Molecular Cancer Research最新文献

{"title":"SOX4-Mediated Post-Transcriptional suppression of PTEN via miR-106b~25 Cluster Contributes to Prostate Cancer Aggressiveness.","authors":"Feifei Sun, Lin Gao, Meng Wang, Ping Liu, Baozhen Wang, Jing Hu, Weiqing Wang, Hui Liu, Bo Han","doi":"10.1158/1541-7786.MCR-25-0471","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-25-0471","url":null,"abstract":"<p><p>Molecular based risk stratification of prostate cancer (PCa) holds significant potential for guiding precision therapeutic strategies. Previous studies revealed SOX4 activation drives PCa progression in PTEN deficient tumors through the PI3K-AKT signaling pathway. However, the mechanistic interplay between SOX4 and PTEN, as well as their clinical utility for prognostic stratification, remains to be elucidated. In this study, we revealed that SOX4 expression is increased in PCa patients with low PTEN levels, and the expression of SOX4 and PTEN is inversely correlated in PCa patients. Importantly, PCa patients exhibiting SOX4-high/PTEN-low (SOX4+/PTEN-) expression represent an aggressive PCa subtype associated with unfavorable prognosis. Mechanistically, we found that SOX4 downregulates PTEN protein expression at the post-transcriptional level. Through high-throughput microRNA profiling and bioinformatics analysis, we identified that SOX4 transcriptionally activates the expression of miR-106b∼25 cluster, which directly targets PTEN. Furthermore, SOX4 overexpression combined with PTEN deficiency leads hyperactivation of the PI3K-AKT pathway. Importantly, dual targeting of SOX4 and PI3K-AKT signaling effectively suppresses PCa cell proliferation, migration and invasion in vivo and in vitro. These data establish a novel SOX4/miR-106b~25/PTEN pathway model in promoting PCa progression and propose a potential therapeutic strategy for this high-risk subtype. Implications: SOX4 suppresses PTEN through the transcriptional upregulation of miR-106b~25, rendering tumors sensitive to combined inhibition of SOX4 and PI3K-AKT in prostate cancer.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145200414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ACYP2 induces temozolomide resistance in glioblastoma by promoting PARP1-mediated DNA damage repair.","authors":"Mengjun Sui, Qing Cai, Zhiwei Sun, Jinjin Li, Yiyang Zhang, Mengdan Li, Penggao Dai, Gang Li","doi":"10.1158/1541-7786.MCR-25-0423","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-25-0423","url":null,"abstract":"<p><p>Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with poor prognosis. Temozolomide (TMZ) is the most widely used chemotherapeutic agent and can significantly improve patient survival rates. However, numerous patients develop TMZ resistance, leading to limited therapeutic benefits. Therefore, it is crucial to investigate the mechanisms of TMZ resistance in patients with GBM and identify the sensitizing targets of TMZ to improve its clinical efficacy. Here, we demonstrated that acylphosphatase 2 (ACYP2) was involved in regulating the sensitivity of GBM to TMZ. ACYP2 knockdown significantly reduced the IC50 values of TMZ in GBM cells, while overexpression of ACYP2 increased their IC50 values. The combination of ACYP2 knockdown and TMZ treatment not only inhibited the malignant behavior of GBM cells in vitro but also slowed the progression of intracranial GBM in mice. Additionally, comet tail and γ-H2AX staining assays showed that ACYP2 knockdown enhanced the TMZ-induced DNA damage. Mechanistically, ACYP2 upregulates the transcription factor c-Myc to promote the transcription of its downstream target poly ADP-ribose polymerase 1 (PARP1), an important regulatory molecule for DNA damage repair, ultimately inducing TMZ resistance in GBM cells. Thus, this study demonstrated that ACYP2 is a potential therapeutic target for TMZ-resistant GBM patients. Implications: The ACYP2-driven c-Myc/PARP1 signaling axis defines a critical pathway driving temozolomide resistance and represents a translationally actionable target for therapeutic intervention in glioblastoma.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145150173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PRC2/FOXO1-Mediated Repression Determines Interchangeability of ETS Oncogenes in Prostate Cancer and Ewing Sarcoma.","authors":"Nicholas F Downing, Kaitlyn M Mills, Peter C Hollenhorst","doi":"10.1158/1541-7786.MCR-25-0389","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-25-0389","url":null,"abstract":"<p><p>Genes encoding ETS family transcription factors are altered by chromosomal rearrangement in 60-70% of prostate cancers and nearly all Ewing sarcomas. Ewing sarcoma rearrangements result in chimeric fusion of ETS proteins to the RNA-binding protein EWSR1. Prostate cancer rearrangements result in aberrant expression of ETS proteins such as ETV1, ETV4, ETV5 or ERG that can interact with wild-type EWSR1, suggesting common mechanisms between these diseases. Here, we find that ETV1, ETV4, and ETV5 can phenocopy EWSR1::FLI1 in Ewing sarcoma cell lines. However, rescue of EWSR1::FLI1 knockdown by ERG requires an ERG mutant that disrupts interaction with PRC2. This suggests that EWSR1::ERG fusions that drive Ewing sarcoma avoid PRC2 interactions. We then identify an endogenous PRC2/FOXO1 complex and demonstrate that FOXO1 bridges the ERG/PRC2 interaction. AKT-mediated degradation of FOXO1 and subsequent loss of the ERG/PRC2 interaction provides a mechanism for ERG synergy with PTEN deletion in prostate cancer. Implications: These findings indicate that ETS transcription factors that drive prostate cancer and Ewing sarcoma utilize similar mechanisms and thus could be targeted by similar therapeutic approaches.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fucosylated N-Glycan Landscape of Triple Negative Breast Cancer.","authors":"Danielle A Scott, Souvik Seal, Laura Spruill, Jaclyn Dunne, Graham Colditz, Anand S Mehta, Richard R Drake, Marvella E Ford, Peggi M Angel","doi":"10.1158/1541-7786.MCR-25-0483","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-25-0483","url":null,"abstract":"<p><p>Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer lacking targeted therapies. While aberrant N-glycosylation is a hallmark of malignancy, the specific roles of core fucosylated (CF) and outer arm fucosylated (OAF) N-glycans in TNBC progression and patient survival remains underexplored. This study utilized multiplexed glycomics by matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI IMS) to spatially profile 348 N-glycans in 59 TNBC tumors with clinical characteristics including survival data. Spatial analysis revealed distinct localization patterns of CF and OAF isomers within tumor microenvironments. Strikingly, OAF glycans, but not CF, were strongly associated with tumor stage, with expression increasing from Stage I to III, then declining in Stage IV. Furthermore, 68 N-glycans were significantly associated with survival outcomes; 36 (52%) of these were OAF-modified, including polylactosamine structures previously linked to metastasis in breast cancer. High expression of OAF polylactosamines correlated with poor prognosis and were detectable in early-stage TNBC tumors, underscoring their potential as prognostic biomarkers. Implications: These findings demonstrate that OAF N-glycans are dynamic, structure-specific markers of TNBC progression and survival and their early detection and strong prognostic value highlight potential utility in patient stratification and personalized therapy.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Metastasis Suppressor PI3KC2β Is Mediated by mTORC1 Signaling in Breast Cancer.","authors":"Kanakaraju Manupati, Mingang Hao, Suhua Li, Sushma Maharjan, Jun-Lin Guan","doi":"10.1158/1541-7786.MCR-24-1045","DOIUrl":"10.1158/1541-7786.MCR-24-1045","url":null,"abstract":"<p><p>HER2 amplification or mutation accounts for 25% of patients with breast cancer that can advance to metastatic disease. Therefore, it is important to identify novel genes that mediate metastasis in HER2+ breast cancer. In this study, we describe a new metastatic suppressor gene, class II phosphatidylinositol 3-kinase β (Pi3kc2β), through in vivo CRISPR-Cas9 library screening of a custom-designed library targeting genes implicated in autophagy using murine HER2+ breast cancer (N418) cells. We further showed that PI3KC2β knockout N418 cells increased their migration and invasion in vitro and lung metastasis in both spontaneous and experimental metastasis assays in vivo. Analysis of databases and tissue samples from patients with breast cancer correlated lower expression of PI3KC2β with decreased metastasis, overall survival, and relapse-free survival. Further, PI3KC2β deletion induced the activation of mTORC1 signaling, independent of affecting its kinase activity. Mechanistically, we found that PI3KC2β forms a complex with intersectin 1 (ITSN1) and raptor that could be decreasing the stability of raptor, and deletion of either PI3KC2β or ITSN1 led to increased raptor levels and mTORC1 signaling. Lastly, rapamycin treatment reduced the migration and invasion of PI3KC2β knockout tumor cells in vitro and their lung metastasis in vivo, supporting an important role of the mTORC1 pathway. Together, our results identify PI3KC2β as a suppressor of HER2+ breast cancer metastasis by negatively regulating mTORC1 signaling by affecting its complex formation with ITSN1 and raptor.</p><p><strong>Implications: </strong>Our findings revealed PI3KC2β as a new metastasis suppressor for HER2+ breast cancer, which might serve as a potential diagnostic and therapeutic target for the disease.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"765-778"},"PeriodicalIF":4.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12353924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PKCδ Regulates DNA Damage and Cell Death through a SIRT6/Nrf2-dependent Antioxidant Response.","authors":"Trisiani Affandi, Angela M Ohm, Jordan T Speidel, M Cecilia Caino, Dillon P Boulton, Mary E Reyland","doi":"10.1158/1541-7786.MCR-24-0805","DOIUrl":"10.1158/1541-7786.MCR-24-0805","url":null,"abstract":"<p><p>Protein kinase C δ (PKCδ) regulates DNA repair and apoptosis, and inhibition of PKCδ provides robust radioprotection. In this study, we show that depletion of PKCδ increases mitochondrial reactive oxygen species (ROS) production and induces an endogenous antioxidant response through nuclear factor erythroid 2-related factor 2 (Nrf2), resulting in decreased basal and irradiation (IR)-induced DNA damage and cell death. Radioprotection by PKCδ depletion can be reversed with the free radical scavenger, N-acetyl-L-cysteine, indicating an essential role for the antioxidant response. Whereas mitochondrial mass and membrane potential are increased in PKCδ-depleted cells, oxidative phosphorylation and the activity of electron transport chain complex I and complex III are reduced, suggesting that electron transport chain dysfunction is the source of the increased mitochondrial ROS. The antioxidant response induced by PKCδ depletion is mediated through Sirtuin 6 (SIRT6) and Nrf2. Increased mitochondrial ROS and Nrf2 activation are reversed in PKCδ/SIRT6 double knockdown cells, indicating a central role for SIRT6 in PKCδ-regulated DNA repair and cell death. Regulation of the endogenous antioxidant state through manipulation of the PKCδ/SIRT6 signaling pathway may be a novel clinical approach for protection of healthy tissues in patients undergoing IR therapy.</p><p><strong>Implications: </strong>Regulation of the endogenous antioxidant state through manipulation of the PKCδ/SIRT6 signaling pathway may be a novel clinical approach for protection of healthy tissues in patients undergoing IR therapy.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"779-791"},"PeriodicalIF":4.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12354018/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DDR2 confers ferroptosis resistance to cancer-associated fibroblasts and attenuates PARPi sensitivity of ovarian tumor cells.","authors":"Julien Lesage, Alessandra DiMauro, Angela M Schab, Seth Stidham, Mary M Mullen, Katherine C Fuh, Gregory D Longmore","doi":"10.1158/1541-7786.MCR-25-0268","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-25-0268","url":null,"abstract":"<p><p>In ovarian cancer, resistance to conventional treatments has prompted the search for alternative targets and/or cells within the tumor microenvironment (TME) that could enhance tumor cell death. Ferroptosis, an iron-dependent, lipid peroxide-triggered form of cell death, is one such pathway. Cancer‑associated fibroblasts (CAFs) are key stromal cells in the ovarian TME that can impact therapeutic responses. Using various genetic approaches, we generated multiple DDR2‑expressing and DDR2‑deficient human ovarian tumor and mouse breast tumor CAFs. We find that DDR2 expression in CAFs protects these cells from ferroptosis by regulating the xCT-GSH-GPX4 antioxidant pathway and cellular iron metabolism. Specifically, DDR2 regulates xCT expression through non-canonical p62‑dependent NRF2 activation and the labile iron pool (LIP) by controlling ferritinophagy. CAFs secrete factors, in a DDR2-dependent manner, that provide protection to ovarian tumor cells against Olaparib‑induced cell death, a clinically relevant PARP inhibitor (PARPi). Finally, we find that high expression of DDR2 in the stromal cells of human ovarian tumors is associated with poor response to PARPi in clinical trials. These findings suggest that ferroptotic regulation by DDR2 in ovarian tumor CAFs could impact therapeutic sensitivity and resistance to PARPi. Implications: The action of the collagen receptor tyrosine kinase DDR2 in CAFs confers PARPi protection to Ovarian tumor cells, by protecting CAFs from ferroptosis.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial HSP90 Paralog TRAP1 Deletion Drives Glutamine Addiction in Tumor Cells via Destablization of the Cys/Glu Antiporter SLC7A11/xCT.","authors":"Abhinav Joshi, Li Dai, Marisa Maisiak, Sunmin Lee, Elizabeth Lopez, Takeshi Ito, Len Neckers","doi":"10.1158/1541-7786.MCR-24-0194","DOIUrl":"10.1158/1541-7786.MCR-24-0194","url":null,"abstract":"<p><p>TRAP1, the mitochondrial isoform of HSP90, has emerged as a key regulator of cancer cell metabolism, yet the mechanisms by which it rewires nutrient utilization remain poorly understood. We previously reported that TRAP1 loss increases glutamine (Gln) dependency of mitochondrial respiration following glucose (Glc) withdrawal. In this study, we investigate how TRAP1 deletion impacts Glc metabolism and the mechanisms enabling Gln retention to support mitochondrial respiration via reductive carboxylation and the oxidative TCA cycle. TRAP1 knockout (KO) in bladder and prostate cancer cells recapitulates the carbon source-specific metabolic rewiring previously observed. Stable isotope tracing reveals that although Glc oxidation remains functional, TRAP1 KO reduces overall Glc uptake and its contribution to glycolysis and the pentose phosphate pathway. This effect is consistent across multiple cell lines. Concurrently, TRAP1-deficient cells exhibit increased Gln retention and reliance, potentially due to downregulation of the cystine/glutamate antiporter SLC7A11/xCT. Supporting this, xCT overexpression reduces Gln-dependent respiration in TRAP1 KO cells. qPCR and proteasome inhibition assays suggest that xCT is regulated posttranslationally via protein stability. Notably, xCT suppression does not trigger ferroptosis, indicating a selective adaptation rather than induction of cell death. Together, our findings suggest that TRAP1 loss decreases Glc uptake while preserving its metabolic fate, promoting Gln conservation through xCT downregulation to maintain mitochondrial respiration without inducing ferroptosis.</p><p><strong>Implications: </strong>These results reveal a TRAP1-dependent mechanism of metabolic rewiring in cancer cells and identify xCT-mediated Gln conservation as a key adaptive response, underscoring TRAP1 as a potential metabolic vulnerability and therapeutic target in tumors with altered nutrient utilization.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"792-806"},"PeriodicalIF":4.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12409285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-9 Promotes Migratory Dissemination of Malignant T Cells by Activating the HIF-1α-Cofilin-1 Axis in Cutaneous T-cell Lymphoma.","authors":"Ditipriya Mukherjee, Soumitra Marathe, Diksha Attrish, Vinanti Sawant, Bhavuk Dhamija, Sushant Kumar, Siddhi Wad, Moumita Basu, Neha Sharma, Hasmukh Jain, Steven R Barthel, Rahul Purwar","doi":"10.1158/1541-7786.MCR-24-1020","DOIUrl":"10.1158/1541-7786.MCR-24-1020","url":null,"abstract":"<p><p>Cutaneous T-cell lymphoma (CTCL) is a multistage disease characterized by rapid dissemination of malignant T lymphocytes from skin lesions to visceral organs and bone marrow. The cytokine IL-9 and its receptor (IL-9R) are aberrantly overexpressed in CTCL lesions and function to enhance tumor cell survival. In this study, we uncovered a critical new role for IL-9 as a potent inducer of migration of malignant T cells. Stimulation of IL-9R-expressing T-cell lymphoma cells with IL-9 induced a pseudohypoxic cellular state by elevating downstream levels of the promigratory and oxygen-sensing transcription factor hypoxia-inducible factor (HIF)-1α. High-throughput quantitative proteomic analyses of pseudohypoxic malignant T cells identified the actin-modulating protein cofilin-1 (CFL-1) as a promigratory CTCL-intrinsic target downstream of IL-9-HIF-1α signaling. Consistently, multicolor immunofluorescence staining revealed marked coexpression of CFL-1 with HIF-1α in both IL-9-treated human lymphoma cell lines and in patient CTCL skin biopsies compared with normal controls. Genetic knockdown of IL9R or HIF1A in human T-cell lymphoma lines by RNAi significantly reduced both HIF-1α and CFL-1 coexpression and reversed IL-9-induced migration. Finally, pharmacologic antagonism of HIF-1α activity using the FDA-designated orphan drug echinomycin significantly abrogated IL-9-triggered migration of both malignant T-cell lines and patient-derived T-cell lymphoma cells from CTCL biospecimens.</p><p><strong>Implications: </strong>Our results uncover a CTCL-intrinsic IL-9-HIF-1α-CFL-1 axis as a critical promoter of malignant T-cell migration. They further identify HIF-1α and CFL-1 as promising therapeutic targets to mitigate IL-9-induced CTCL dissemination.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"807-821"},"PeriodicalIF":4.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer genomic alterations and microenvironmental features encode synergistic interactions with disease outcomes.","authors":"Masroor Bayati, Zoe P Klein, Alexander T Bahcheli, Mykhaylo Slobodyanyuk, Jeffrey To, Kevin C L Cheng, Jigyansa Mishra, Diogo Pellegrina, Kissy Guevara-Hoyer, Chris McIntosh, Mamatha Bhat, Jüri Reimand","doi":"10.1158/1541-7786.MCR-25-0475","DOIUrl":"10.1158/1541-7786.MCR-25-0475","url":null,"abstract":"<p><p>Oncogenesis, tumor progression and therapy response are shaped by somatic alterations in the cancer genome and features of the tumor immune microenvironment (TME). How interactions between these two systems influence tumor evolution and clinical outcomes remains incompletely understood. To address this challenge, we developed the multi-omics analysis framework PACIFIC that systematically integrates genetic cancer drivers and infiltration profiles of immune cells to find pairwise combinations of drivers and TME characteristics that jointly associate with clinical outcomes. By analyzing 8500 primary tumor samples of 26 cancer types, we report 34 immunogenomic interactions (IGXs) in 13 cancer types in which context-specific combinations of genomic alterations and immune cell levels were significantly correlated with patient survival. Subsets of tumor samples defined by some IGXs were characterized by tumor-intrinsic and microenvironmental metrics of immunogenicity and differential expression of immunotherapy target genes. In luminal-A breast cancer, an IGX involving MEN1 deletion combined with reduced levels of neutrophils associated with lower progression-free survival and deregulation of immune signaling pathways, as observed in two independent cancer genomics datasets. These results showcase the ability of PACIFIC to integrate complex multi-omics datasets with clinical information, enabling the identification of clinically relevant immunogenomic interactions. Such interactions provide a rich set of hypotheses for mechanistic studies and the development of biomarkers and therapeutic targets. Implications: Co-occurrence patterns of cancer drivers and TME characteristics highlight synergistic interactions with prognostic potential.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144962355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}