvented. Moreover, identification of the critical changes that convert a pre-malignant cell into a metastatic, therapy resistant tumor cell, however, is one necessary step to develop effective and selective anti-cancer drugs. Thus, for the current study a cell culture model for malignant transformation was used: Primary human fibroblasts of the BJ strain were sequentially transduced with retroviral vectors encoding the genes for hTERT (cell line BJ-T), simian virus 40 early region (SV40 ER, cell line BJ-TE) and H-Ras V12 (cell line BJ-TER). Results The stepwise malignant transformation of human fibroblasts was analyzed on the protein level by differential proteome analysis. We observed 39 regulated protein spots and therein identified 67 different proteins. The strongest change of spot patterns was detected due to integration of SV40 ER. Among the proteins being significantly regulated during the malignant transformation process well known proliferating cell nuclear antigen (PCNA) as well as the chaperones mitochondrial heat shock protein 75 kDa (TRAP-1) and heat shock protein HSP90 were identified. Moreover, we find out, that TRAP-1 is already up-regulated by means of SV40 ER expression instead of H-Ras V12. Furthermore Peroxiredoxin-6 (PRDX6), Annexin A2 (p36), Plasminogen activator inhibitor 2 (PAI-2) and Keratin type II cytoskeletal 7 (CK-7) were identified to be regulated. For some protein candidates we confirmed our 2D-PAGE results by Western Blot. Conclusion These findings give further hints for intriguing interactions between the p16-RB pathway, the mitochondrial chaperone network and the cytoskeleton. In summary, using a cell culture model for malignant transformation analyzed with 2D-PAGE, proteome and cellular changes can be related to defined steps of tumorigenesis.

Therapy-induced molecular adaptation of triple-negative breast cancer is crucial for immunotherapy response and resistance. We analyze tumor biopsies from three different time points in the randomized neoadjuvant GeparNuevo trial (NCT02685059), evaluating the combination of durvalumab with chemotherapy, for longitudinal alterations of gene expression. Durvalumab induces an activation of immune and stromal gene expression as well as a reduction of proliferation-related gene expression. Immune genes are positive prognostic factors irrespective of treatment, while proliferation genes are positive prognostic factors only in the durvalumab arm. We identify stromal-related gene expression as a contributor to immunotherapy resistance and poor therapy response. The results provide evidence from clinical trial cohorts suggesting a role for stromal reorganization in therapy resistance to immunotherapy and in the generation of an immune-suppressive microenvironment, which might be relevant for future therapy approaches targeting the tumor stroma parallel to immunotherapy, such as combinations of immunotherapy with anti-angiogenic therapy., Competing Interests: Declaration of interests C.D. reports grants from European Commission H2020, grants from German Cancer Aid Translational Oncology, grants from German Breast Group, and grants from BMBF to the institution during the conduct of the study; personal fees from Novartis, personal fees from Roche, personal fees from MSD Oncology, personal fees from Daiichi Sankyo, personal fees from AstraZeneca and Molecular Health, grants from Myriad, personal fees from Merck, and other funding from Sividon Diagnostics outside the submitted work; in addition, C.D. has a patent VMScope digital pathology software with royalties paid, a patent WO2020109570A1—cancer immunotherapy pending, and a patent WO2015114146A1 and WO2010076322A1—therapy response issued. J.R. declares to be a GBG Forschungs GmbH employee. GBG Forschungs GmbH received funding for research grants from AbbVie, Amgen, AstraZeneca, BMS, Daiichi Sankyo, Gilead, Molecular Health, Novartis, Pfizer, and Roche (paid to the institution). Funding was also received (non-financial/medical writing) from Daiichi Sankyo, Gilead, Novartis, Pfizer, Roche, and Seagen (paid to the institution). GBG Forschungs GmbH has royalties in VM Scope and patents pending: EP14153692.0, EP21152186.9, and EP15702464.7. T.K. reports a patent WO2020109570A1 pending. S.R. declares to be a GBG Forschungs GmbH employee. GBG Forschungs GmbH received funding for research grants from AbbVie, Amgen, AstraZeneca, BMS, Daiichi Sankyo, Gilead, Molecular Health, Novartis, Pfizer, and Roche (paid to the institution). J.H. reports research funding from Lilly; honoraria from Lilly, Novartis, Roche, Pfizer, AstraZeneca, Seagen, Gilead, and Daiichi; consulting and advisory relationships with Lilly, Novartis, Roche, Pfizer, AstraZeneca, Gilead, and Daiichi; travel expenses from Roche, Novartis, Daiichi, and Gilead. P.J. reports research funding and travel expenses from Gilead Sciences GmbH. C.H. reports an advisory role and speakers bureau role for AstraZeneca, Roche, Novartis, and Aristo Pharma. B.V.S. is an employee of BioNTech SE and reports a patent WO2020109570A1 pending. J.-U.B. reports consultation fees, honoraria, and reimbursement for attending symposia from AstraZeneca, Amgen, Daiichi Sankyo, Eisai, Gilead, Lilly, MSD, Novartis, Pfizer, Roche, and Seagen. M.v.M. reports personal fees, honoraria, or travel grants from Amgen, AstraZeneca, Daiichi Sankyo, Genomic Health, GSK, Lilly, Molecular Health, MSD, Mylan, Novartis, Pfizer, Pierre Fabre, Roche, and Seagen. C. Schem reports speaker activities for Roche, Pfizer, Novartis, Celgen, Novartis, Exact Sciences, MSD, AstraZeneca, Lilly, and Seagen, as well as advisory boards for Roche, Astra Zeneca, Pfizer, Novartis, MSD, Amgen, Exact Sciences, Stemline, Lilly, and Novartis. T.L. reports personal fees from Amgen, Roche, Teva, Clovis, Tesaro, MSD, Novartis, Pfizer, Lilly, GSK, Gilead, AstraZeneca, Daiichi Sankyo, Stemline, and Seagen outside of the submitted work. T.L. participates in advisory boards from Amgen, MSD, Tesaro, Roche, Pfizer, Lilly, Myriad, Esai, GSK, Gilead, Daiichi Sankyo, Roche, and AstraZeneca outside of the submitted work and T.L. received travel support from Pfizer, PharmaMar, MSD, Celgene, Roche, AstraZeneca, Gilead, Daiichi Sankyo, Stemline, and Clovis outside of the submitted work. P.S. reports grants, personal fees, and non-financial support from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb Company, MSD, Incyte, Janssen-Cilag, Novartis, Takeda, Pfizer, and Roche. V.M. received speaker honoraria from AstraZeneca, Daiichi Sankyo, Eisai, GSK, Pfizer, MSD, Medac, Novartis, Roche, Seagen, Onkowissen, high5 Oncology, Medscape, Gilead, and Pierre Fabre; consultancy honoraria from Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi Sankyo, Eisai, Lilly, Sanofi, Seagen, Gilead, and Stemline; institutional research support from Novartis, Roche, Seagen, and Genentech; and travel grants from Roche, Pfizer, Daiichi Sankyo, and Gilead. L.P. has received consulting fees and honoraria for advisory board participation from Pfizer, AstraZeneca, Merck, Novartis, Bristol Myers Squibb, GlaxoSmithKline, Genentech/Roche, Personalis, Daiichi, Natera, and Exact Sciences and institutional research funding from Seagen, GlaxoSmithKline, AstraZeneca, Merck, Pfizer, and Bristol Myers Squibb. C.E.G. reports the following competing interests: Exact Sciences, Advisory Board, personal; AbbVie, Steering Committee member, institutional, co-chair of SC for BrighTNess; Daiichi Sankyo, member SC, institutional, co-chair of SC for DESTINY-Breast05; Genentech/Roche, SC member, institutional, co-chair of SC for lidERA; Genentech/Roche, coordinating PI, institutional, NSABP B-59/GeparDouze; and Genentech/Roche, SC member, institutional, co-chair of SC for KATHERINE. C.J. reports honoraria from AstraZeneca, Amgen, Daiichi Sankyo, Lilly, Roche, Pfizer, MSD Oncology, Pierre Fabre, Sanofi-Aventis, Seagen, Gilead, and Novartis and has a consulting or advisory role for Amgen, Lilly, Roche, Pfizer, Pierre Fabre, Novartis, MSD Oncology, Agendia, Seagen, Gilead, Lilly, Stemline, and Medac. V.N. declares to be a GBG Forschungs GmbH employee. GBG Forschungs GmbH received funding for research grants from AbbVie, AstraZeneca, BMS, Daiichi Sankyo, Gilead, Novartis, Pfizer, and Roche (paid to the institution). GBG Forschungs GmbH received other funding from Daiichi Sankyo, Gilead, Novartis, Pfizer, Roche, and Seagen (paid to the institution). GBG Forschungs GmbH has the following royalties/patents: EP14153692.0, EP21152186.9, EP15702464.7, EP19808852.8, and VM Scope GmbH. M.U. reports honoraria from AstraZeneca, Amgen, Daiichi Sankyo, Lilly, Roche, Pfizer, MSD Oncology, Pierre Fabre, Sanofi-Aventis, Myriad, Seagen, Gilead, and Novartis; has a consulting or advisory role for Amgen, Lilly, Roche, Pfizer, Pierre Fabre, Novartis, MSD Oncology, Agendia, Seagen, Gilead, Lily, Stemline, Genzyme, and Medac; and all honoraria and fees are paid to the employer/institution. S.L. reports grants and other funding from AbbVie; other funding from Amgen; grants and other funding from AstraZeneca; other funding from BMS; grants and other funding from Celgene; grants, non-financial support, and other funding from Daiichi Sankyo; other funding from EirGenix; other funding from Eisai Europe Ltd; other funding from GSK; grants, non-financial support, and other funding from Immunomedics/Gilead; other funding from Lilly; other funding from Merck; grants from Molecular Health; grants, non-financial support, and other funding from Novartis; grants, non-financial support, and other funding from Pfizer; other funding from Pierre Fabre; other funding from Relay Therapeutics; grants, non-financial support, and other funding from Roche; other funding from Sanofi; non-financial support and other funding from Seagen; and other funding from Olema Pharmaceuticals, outside the submitted work. In addition, S.L. has a patent EP14153692.0 pending, a patent EP21152186.9 pending, a patent EP15702464.7 issued, a patent EP19808852.8 pending, and a patent Digital Ki67 Evaluator with royalties paid., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: High levels of the polyunsaturated fatty acid arachidonic acid (AA) within the ovarian carcinoma (OC) microenvironment correlate with reduced relapse-free survival. Furthermore, OC progression is tied to compromised immunosurveillance, partially attributed to the impairment of natural killer (NK) cells. However, potential connections between AA and NK cell dysfunction in OC have not been studied., Methods: We employed a combination of phosphoproteomics, transcriptional profiling and biological assays to investigate AA's impact on NK cell functions., Results: AA (i) disrupts interleukin-2/15-mediated expression of pro-inflammatory genes by inhibiting STAT1-dependent signaling, (ii) hampers signaling by cytotoxicity receptors through disruption of their surface expression, (iii) diminishes phosphorylation of NKG2D-induced protein kinases, including ERK1/2, LYN, MSK1/2 and STAT1, and (iv) alters reactive oxygen species production by transcriptionally upregulating detoxification. These modifications lead to a cessation of NK cell proliferation and a reduction in cytotoxicity., Conclusion: Our findings highlight significant AA-induced alterations in the signaling network that regulates NK cell activity. As low expression of several NK cell receptors correlates with shorter OC patient survival, these findings suggest a functional linkage between AA, NK cell dysfunction and OC progression., Competing Interests: Declarations Ethics approval and consent to participate Blood cells from healthy individuals were used with the informed consent of the donors and approved by the local ethics committee (205/10). Consent for publication All participants consented to submit the manuscript to the journal. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The transcription factor p53 plays a key role in the cellular defense against cancer development. It is inactivated in virtually every tumor, and in every second tumor this inactivation is due to a mutation in the TP53 gene. In this perspective, we show that this diverse mutational spectrum is unique among all other cancer-associated proteins and discuss what drives the selection of TP53 mutations in cancer. We highlight that several factors conspire to make the p53 protein particularly vulnerable to inactivation by the mutations that constantly plague our genome. It appears that the TP53 gene has emerged as a victim of its own evolutionary past that shaped its structure and function towards a pluripotent tumor suppressor, but came with an increased structural fragility of its DNA-binding domain. TP53 loss of function - with associated dominant-negative effects - is the main mechanism that will impair TP53 tumor suppressive function, regardless of whether a neomorphic phenotype is associated with some of these variants., (© 2024. The Author(s).)

The large group of negative-strand RNA viruses (NSVs) comprises many important pathogens. To identify conserved patterns in host responses, we systematically compared changes in the cellular RNA levels after infection of human hepatoma cells with nine different NSVs of different virulence degrees. RNA sequencing experiments indicated that the amount of viral RNA in host cells correlates with the number of differentially expressed host cell transcripts. Time-resolved differential gene expression analysis revealed a common set of 178 RNAs that are regulated by all NSVs analyzed. A newly developed open access web application allows downloads and visualizations of all gene expression comparisons for individual viruses over time or between several viruses. Most of the genes included in the core set of commonly differentially expressed genes (DEGs) encode proteins that serve as membrane receptors, signaling proteins and regulators of transcription. They mainly function in signal transduction and control immunity, metabolism, and cell survival. One hundred sixty-five of the DEGs encode host proteins from which 47 have already been linked to the regulation of viral infections in previous studies and 89 proteins form a complex interaction network that may function as a core hub to control NSV infections.IMPORTANCEThe infection of cells with negative-strand RNA viruses leads to the differential expression of many host cell RNAs. The differential spectrum of virus-regulated RNAs reflects a large variety of events including anti-viral responses, cell remodeling, and cell damage. Here, these virus-specific differences and similarities in the regulated RNAs were measured in a highly standardized model. A newly developed app allows interested scientists a wide range of comparisons and visualizations., Competing Interests: The authors declare no conflict of interest.

It has remained yet unclear which soluble factors regulate the anti-inflammatory macrophage phenotype observed in both homeostasis and tumourigenesis. We show here that haptoglobin, a major serum protein with elusive immunoregulatory properties, binds and buffers bacterial lipopolysaccharides to attenuate activation of NFκB in macrophages. Haptoglobin binds different lipopolysaccharides with low micromolar affinities. Given its abundance, haptoglobin constitutes a buffer for serum-borne lipopolysaccharides, shielding them to safeguard against aberrant inflammatory reactions by reducing the amount of free lipopolysaccharides available for binding to TLR4. Concordantly, NFκB activation by haptoglobin-associated lipopolysaccharides was markedly delayed relative to stimulation with pure lipopolysaccharide. Our findings warrant evaluation of therapeutic benefits of haptoglobin for inflammatory conditions and re-evaluation of purification strategies. Finally, they allow to elucidate mechanisms of enhanced immunosuppression by oncofetal haptoglobin., 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 © 2024 Zein, Grossmann, Swoboda, Borgel, Wilke, Awe, Nist, Stiewe, Stehling, Freibert, Adhikary and Chung.)

Objective: Highly malignant pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant immunosuppressive and fibrotic tumour microenvironment (TME). Future therapeutic attempts will therefore demand the targeting of tumours and stromal compartments in order to be effective. Here we investigate whether dual specificity and tyrosine phosphorylation-regulated kinase 1B (DYRK1B) fulfil these criteria and represent a promising anticancer target in PDAC., Design: We used transplantation and autochthonous mouse models of PDAC with either genetic Dyrk1b loss or pharmacological DYRK1B inhibition, respectively. Mechanistic interactions between tumour cells and macrophages were studied in direct or indirect co-culture experiments. Histological analyses used tissue microarrays from patients with PDAC. Additional methodological approaches included bulk mRNA sequencing (transcriptomics) and proteomics (secretomics)., Results: We found that DYRK1B is mainly expressed by pancreatic epithelial cancer cells and modulates the influx and activity of TME-associated macrophages through effects on the cancer cells themselves as well as through the tumour secretome. Mechanistically, genetic ablation or pharmacological inhibition of DYRK1B strongly attracts tumoricidal macrophages and, in addition, downregulates the phagocytosis checkpoint and 'don't eat me' signal CD24 on cancer cells, resulting in enhanced tumour cell phagocytosis. Consequently, tumour cells lacking DYRK1B hardly expand in transplantation experiments, despite their rapid growth in culture. Furthermore, combining a small-molecule DYRK1B-directed therapy with mammalian target of rapamycin inhibition and conventional chemotherapy stalls the growth of established tumours and results in a significant extension of life span in a highly aggressive autochthonous model of PDAC., Conclusion: In light of DYRK inhibitors currently entering clinical phase testing, our data thus provide a novel and clinically translatable approach targeting both the cancer cell compartment and its microenvironment., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Pancreatic ductal adenocarcinoma (PDAC) poses a significant threat due to its tendency to evade early detection, frequent metastasis, and the subsequent challenges in devising effective treatments. Processes that govern epithelial-mesenchymal transition (EMT) in PDAC hold promise for advancing novel therapeutic strategies. SAMD1 (SAM domain-containing protein 1) is a CpG island-binding protein that plays a pivotal role in the repression of its target genes. Here, we revealed that SAMD1 acts as a repressor of genes associated with EMT. Upon deletion of SAMD1 in PDAC cells, we observed significantly increased migration rates. SAMD1 exerts its effects by binding to specific genomic targets, including CDH2, encoding N-cadherin, which emerged as a driver of enhanced migration upon SAMD1 knockout. Furthermore, we discovered the FBXO11-containing E3 ubiquitin ligase complex as an interactor and negative regulator of SAMD1, which inhibits SAMD1 chromatin-binding genome-wide. High FBXO11 expression in PDAC is associated with poor prognosis and increased expression of EMT-related genes, underlining an antagonistic relationship between SAMD1 and FBXO11. In summary, our findings provide insights into the regulation of EMT-related genes in PDAC, shedding light on the intricate role of SAMD1 and its interplay with FBXO11 in this cancer type., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Simon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Advances in cancer therapeutics have improved patient survival rates. However, cancer survivors may suffer from adverse events either at the time of therapy or later in life. Cardiovascular diseases (CVD) represent a clinically important, but mechanistically understudied complication, which interfere with the continuation of best-possible care, induce life-threatening risks, and/or lead to long-term morbidity. These concerns are exacerbated by the fact that targeted therapies and immunotherapies are frequently combined with radiotherapy, which induces durable inflammatory and immunogenic responses, thereby providing a fertile ground for the development of CVDs. Stressed and dying irradiated cells produce 'danger' signals including, but not limited to, major histocompatibility complexes, cell-adhesion molecules, proinflammatory cytokines, and damage-associated molecular patterns. These factors activate intercellular signaling pathways which have potentially detrimental effects on the heart tissue homeostasis. Herein, we present the clinical crosstalk between cancer and heart diseases, describe how it is potentiated by cancer therapies, and highlight the multifactorial nature of the underlying mechanisms. We particularly focus on radiotherapy, as a case known to often induce cardiovascular complications even decades after treatment. We provide evidence that the secretome of irradiated tumors entails factors that exert systemic, remote effects on the cardiac tissue, potentially predisposing it to CVDs. We suggest how diverse disciplines can utilize pertinent state-of-the-art methods in feasible experimental workflows, to shed light on the molecular mechanisms of radiotherapy-related cardiotoxicity at the organismal level and untangle the desirable immunogenic properties of cancer therapies from their detrimental effects on heart tissue. Results of such highly collaborative efforts hold promise to be translated to next-generation regimens that maximize tumor control, minimize cardiovascular complications, and support quality of life in cancer survivors., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Recent studies reveal a critical role of tumor cell-released extracellular vesicles (EVs) in pancreatic cancer (PC) progression. However, driver genes that direct EV function, the EV-recipient cells, and their cellular response to EV uptake remain to be identified. Therefore, we studied the role of Bcl-2-associated-anthanogene 6 (BAG6), a regulator of EV biogenesis for cancer progression. We used a Cre recombinase/LoxP-based reporter system in combination with single-cell RNA sequencing to monitor in vivo EV uptake and tumor microenvironment (TME) changes in mouse models for pancreatic ductal adenocarcinoma (PDAC) in a Bag6 pro- or deficient background. In vivo data were validated using mouse and human organoids and patient samples. Our data demonstrated that Bag6-deficient subcutaneous and orthotopic PDAC tumors accelerated tumor growth dependent on EV release. Mechanistically, this was attributed to mast cell (MC) activation via EV-associated IL33. Activated MCs promoted tumor cell proliferation and altered the composition of the TME affecting fibroblast polarization and immune cell infiltration. Tumor cell proliferation and fibroblast polarization were mediated via the MC secretome containing high levels of PDGF and CD73. Patients with high BAG6 gene expression and high protein plasma level have a longer overall survival indicating clinical relevance. The current study revealed a so far unknown tumor-suppressing activity of BAG6 in PDAC. Bag6-deficiency allowed the release of EV-associated IL33 which modulate the TME via MC activation promoting aggressive tumor growth. MC depletion using imatinib diminished tumor growth providing a scientific rationale to consider imatinib for patients stratified with low BAG6 expression and high MC infiltration. EVs derived from BAG6-deficient pancreatic cancer cells induce MC activation via IL33/Il1rl1. The secretome of activated MCs induces tumor proliferation and changes in the TME, particularly shifting fibroblasts into an inflammatory cancer-associated fibroblast (iCAF) phenotype. Blocking EVs or depleting MCs restricts tumor growth., (© 2024. The Author(s).)

Background: Predictive biomarkers in use for immunotherapy in advanced non-small cell lung cancer are of limited sensitivity and specificity. We analysed the potential of activating KRAS and pathogenic TP53 mutations to provide additional predictive information., Methods: The study cohort included 713 consecutive immunotherapy patients with advanced lung adenocarcinomas, negative for actionable genetic alterations. Additionally, two previously published immunotherapy and two surgical patient cohorts were analyzed. Therapy benefit was stratified by KRAS and TP53 mutations. Molecular characteristics underlying KRASmut/TP53mut tumours were revealed by the analysis of TCGA data., Results: An interaction between KRAS and TP53 mutations was observed in univariate and multivariate analyses of overall survival (Hazard ratio [HR] = 0.56, p = 0.0044 and HR = 0.53, p = 0.0021) resulting in a stronger benefit for KRASmut/TP53mut tumours (HR = 0.71, CI 0.55-0.92). This observation was confirmed in immunotherapy cohorts but not observed in surgical cohorts. Tumour mutational burden, proliferation, and PD-L1 mRNA were significantly higher in TP53-mutated tumours, regardless of KRAS status. Genome-wide expression analysis revealed 64 genes, including CX3CL1 (fractalkine), as specific transcriptomic characteristic of KRASmut/TP53mut tumours., Conclusions: KRAS/TP53 co-mutation predicts ICI benefit in univariate and multivariate survival analyses and is associated with unique molecular tumour features. Mutation testing of the two genes can be easily implemented using small NGS panels., (© 2024. The Author(s).)

Acute myeloid leukemia (AML) is a hematological malignancy characterized by abnormal proliferation and accumulation of immature myeloid cells in the bone marrow. Inflammation plays a crucial role in AML progression, but excessive activation of cell-intrinsic inflammatory pathways can also trigger cell death. IRF2BP2 is a chromatin regulator implicated in AML pathogenesis, although its precise role in this disease is not fully understood. In this study, we demonstrate that IRF2BP2 interacts with the AP-1 heterodimer ATF7/JDP2, which is involved in activating inflammatory pathways in AML cells. We show that IRF2BP2 is recruited by the ATF7/JDP2 dimer to chromatin and counteracts its gene-activating function. Loss of IRF2BP2 leads to overactivation of inflammatory pathways, resulting in strongly reduced proliferation. Our research indicates that a precise equilibrium between activating and repressive transcriptional mechanisms creates a pro-oncogenic inflammatory environment in AML cells. The ATF7/JDP2-IRF2BP2 regulatory axis is likely a key regulator of this process and may, therefore, represent a promising therapeutic vulnerability for AML. Thus, our study provides new insights into the molecular mechanisms underlying AML pathogenesis and identifies a potential therapeutic target for AML treatment., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Radiotherapy is essential in the treatment of prostate cancer. An alternative to conventional photon radiotherapy is the application of carbon ions, which provide a superior intratumoral dose distribution and less induced damage to adjacent healthy tissue. A common characteristic of prostate cancer cells is their dependence on androgens which is exploited therapeutically by androgen deprivation therapy in the advanced prostate cancer stage. Here, we aimed to analyze the transcriptomic response of prostate cancer cells to irradiation by photons in comparison to carbon ions, focusing on DNA damage, DNA repair and androgen receptor signaling., Methods: Prostate cancer cell lines LNCaP (functional TP53 and androgen receptor signaling) and DU145 (dysfunctional TP53 and androgen receptor signaling) were irradiated by photons or carbon ions and the subsequent DNA damage was assessed by immuno-cytofluorescence. Furthermore, the cells were treated with an androgen-receptor agonist. The effects of irradiation and androgen treatment on the gene regulation and the transcriptome were investigated by RT-qPCR and RNA sequencing, followed by bioinformatic analysis., Results: Following photon or carbon ion irradiation, both LNCaP and DU145 cells showed a dose-dependent amount of visible DNA damage that decreased over time, indicating occurring DNA repair. In terms of gene regulation, mRNAs involved in the TP53-dependent DNA damage response were significantly upregulated by photons and carbon ions in LNCaP but not in DU145 cells, which generally showed low levels of gene regulation after irradiation. Both LNCaP and DU145 cells responded to photons and carbon ions by downregulation of genes involved in DNA repair and cell cycle, partially resembling the transcriptome response to the applied androgen receptor agonist. Neither photons nor carbon ions significantly affected canonical androgen receptor-dependent gene regulation. Furthermore, certain genes that were specifically regulated by either photon or carbon ion irradiation were identified., Conclusion: Photon and carbon ion irradiation showed a significant congruence in terms of induced signaling pathways and transcriptomic responses. These responses were strongly impacted by the TP53 status. Nevertheless, irradiation mode-dependent distinct gene regulations with undefined implication for radiotherapy outcome were revealed. Androgen receptor signaling and irradiations shared regulation of certain genes with respect to DNA-repair and cell-cycle., (© 2024. The Author(s).)