Molecular Cancer Research最新文献

{"title":"ERG Orchestrates a Dedifferentiation-Senescence-Inflammation Triad in Prostate Cancer.","authors":"Francesca Lorenzin, Giulia Fracassi, Federico Vannuccini, Mazlina Ismail, Yari Ciani, Riccardo Bevilacqua, Paola Gasperini, Francesco G Carbone, Sebastiano Cinalli, Emily Grist, Wout Devlies, Alexander Giesen, Jasper Van Goubergen, Frank Claessens, Steven Joniau, Elai Davicioni, Mattia Barbareschi, David S Rickman, Andrea Lunardi, Gerhardt Attard, Amina Zoubeidi, Francesca Demichelis","doi":"10.1158/1541-7786.MCR-25-1310","DOIUrl":"10.1158/1541-7786.MCR-25-1310","url":null,"abstract":"<p><p>ERG fusions occur in about 50% of prostate cancers and represent early somatic events that co-initiate tumorigenesis. Yet, the molecular programs unleashed by ERG at disease onset remain elusive. In this study, the inducible, temporally controlled expression of ERG enabled the accurate mapping of early ERG-driven processes associated with an apparent decrease in cell fitness across a panel of prostate cells. We observed that ERG triggers senescence and epithelial-mesenchymal transition (EMT), generating distinct cellular states in which EMT and senescence coexist in the same cell or occur independently. ERG-mediated activation of canonical and noncanonical TGFβ signaling differentially regulates EMT and senescence markers. Moreover, ERG drives context-dependent changes in cell identity and promotes an intermediate basal-luminal cell population with stem cell gene expression. Notably, p53 loss enhances ERG-driven expression of cell plasticity markers without affecting senescence. Transcriptomic investigation of ERG-expressing epithelial cells revealed activation of inflammatory signals. Conditioned medium experiments demonstrated paracrine-mediated inflammation in epithelial ERG-negative, stromal, and myeloid cells. Consistently, patient-derived expression data from five independent cohorts and 2,048 men showed activation of TNFA-NFKB and TGFβ signaling in ERG-rearranged tumors. Furthermore, deconvolution analysis indicated a higher infiltration of inflammatory macrophages in ERG-positive tumors. Altogether, we uncovered a previously unrecognized triad of ERG-driven processes-dedifferentiation, senescence, and inflammation-that may underpin its oncogenic potential and shape prostate cancer initiation and therapeutic response.</p><p><strong>Implications: </strong>Temporal control of ERG expression in prostate cells enabled accurate mapping of ERG-driven processes, identifying dedifferentiation, senescence, and inflammation as candidate contributors to ERG-dependent tumorigenesis and therapeutic response.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"821-836"},"PeriodicalIF":5.8,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148295812","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":"Immunometabolic effects of oral testosterone for castration-resistant prostate cancer in the ACROBAT trial.","authors":"Sarah Zipkowitz, Karli Redinger, Sheila Jonnatan, Varsha Vakkala, Jiayun Lu, Kathleen Schultz, Irina Rifkind, Amber Michalik, Serina King, Keith McIntyre, Victoria Sinibaldi, Mark C Markowski, Catherine H Marshall, Channing J Paller, Hao Wang, Shifeng S Mao, Samuel R Denmeade, David E Sanin, Elizabeth A Thompson, Laura A Sena","doi":"10.1158/1541-7786.MCR-26-0573","DOIUrl":"10.1158/1541-7786.MCR-26-0573","url":null,"abstract":"<p><p>High-dose testosterone is an emerging treatment option for selected patients with castration-resistant prostate cancer (CRPC), but its efficacy is limited by frequent primary and acquired resistance. Preclinical studies suggest that high-dose testosterone induces tumor metabolic reprogramming that promotes resistance, however clinical validation is lacking. In the prospective ACROBAT trial, we performed longitudinal plasma metabolomic profiling and high-dimensional immune cell phenotyping of 10 patients with CRPC treated with high-dose oral testosterone undecanoate. Testosterone exposure increased circulating metabolites within the arginine-ornithine-polyamine axis, including guanidoacetic acid, creatine, homoarginine, and N1-acetylspermidine. Notably, non-responders exhibited elevated levels of circulating polyamines, including putrescine. Although we observed no significant changes in circulating immune cell subset frequencies, integrative analyses revealed positive associations between polyamine-related metabolites and immunosuppressive myeloid populations, including monocytic myeloid-derived suppressor cells. Collectively, these data provide clinical evidence that high-dose testosterone therapy increases polyamine synthesis from arginine, which is associated with therapy resistance and abundance of immunosuppressive myeloid cells. Implications: High-dose testosterone treatment of patients with castration-resistant prostate cancer enrolled on the ACROBAT trial increased circulating polyamines, which were associated with non-response to treatment and greater abundance of circulating immunosuppressive myeloid cells.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112659","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":"Spatial transcriptomic analysis of progressing oral epithelial dysplasia reveals unique differentially expressed genes and microenvironmental changes.","authors":"Vincent Lavoie, Erison Santana Dos Santos, Will Jeong, James S Jeon, Juan Fernandez Andrade, Aiman Ali, Graziella R Molska, Najmeh Esfandiari, Hui Ling Yeo, Igor Jurisica, Deepika Chugh, Iona Leong, Justin Bubola, Grace Bradley, Marco Magalhaes","doi":"10.1158/1541-7786.MCR-26-0216","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-26-0216","url":null,"abstract":"<p><p>Oral squamous cell carcinoma (OSCC) often arises from oral epithelial dysplasia (OED); however, the gene expression changes during OED progression and its microenvironment are not fully understood. This study used spatial transcriptomics to identify differentially expressed genes and microenvironmental alterations associated with malignant transformation of OED. A retrospective analysis of paired OSCC and OED samples was conducted at the Faculty of Dentistry, University of Toronto. A total of 24 paired progressing OED (OED-P) and 23 matched non-progressing OED (OED-NP) cases were examined using spatial transcriptomics in PanCK+ (epithelium) and PanCK- (stroma) regions. The analysis included differential gene expression, pathway analysis, and spatial deconvolution. Our results identified differentially expressed genes in OED-P compared with OED-NP and even more extensive changes between OED-P and matching OSCC. Pathway analysis supported the activation of immune pathways, ubiquitination, metabolic reprogramming, and matrix-remodeling signatures during progression. Functional validation shows that TNFRSF12A (Fn14) contributes to the molecular mechanisms underlying OED progression to OSCC. The OSCC microenvironment showed increased numbers of fibroblasts, neutrophils, monocytes, and mast cells compared with OED. We report a comprehensive transcriptional analysis of matched OED cases, and our results suggest that spatial profiling of OED can help identify unique and actionable gene signatures and microenvironmental changes that occur before oral malignant transformation. Implications: Our study identifies spatially resolved molecular alterations associated with oral cancer development and highlights Fn14 as a promising biomarker and therapeutic target for intercepting malignant transformation.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075538","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":"ANAPC7 promotes triple-negative breast cancer progression through ANAPC2-dependent degradation of PCGF2 and activation of STAT3.","authors":"Xiaoran Wang, Ran Hao, Mingxin Diao, Dong Ma, Hongyu Zhang, Yingzhan Wang, Jie Hu, Yixin Qi","doi":"10.1158/1541-7786.MCR-26-0497","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-26-0497","url":null,"abstract":"<p><p>Although dysregulation of the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C) and the STAT3 activation has been linked to tumorigenesis, it is unclear how ANAPC7 (a subunit of APC/C) mediates the link between STAT3 and triple-negative breast cancer (TNBC). In this study, ANAPC7 expression in fresh TNBC and adjacent normal tissues were analyzed, and the correlation of high ANAPC7 expression with clinical pathological features and prognosis in TNBC patients was further tested. Gain- and loss-of-function, xenograft tumor model, co-immunoprecipitation assay, and ubiquitination studies were employed to elucidate the role and underlying mechanisms of ANAPC7-mediated STAT3 activity in TNBC. We showed thatANAPC7 expression was significantly elevated in TNBC tissues, and high ANAPC7 expression was correlated with clinical severity in TNBC patients. Moreover, gain- and loss-of-function experiments showed that ANAPC7 facilitates malignant progression of TNBC cells, which was also verified in a xenograft tumor model. Mechanistically, ANAPC7 promotes the ubiqui-tin-proteasome degradation of tumor suppressor PCGF2 through dependence on ANAPC2, which in turn abrogates the suppression of STAT3 activity by PCGF2, finally increased STAT3 phosphorylation, along with upregulated the expression of c-Myc, N-cadherin, Vimentin and downregulation of E-cadherin. Additionally, both restoration of PCGF2 and pharmacological inhibition of STAT3 can reverse ANAPC7-induced malignant progression of TNBC. These findings revealed how ANAPC7 coordinates ubiquitin-proteasome system to activate STAT3 signaling and exert oncogenic functions, offering new avenues to improve prognosis and treatment in TNBC. Implications: Our findings provide a rationale for further investigation of the ANAPC7-PCGF2-STAT3 axis as a potential therapeutic target in TNBC.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149017396","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":"Comparative Transcriptomic and Immune Profiling Reveals a Shared Molecular Identity Between Clear Cell Odontogenic Carcinoma and Hyalinizing Clear Cell Carcinoma.","authors":"Helen X Hou, Annie Li, Bidish K Patel, Emily E Ackerman, Tom Bisson, Samantha Flynn, Samyukta Singh, Afrah M Ahmed, Navkiran Deol, Camron Rivera, Yasusei Kudo, Chloe Bertolus, Ajiravudh Subarnbhesaj, Antonio Villanueva, Karla Rubio, Peter M Richieri, Liron Bar-Peled, David T Ting, William C Faquin, Maria J Troulis, Miguel N Rivera, A John Iafrate","doi":"10.1158/1541-7786.MCR-26-0463","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-26-0463","url":null,"abstract":"<p><p>Clear cell odontogenic carcinoma (CCOC) and hyalinizing clear cell carcinoma (HCCC), rare head-and-neck malignancies with recurrent EWSR1::CREB family fusions, show overlapping morphologic and immunophenotypic features; no standardized systemic therapy for either exists. Given tissue constraints, the molecular relationship of CCOC and HCCC to each other and to relevant head-and-neck cancers remains incompletely defined. We used spatial transcriptomic profiling, multiplex immunofluorescence (mIF), and RNA in situ hybridization (RNA-ISH) to characterize the molecular and immune landscape of CCOC, HCCC, and relevant head-and-neck and fusion-associated comparators. Key transcriptomic findings were validated by RNA-ISH (image-based signal quantification), complemented by mIF-defined immune-cell composition, antigen-presentation features, and architecture. CCOC and HCCC demonstrated highly overlapping transcriptomic profiles; clear cell sarcoma, despite shared EWSR1::CREB family fusion contexts, remained distinct. CCOC and HCCC showed enrichment of a shared epithelial-secretory program, with ductal, luminal, and regulated secretory pathway features. IGF2, among the most enriched shared transcripts, showed strong tumor-cell associated expression. Candidate targets included: TACSTD2 (TROP2), FGFR2, FOLR1, KDR, MSLN, and MUC1. mIF profiling demonstrated low B2M and HLA-I expression, sparse lymphoid infiltration, minimal PD-L1 expression, and an overall immune-cold phenotype, consistent with impaired antigen presentation. Transcriptome-wide evidence showed CCOC and HCCC share a common molecular identity, particularly distinct from myoepithelial carcinoma and squamous cell carcinoma. Implications: This study - the most comprehensive molecular comparison to date of CCOC and HCCC, set against each other and relevant differential diagnoses - establishes a shared molecular framework that may improve diagnostic classification and guide biomarker and therapeutic development for these exceptionally rare tumors.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148977595","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":"Variation at the R181 Residue of p53 Confers Loss of p53 DNA Binding Cooperativity with the Retention of Mitochondria-Associated Apoptosis.","authors":"Renyta Moses, Alexandra Indeglia, Alison S Levine, Ryan Hausler, Gregory Kelly, Sven A Miller, Isabel Anez, Melissa Heller, Rosella Delgado, Caitlin Orr, Wendy Kohlmann, Anne Naumer, Jennie Vagher, Sophie R Cahill, Luke D Maese, John Karanicolas, Judy E Garber, Maureen E Murphy, Kara N Maxwell","doi":"10.1158/1541-7786.MCR-26-0030","DOIUrl":"10.1158/1541-7786.MCR-26-0030","url":null,"abstract":"<p><p>The p53 tumor suppressor binds DNA cooperatively as a tetramer, mediated by salt-bridge interactions between p53 residues E180 and R181 from 2 different p53 monomers. Variants at the R181 residue are one of the most identified TP53 pathogenic variants by germline genetic testing. We show that families with TP53 p.R181H and p.R181C variants have an attenuated cancer risk phenotype compared with patients with hotspot dominant-negative loss-of-function TP53 variants. Despite this phenotype, we find that p53 R181H and R181C variants have significantly reduced ability to bind to p53 promoter/enhancer target sequences and transactivate p53 target genes, similar to null variants. However, p53 R181H and R181C retain wild-type (WT) p53 structure and tetramerization. In addition, R181-mutant cells undergo apoptosis through WT p53 activity at the mitochondria. These results suggest that retention of transcription-independent p53 tumor suppressor function results in a reduced penetrance cancer risk syndrome in humans.</p><p><strong>Implications: </strong>We report the first separation of function DNA-binding domain p53 mutation that results in retention of transcription-independent p53 functions despite loss of p53 transactivation activity, resulting in a reduced penetrance phenotype.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"723-736"},"PeriodicalIF":5.8,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13333167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147964239","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":"Editor's Note: PRMT6 Promotes Lung Tumor Progression via the Alternate Activation of Tumor-Associated Macrophages.","authors":"Sreedevi Avasarala, Pei-Ying Wu, Samia Q Khan, Su Yanlin, Michelle Van Scoyk, Jianqiang Bao, Alessandra Di Lorenzo, Odile David, Mark T Bedford, Vineet Gupta, Robert A Winn, Rama Kamesh Bikkavilli","doi":"10.1158/1541-7786.MCR-26-0600","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-26-0600","url":null,"abstract":"","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":"24 9","pages":"802"},"PeriodicalIF":5.8,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874213","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":"Archetype Analysis of Lung Adenocarcinoma Premalignancy Links Heterogeneity in Premalignant Lesions to Diverging Features of Invasive Disease.","authors":"Kelley E Anderson, Linh M Tran, Kostyantyn Krysan, Yohana Kefella, Lingge Yu, Gregory A Fishbein, Erika F Rodriguez, Maryam Shabihkhani, Daniel P Stefanko, Emily Green, Gang Liu, Hanqiao Liu, Sherry Zhang, Erin Kane, Mitra Mehrad, Avrum E Spira, Steven M Dubinett, Eric J Burks, Sarah A Mazzilli, Marc E Lenburg, Jennifer E Beane","doi":"10.1158/1541-7786.MCR-25-1093","DOIUrl":"10.1158/1541-7786.MCR-25-1093","url":null,"abstract":"<p><p>Lung adenocarcinoma (LUAD), the most common subtype of lung cancer, is a heterogeneous disease with highly variable histopathologic features and clinical outcomes. LUAD premalignant lesions (PML) are localized proliferations of atypical pneumocytes that spread along the alveolar walls. In this study, we characterized the molecular heterogeneity across PMLs, regardless of histologic classification, and identified four distinct groups or \"archetypes\" of PMLs using bulk RNA and DNA exome sequencing data from laser-captured microdissected PMLs, normal, and tumor tissues from LUAD resection cases. The archetypes were defined byrecurrent gene coexpression modules discovered using the LUAD PMLs we profiled and three publicly available datasets. One PML archetype, termed \"proliferation,\" was associated with increased expression of genes involved in cell proliferation, a protumor immune environment, and enrichment for EGFR driver mutations. In contrast, the \"normal-like\" archetype exhibited molecular features similar to normal tissue, an antitumor immune response, and lacked driver mutation enrichment. We projected the PML archetypes into independent gene expression datasets profiling LUAD and found that tumors closest to the proliferation archetype were enriched for multiple features of aggressive LUAD, including high tumor grade and lymph node invasion, and were significantly associated with shorterdisease-free survival. Proliferation archetype PMLs may represent a subset of lesions with increased malignant potential and may provide opportunities to improve patient stratification and identify novel targets for lung cancer interception.</p><p><strong>Implications: </strong>Molecular signatures that distinguish indolent from aggressive LUAD PMLs may help personalize lung cancer screening and interception protocols.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"737-753"},"PeriodicalIF":5.8,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13455826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840789","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":"Integrative Surface Antigen Profiling of KLK2 and STEAP1 in Advanced Prostate Cancer.","authors":"Erolcan Sayar, Helen M Richards, Roman Gulati, Radhika A Patel, Brian Hanratty, Hyun Jung Lee, Ilsa Coleman, Pallabi Mustafi, Chien-Kuang Cornelia Ding, William S Chen, David Quigley, Manu Setty, Joshua M Lang, Lawrence D True, Lori Kollath, Daniel W Lin, Jun Luo, John K Lee, Gavin Ha, Evan Y Yu, Heather H Cheng, Bruce Montgomery, Eva Corey, Colm Morrissey, Michael T Schweizer, Peter S Nelson, Ruben Raychaudhuri, Michael C Haffner","doi":"10.1158/1541-7786.MCR-26-0052","DOIUrl":"10.1158/1541-7786.MCR-26-0052","url":null,"abstract":"<p><p>Kallikrein 2 (KLK2) and six-transmembrane epithelial antigen of the prostate 1 (STEAP1) are two cell surface targets with relevance for prostate cancer therapy. The objective of this study was to characterize the expression landscape of KLK2 and STEAP1 in metastatic castration-resistant prostate cancer (mCRPC) and to define associated transcriptomic, genomic, and epigenomic features. We analyzed a total of 1,095 patient samples from three mCRPC cohorts, including in situ studies of rapid autopsy cases and patient-derived xenograft models. We found that KLK2 and STEAP1 expression is strongly enriched in androgen receptor (AR)-positive tumors and largely absent in neuroendocrine and double-negative phenotypes. Within AR+ tumors, pairwise comparisons revealed coexpression and high combined positivity rates for STEAP1, KLK2, and prostate-specific membrane antigen, suggesting that cotargeting any two of these antigens increases overall tumor coverage. Analysis of samples from a rapid autopsy cohort, which enabled assessment of intra- and intertumoral diversity, showed comparable degrees of expression heterogeneity for KLK2 and STEAP1. Antigen expression correlated positively with AR genomic alterations and serum prostate-specific antigen levels and negatively with RB1 and PTEN loss. Transcriptomic and epigenome analyses demonstrated distinct mechanisms governing antigen expression: KLK2 showed a strict AR dependence with coordinated AR/FOXA1/HOXB13 binding and enhancer activation, whereas STEAP1 was only partially AR-dependent and additionally regulated by locus-specific DNA methylation changes. Furthermore, KLK2 and STEAP1 expression states were associated with distinct transcriptional programs and immune microenvironmental features.</p><p><strong>Implications: </strong>These findings establish KLK2 and STEAP1 as key prostate adenocarcinoma-lineage antigens and provide critical insights to inform the rational design and clinical development of cell surface antigen-directed therapies in prostate cancer.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"754-769"},"PeriodicalIF":5.8,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13356882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148033533","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":"Ceramide-Induced Endoplasmic Reticulum Stress Reveals a Targetable Vulnerability in Endocrine Therapy-Resistant Breast Cancer.","authors":"Purab Pal, Shweta Chitkara, Godwin K Sarpey, Aanshi Vashi, Vipin Rawat, Fatimah Alani, Huiping Zhao, Malik Ata, Jun Qu, Rachel Schiff, Debra Tonetti, Geoffrey L Greene, Jonna Frasor, Gunes Ekin Atilla-Gokcumen, Jonathan L Coloff","doi":"10.1158/1541-7786.MCR-25-0964","DOIUrl":"10.1158/1541-7786.MCR-25-0964","url":null,"abstract":"<p><p>Despite the success of endocrine therapy (ET) in treating hormone receptor-positive breast cancer, a significant proportion of patients relapse during or after treatment, making ET resistance a major clinical challenge. Previously, we have shown that ET-resistant breast cancer cells exhibit reduced ceramide levels and an increased sensitivity to ceramide-induced cell death. In this study, we demonstrate that ceramides induce a distinct transcriptional reprogramming in ET-resistant cells, characterized by upregulation of endoplasmic reticulum stress (EnRS) pathways. Ceramide-induced EnRS is PERK-dependent and functionally linked to cell death in multiple models of ET resistance. Using a photoactivatable ceramide probe, we identify TRAM1 as a functionally important ceramide-interacting protein (CIP) in ET-resistant cells that correlates with worse relapse-free survival and a more aggressive breast cancer phenotype in patients with luminal breast cancer. Additionally, knockdown of TRAM1 phenocopies ceramide action in ET resistance, thereby suggesting its role in mediating ceramide-induced lethal actions in ET resistance. Together, our findings reveal that ET-resistant breast cancer cells are highly sensitive to PERK-mediated EnRS relative to ET-sensitive cells. Ceramides, likely via interactions with CIPs such as TRAM1, lead to PERK activation and consequential cell death in the ET-resistant breast cancer models. This sensitivity to ceramide-induced EnRS and cell death is a vulnerability that could be taken advantage of to treat ET-resistant breast cancer.</p><p><strong>Implications: </strong>This study elucidates the functional relevance of ceramide depletion in ET-resistant breast cancer cells.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"784-800"},"PeriodicalIF":5.8,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13375114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148150699","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}