Molecular Cancer Research最新文献

{"title":"Spatial-in-Spatial: The Utility of Combining Fluorescence-Guided Multiple Sampling with Spatial-Omics in Human Glioblastoma.","authors":"Shubhang Bhalla, Bethsabe Romero, Yusor Al-Nuaimy, Felix Toussaint, Sina Zoghi, Niels Pacheco-Barrios, Stefan T Prvulovic, Christian A Bowers, Sara G M Piccirillo","doi":"10.1158/1541-7786.MCR-25-0194","DOIUrl":"10.1158/1541-7786.MCR-25-0194","url":null,"abstract":"<p><p>Human glioblastoma (GBM) is a remarkable example of a highly aggressive and untreatable tumor. A formidable challenge in treating GBM is its extensive intratumor heterogeneity, which traditional bulk tissue analysis fails to capture. Fluorescence-guided multiple sampling, utilizing 5-aminolevulinic acid for tumor visualization, offers objective tumor tissue identification and enhanced spatial resolution. In this study, we present a perspective on a novel \"spatial-in-spatial\" approach that enables comprehensive analysis of tumor areas and their microenvironment-at macroscopic and microscopic levels-by combining fluorescence-guided multiple sampling with spatial-omics technologies. This perspective discusses how this integrated methodology has the potential to advance our understanding of GBM biology through the high-resolution, multidimensional characterization of tumor heterogeneity and identification of novel, area-specific therapeutic targets.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"839-843"},"PeriodicalIF":4.7,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144708313","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":"PAD2-Mediated Histone Citrullination Drives Tumor Progression by Enhancing Cell Proliferation and Modifying the Microenvironment in Pancreatic Cancer.","authors":"Kentaro Umemura, Yoshimitsu Akiyama, Shu Shimada, Megumi Hatano, Ayumi Kono, Koya Yasukawa, Atsushi Kamachi, Yosuke Igarashi, Shu Tsukihara, Yoshiaki Tanji, Koichiro Morimoto, Atsushi Nara, Masahiro Yamane, Keiichi Akahoshi, Hiroaki Ono, Akira Shimizu, Yuji Soejima, Minoru Tanabe, Daisuke Ban, Shinji Tanaka","doi":"10.1158/1541-7786.MCR-24-1095","DOIUrl":"10.1158/1541-7786.MCR-24-1095","url":null,"abstract":"<p><p>Histone citrullination is catalyzed by peptidyl-arginine deiminases (PAD) that play a role in gene regulation, and several specific inhibitors have been developed. However, the clinical significance, molecular mechanisms of histone citrullination and PADs, and effects of PAD inhibitors in pancreatic ductal adenocarcinoma (PDAC) remain unclear. This study aimed to investigate the role and potential molecular mechanisms of PADs in PDAC. Histone citrullination was upregulated and strongly associated with the nuclear expression of PAD2, one of the PAD family, in human PDAC tissues, correlating with aggressiveness and poor prognosis. PAD2 overexpression increased PDAC cell proliferation, whereas its knockdown had the opposite effect in vitro. PAD2 was recruited to the promoter regions of PRUNE1 and E2F1, resulting in the activation of their mRNA expression via increased histone citrullination and chromatin accessibility. PAD2 overexpression enhanced tumorigenicity and increased PRUNE1 expression and M2 tumor-associated macrophage (M2 TAM) infiltration in vivo. PAD2 inhibitor suppressed the growth and tumorigenicity of PAD2-expressing PDAC mouse models by reducing PRUNE1 expression and M2 macrophage infiltration. Pad2 knockdown and PAD inhibitor treatment showed similar effects in syngeneic mouse models. The triple-high expression of nuclear PAD2, PRUNE1, and the M2 TAM marker CD206 may serve as independent adverse prognostic factors for human PDAC. Conclusively, PAD2-mediated histone citrullination drives PDAC progression by epigenetically regulating downstream target genes and influencing the tumor microenvironment. The PAD2-PRUNE1-M2 TAM axis presents a promising therapeutic target and prognostic indicator for PDAC.</p><p><strong>Implications: </strong>Elevated PAD2 expression promotes PDAC progression by epigenetically activating PRUNE1 and enhancing M2 macrophage polarization.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"844-858"},"PeriodicalIF":4.7,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285772","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":"A Novel Bispecific Integrin α5β1/αv Antibody Reprograms the Myc-Regulated Basal Phenotype of Prostate Cancer with NK Cell-Mediated Tumor Elimination.","authors":"Raghav Joshi, Ming Zhou, Jeffrey H Lin, Fei Song, Daniel Fein, Colm Morrissey, Kun Hu, Alexander Poltorak, Paul Mathew","doi":"10.1158/1541-7786.MCR-25-0104","DOIUrl":"10.1158/1541-7786.MCR-25-0104","url":null,"abstract":"<p><p>Integrin α5β1 and αv cross-talk in chemotaxis, and clonogenic survival of prostate cancer cells is abrogated by a bispecific α5β1/αv antibody (BsAbα5β1/αv), which uniquely induces internalization and lysosomal degradation of target integrins. We hypothesized that the BsAbα5β1/αv inactivates pathologic mechanosignaling pathways that correlate with integrin expression from patient samples. Mechanistic studies indicate that the BsAbα5β1/αv uniquely reverses Yes-associated protein, β-catenin, and focal adhesion kinase nuclear localization compared with monospecific integrin α5β1 and αv antibody controls in basal-type androgen receptor-negative prostate cancer cells. Dual integrin αv and α5 knockdown alone phenocopied the BsAbα5β1/αv effect. Following BsAbα5β1/αv treatment, Assay for Transposase-Accessible Chromatin using sequencing studies indicated the chromatin accessibility to TEAD and AP-1 family members was markedly reduced. In vitro and in vivo RNA sequencing indicated downregulation of Myc/E2F, TGF-β, and epithelial-mesenchymal transition and upregulation of type I and II IFN transcriptomic pathways. The BsAbα5β1/αv induced CXCL10 and CCL5 cytokine secretion, immune-infiltration of tumors, and NK cell-mediated elimination of the basal-type prostate cancer xenografts in nude mice. αv integrin was highly expressed and principally correlated with the Myc signaling pathway in rapid autopsy tissue microarrays, consistent with correlative data from the SU2C metastatic castration-resistant prostate cancer and Deutsches Krebsforschungszentrum early-onset prostate cancer cohorts. These studies connect integrin signaling with the central biology of basal-type and castration-resistant prostate cancers and define a novel therapeutic strategy that controls critical immunosuppressive pathways.</p><p><strong>Implications: </strong>Dual integrin α5β1/αv targeting with a bispecific antibody represents a novel therapeutic strategy that reprograms the epigenetic and transcriptomic signatures of basal-type prostate cancer with induction of immunologic tumor control.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"873-888"},"PeriodicalIF":4.7,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12323549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144476115","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":"LINC01235 Is an Upstream Regulator of the NFIB Gene and the Notch Pathway in Triple-Negative Breast Cancer.","authors":"Wenbo Xu, Sonam Bhatia, Yunus Sahin, David L Spector","doi":"10.1158/1541-7786.MCR-24-1143","DOIUrl":"10.1158/1541-7786.MCR-24-1143","url":null,"abstract":"<p><p>We identified a long noncoding RNA, LINC01235, with significant enrichment in luminal progenitor (LP)-like cells in triple-negative breast cancer (TNBC) organoids and cell lines. Antisense-mediated knockdown or genetic knockout of LINC01235 in TNBC cell lines led to a decline in cell proliferation and adversely affected the ability to form organoids. A comprehensive co-expression analysis, leveraging The Cancer Genome Atlas data, revealed a distinct correlation between LINC01235 expression and the expression of NFIB, a neighboring gene encoding a transcription factor. Subsequent CRISPR knockout or antisense oligonucleotide-mediated knockdown studies demonstrated an upstream regulatory role of LINC01235 over NFIB. Moreover, our investigations demonstrated that LINC01235 regulates the Notch pathway through NFIB, and chromatin isolation by RNA purification followed by qPCR results indicated the direct binding of LINC01235 to the NFIB promoter. Our findings demonstrate that LINC01235 positively regulates NFIB transcription, which in turn modulates the Notch pathway, influencing LP-like cell proliferation in breast cancer progression. This study highlights a pivotal role of LINC01235 in TNBC and its potential as a therapeutic target.</p><p><strong>Implications: </strong>This study demonstrates the central role of LINC01235 as an upstream positive regulator of NFIB and the Notch signaling pathway to induce the production of LP-like cells in TNBC.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"859-872"},"PeriodicalIF":4.7,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12221212/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528958","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":"Myeloid-Derived Suppressor Cells: Orchestrators of Tumor Immune Evasion and Therapeutic Vulnerabilities.","authors":"Ziyu Wang, Xiaoping Du, Xiangxue Xing, Wenjing Xie, Haina Xin, Wan Liu","doi":"10.1158/1541-7786.MCR-25-0251","DOIUrl":"10.1158/1541-7786.MCR-25-0251","url":null,"abstract":"<p><p>Myeloid-derived suppressor cells (MDSCs) are characterized by abnormal phenotypes, high heterogeneity, and immunosuppressive function. MDSCs are critical components in the tumor immune microenvironment, contributing to cancer progression by inhibiting T cells, B cells, NK cells, and dendritic cells while promoting regulatory T cells, tumor-associated macrophages, and Th17 cells. Beyond immunosuppression, MDSCs facilitate tumor angiogenesis, tumor cell stemness, epithelial-mesenchymal transition, and premetastatic niche formation. Current therapeutic strategies targeting MDSCs include depletion, functional inhibition, induction of differentiation, and disruption of MDSC recruitment and activation. Various therapeutic agents-including chemotherapeutics, mAbs, small-molecule inhibitors, and natural compounds-have shown efficacy in modulating MDSC activity. Combining MDSC-targeted therapy with existing immunotherapies, such as immune checkpoint inhibitors, may further improve antitumor responses.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"829-838"},"PeriodicalIF":4.7,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775868","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":"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}