Molecular Cancer Research最新文献

{"title":"A novel bispecific integrin α5β1/αv antibody reprograms the Myc-regulated basal phenotype of prostate cancer with natural killer 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":"https://doi.org/10.1158/1541-7786.MCR-25-0104","url":null,"abstract":"<p><p>Integrin α5β1 and αv crosstalk 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 pathological mechanosignaling pathways that correlate with integrin expression from patient samples. Mechanistic studies indicate that the BsAbα5β1/αv uniquely reverses YAP, beta-catenin and FAK nuclear localization compared to 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, ATAC-seq studies indicated the chromatin accessibility to TEAD and AP-1 family members was markedly reduced. In vitro and in vivo RNA-seq indicated down-regulation of Myc/E2F, TGF-beta and epithelial mesenchymal transition (EMT) and upregulation of Type I and II interferon transcriptomic pathways. The BsAbα5β1/αv induced CXCL10 and CCL5 cytokine secretion, immune-infiltration of tumors, and natural-killer 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 DKFZ early-onset prostate cancer cohorts. These studies connect integrin signaling with the central biology of basal-type and castration-resistant prostate cancer and define a novel therapeutic strategy that controls critical immunosuppressive pathways. Implications: Dual integrin α5β1/αv targeting with a bispecific antibody represents a novel therapeutic strategy that reprograms the epigenetic and transcriptomic signature of basal-type prostate cancer with induction of immunological tumor control.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/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 nuclear expression of PAD2, a 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 increasing 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 mice 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. Implications: 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":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-12","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":"The impact of cancer therapy on the cells and extracellular vesicles of the tumor immune microenvironment.","authors":"Claire Bruno, Andrew Whitcomb, Brooke Pincock, Israel Davila Aleman, Jacob H Neves, Matthew Shaw, Amber Gonda","doi":"10.1158/1541-7786.MCR-25-0101","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-25-0101","url":null,"abstract":"<p><p>Cancer remains one of the leading causes of morbidity and mortality worldwide, necessitating the development of diverse treatment options to improve patient outcomes. The tumor microenvironment (TME) plays a critical role in determining the efficacy of these different therapies, yet the reciprocal impact of treatment on the TME, particularly the tumor immune microenvironment (TIME), remains incompletely understood. This review investigates the different effects of cancer therapies - chemotherapy, targeted therapy, immunotherapy, and radiotherapy - on immune cells within the TIME and associated extracellular vesicles (EVs). The broader impact on the TME belies a complex and nuanced tumor response. These treatments have been shown to have an impact on the function of various immune cells, influencing their activity to either promote or block tumor growth. Importantly, this review also considers how these therapies play an indirect role in modulating the TIME by influencing the release and contents of EVs, highlighting the significant role that EVs play in intercellular communication within the TIME. By analyzing recent findings, this review aims to provide a comprehensive understanding of how different cancer therapies reshape the TIME. Understanding these dynamic relationships can help pave the way for optimizing existing treatments, developing new therapies, and enhancing patient outcomes.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234612","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":"SIRT2 Regulates the SMARCB1 Loss-Driven Differentiation Block in ATRT.","authors":"Irina Alimova, Dong Wang, John DeSisto, Etienne Danis, Senthilnath Lakshmanachetty, Eric Prince, Gillian Murdock, Angela Pierce, Andrew Donson, Ilango Balakrishnan, Natalie Serkova, Hening Lin, Nicholas K Foreman, Nathan Dahl, Sujatha Venkataraman, Rajeev Vibhakar","doi":"10.1158/1541-7786.MCR-24-0926","DOIUrl":"10.1158/1541-7786.MCR-24-0926","url":null,"abstract":"<p><p>An atypical teratoid rhabdoid tumor (ATRT) is a highly aggressive pediatric brain tumor driven by the loss of SMARCB1, which results in epigenetic dysregulation of the genome. SMARCB1 loss affects lineage commitment and differentiation by controlling gene expression. We hypothesized that additional epigenetic factors cooperate with SMARCB1 loss to control cell self-renewal and drive ATRT. We performed an unbiased epigenome-targeted screen to identify genes that cooperate with SMARCB1 and identified SIRT2 as a key regulator. Using in vitro pluripotency assays combined with in vivo single-cell RNA transcriptomics, we examined the impact of SIRT2 on differentiation of ATRT cells. We used a series of orthotopic murine models treated with SIRT2 inhibitors to examine the impact on survival and clinical applicability. We found that ATRT cells are highly dependent on SIRT2 for survival. Genetic or chemical inhibition led to decreased cell self-renewal and induction of differentiation in tumor spheres and in vivo models. We found that SIRT2 inhibition can restore gene expression programs lost because of SMARCB1 loss and reverse the differentiation block in ATRT in vivo. Finally, we showed the in vivo efficacy of a clinically relevant inhibitor demonstrating SIRT2 inhibition as a potential therapeutic strategy. We concluded that SIRT2 is a critical dependency in SMARCB1-deficient ATRT cells and acts by controlling the pluripotency-differentiation switch. Thus, SIRT2 inhibition is a promising therapeutic approach that warrants further investigation and clinical development.</p><p><strong>Implications: </strong>SIRT2 inhibition is a molecular vulnerability in SMARCB1-deleted tumors.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"515-529"},"PeriodicalIF":4.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12133431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441498","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":"Extrachromosomal DNA Dynamics Contribute to Intratumoral Receptor Tyrosine Kinase Genetic Heterogeneity and Drug Resistance in Gastric Cancer.","authors":"Kazuki Kanayama, Hiroshi Imai, Ryotaro Hashizume, Chise Matsuda, Eri Usugi, Yoshifumi S Hirokawa, Masatoshi Watanabe","doi":"10.1158/1541-7786.MCR-24-0741","DOIUrl":"10.1158/1541-7786.MCR-24-0741","url":null,"abstract":"<p><p>Chromosomal instability in gastric cancer cells is associated with the amplification of oncogenes that encode receptor tyrosine kinases (RTK), such as HER2 and FGFR2; such gene amplification varies from cell to cell and manifests as genetic heterogeneity within tumors. The intratumoral genetic heterogeneity of RTK gene amplification causes heterogeneity in RTK protein expression, which has been suggested to be associated with therapeutic resistance to RTK inhibitors; however, the underlying mechanism is not fully understood. In this study, we show that extrachromosomal DNA (ecDNA) causes intratumoral genetic heterogeneity in RTKs and drug resistance due to diverse dynamic changes. We analyzed the dynamics of FGFR2 and MYC ecDNA in a gastric cancer cell line after single-cell cloning. Similar to those in parental cells, the copy numbers of FGFR2 and MYC in subclones differed significantly between cells, indicating intraclonal genetic heterogeneity. Furthermore, the ecDNA composition differed between subclones, which affected FGFR2 protein expression and drug sensitivity. Interestingly, clone cells that were resistant to the FGFR2 inhibitor AZD4547 presented diverse changes in ecDNA, including chimeric ecDNA, large ecDNA, and increased ecDNA numbers; these changes were associated with high expression and rephosphorylation of FGFR2. Conversely, when resistant clone cells were cultured under conditions that excluded AZD4547, the ecDNA status became similar to that of the original clone cells, and the inhibitory effect on cell growth was restored.</p><p><strong>Implications: </strong>Our results show that dynamic quantitative and qualitative changes in ecDNA can drive the intratumoral genetic heterogeneity of RTKs and resistance to RTK inhibitors.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"503-514"},"PeriodicalIF":4.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449625","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":"Exploring STEAP1 Expression in Prostate Cancer Cells in Response to Androgen Deprivation and in Small Extracellular Vesicles.","authors":"Candice L Bizzaro, Camila A Bach, Ricardo A Santos, Cecilia E Verrillo, Nicole M Naranjo, Ishan Chaudhari, Francis J Picone, Waleed Iqbal, Ada G Blidner, Gabriel A Rabinovich, Alessandro Fatatis, Justine Jacobi, David W Goodrich, Kevin K Zarrabi, Wm Kevin Kelly, Matthew J Schiewer, Lucia R Languino","doi":"10.1158/1541-7786.MCR-24-0903","DOIUrl":"10.1158/1541-7786.MCR-24-0903","url":null,"abstract":"<p><p>The six-transmembrane epithelial antigen of the prostate (STEAP; STEAP1 and STEAP2) metalloreductases are therapeutic targets for advanced prostate cancer, and their expression has been linked to androgen receptor (AR) signaling; however, the regulatory mechanism and functions of STEAP1 and STEAP2 in prostate cancer progression remain elusive. In this study, we explore how in vitro androgen modulation and AR inhibition influence the expression of STEAP family members in cell lines with varying reliance on androgen signaling. Our data show that in response to androgen deprivation, STEAP1 and STEAP2 exhibit elevated transcript levels, whereas STEAP4 levels are reduced, mirroring the expression profile of kallikrein-related peptidase 3 (KLK3). As STEAP1 and STEAP2 are implicated in the exocytic pathway, we evaluated expression profiles in small extracellular vesicles (sEV) released from prostate cancer cells and in circulating sEVs. STEAP1, but not STEAP2, is upregulated in sEVs from AR-negative cells, which express low cellular STEAP1, and AR-positive cells, which express high cellular STEAP1. These results indicate selective packaging of STEAP1 in prostate cancer cell-derived sEVs, irrespective of AR status and cellular STEAP1 expression levels. Finally, ex vivo analysis of circulating sEVs from genetically engineered mice carrying prostate cancer shows that STEAP1 is found in the sEV cargo and that its levels are independent of protumorigenic β1 integrin expression in the prostatic epithelium.</p><p><strong>Implications: </strong>Understanding how androgen dependence affects STEAP1 expression in both tumor cells and sEVs across distinct disease stages will illuminate the clinical benefit of combinatorial AR and STEAP1-directed therapies and inform the optimal placement of STEAP1 targeting within the prostate cancer disease continuum.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"542-552"},"PeriodicalIF":4.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12133427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144064165","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":"Insulin Resistance Increases TNBC Aggressiveness and Brain Metastasis via Adipocyte-Derived Exosomes.","authors":"Yuhan Qiu, Andrew Chen, Rebecca Yu, Pablo Llevenes, Michael Seen, Naomi Y Ko, Stefano Monti, Gerald V Denis","doi":"10.1158/1541-7786.MCR-24-0494","DOIUrl":"10.1158/1541-7786.MCR-24-0494","url":null,"abstract":"<p><p>Patients with triple-negative breast cancer (TNBC) and comorbid type 2 diabetes (T2D), characterized by insulin resistance of adipose tissue, have a higher risk of metastasis and shorter survival. Adipocytes are the main nonmalignant cells of the breast tumor microenvironment (TME). However, adipocyte metabolism is usually ignored in oncology, and the mechanisms that couple T2D to TNBC outcomes are poorly understood. In this study, we hypothesized that exosomes, small vesicles secreted by TME breast adipocytes, drive epithelial-to-mesenchymal transition (EMT) and metastasis in TNBC via miRNAs. Exosomes were purified from conditioned media of 3T3-L1 mature adipocytes, either insulin-sensitive (IS) or insulin-resistant (IR). Murine 4T1 cells, a TNBC model, were treated with exosomes in vitro (72 hours). EMT, proliferation, and angiogenesis were elevated in IR versus control and IS. Brain metastases showed more mesenchymal morphology and EMT enrichment in the IR group. MiR-145a-3p is highly differentially expressed between IS and IR and potentially regulates metastasis.</p><p><strong>Implications: </strong>IR adipocyte exosomes modify the TME, enhance EMT, and promote brain metastasis-likely via miRNA pathways-suggesting that metabolic diseases such as T2D foster a prometastatic TME, reducing survival and warranting close monitoring and potential metabolic interventions in patients with TNBC and T2D.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"567-578"},"PeriodicalIF":4.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12133429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566495","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":"KSR1 Mediates Small Cell Lung Carcinoma Tumor Initiation and Cisplatin Resistance.","authors":"Deepan Chatterjee, Robert A Svoboda, Dianna H Huisman, Benjamin J Drapkin, Heidi M Vieira, Chaitra Rao, James W Askew, Kurt W Fisher, Robert E Lewis","doi":"10.1158/1541-7786.MCR-24-0652","DOIUrl":"10.1158/1541-7786.MCR-24-0652","url":null,"abstract":"<p><p>Small cell lung cancer (SCLC) has a dismal 5-year survival rate of less than 7%, with limited advances in first-line treatment over the past four decades. Tumor-initiating cells (TIC) contribute to resistance and relapse, a major impediment to SCLC treatment. In this study, we identify kinase suppressor of Ras 1 (KSR1), a molecular scaffold for the Raf/MEK/ERK signaling cascade, as a critical regulator of SCLC TIC formation and tumor initiation in vivo. We further show that KSR1 mediates cisplatin resistance in SCLC. Whereas 50% to 70% of control cells show resistance after 6-week exposure to cisplatin, CRISPR/Cas9-mediated KSR1 knockout prevents resistance in >90% of SCLC cells in ASCL1, NeuroD1, and POU2F3 subtypes. KSR1 knockout significantly enhances the ability of cisplatin to decrease SCLC TICs via in vitro extreme limiting dilution analysis, indicating that KSR1 disruption enhances the cisplatin toxicity of cells responsible for therapeutic resistance and tumor initiation. The ability of KSR1 disruption to prevent cisplatin resistance in H82 tumor xenograft formation supports this conclusion. Previous studies indicate that ERK activation inhibits SCLC tumor growth and development. We observe a minimal effect of pharmacologic ERK inhibition on cisplatin resistance and no impact on TIC formation via in vitro extreme limiting dilution analysis. However, mutational analysis of the KSR1 DEF domain, which mediates interaction with ERK, suggests that ERK interaction with KSR1 is essential for KSR1-driven cisplatin resistance. These findings reveal KSR1 as a key regulatory protein in SCLC biology and a potential therapeutic target across multiple SCLC subtypes.</p><p><strong>Implications: </strong>Genetic manipulation of the molecular scaffold KSR1 in SCLC cells reveals its contribution to cisplatin resistance and tumor initiation.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"553-566"},"PeriodicalIF":4.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12133430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382792","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":"The Bridging Role of Schwann Cells in the Interaction between Tumors and the Nervous System: A Potential Target for Cancer Therapy.","authors":"Yonghui Zhang, Ye Yuan, Ying Wang, Zhixin Ye, Ting Liu, Guangming Lv, Gang Chen","doi":"10.1158/1541-7786.MCR-25-0124","DOIUrl":"10.1158/1541-7786.MCR-25-0124","url":null,"abstract":"<p><p>Nerves are important components of the tumor microenvironment and can regulate the progression of various solid tumors. Tumor innervation (TIN) and perineural invasion (PNI) are the two main modes of interaction between tumors and the nervous system. The former simulates neurogenesis or axonogenesis during neural development, whereas the latter causes neuroinflammation during nerve injury. As the principal glial cells of the peripheral nervous system, Schwann cells (SC) are easily hijacked and utilized by cancer cells due to their high plasticity and versatility. Whether TIN or PNI occurs in a tumor, SCs are believed to be associated with these processes, which indicate that SCs may be a target for cancer neurotherapy. This review focuses on elucidating the interactions between tumors and the peripheral nervous system and the underlying mechanisms involved. Specifically, we delineated the pivotal role of SCs in TIN, PNI, cancer pain, and the immunosuppressive microenvironment. Furthermore, we compared the advantages and disadvantages of several preclinical trials that have exploited the nervous system to treat cancer and discussed the importance of SCs as a new target in cancer neuroscience research. We hope that this review will contribute to a deeper understanding of the significant involvement of SCs within the tumor-neuroimmune axis and provide novel insights for innovative antitumor therapies.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"494-502"},"PeriodicalIF":4.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811921","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":"Emerging Roles of ACTL6A as an Oncogenic Hub: Transcriptional Regulation and Beyond.","authors":"Kelvin K Tsai, Li-Hsin Cheng, Chung-Chi Hsu, Pei-Ming Yang, Chih-Pin Chuu","doi":"10.1158/1541-7786.MCR-25-0059","DOIUrl":"10.1158/1541-7786.MCR-25-0059","url":null,"abstract":"<p><p>The malignant progression of human cancer is dictated by specific regulatory hubs coordinating multiple signaling modules. Identifying key oncogenic hubs of human cancers may lay the groundwork for developing breakthrough therapeutic strategies. Actin-like 6A (ACTL6A; also known as BAF53A) was originally identified as a chromatin remodeling factor involved in the transcriptional regulation of genes, especially in stem and progenitor cells. The preponderance of evidence revealed the overexpression of ACTL6A in most cancers and its crucial role in various malignant phenotypes, including cell-cycle progression, cancer stemness, epithelial-to-mesenchymal transition, redox and glucose metabolism, and DNA replication and repair. Interestingly, emerging data suggest that the oncogenic function of ACTL6A is mediated through diverse mechanisms beyond its canonical function in transcriptional regulation, including notably the stabilization of oncoproteins and stemness factors, such as YAP, VPS72, and MYC. In this review, we describe the isoforms and the putative functional domains of ACTL6A. We summarize the expression pattern and prognostic significance of ACTL6A in human cancers and the upstream regulatory mechanisms of its expression. We summarize recent progress in understanding the diverse pro-oncogenic functions of ACTL6A and emphasize its pleiotropic mechanisms of action as a regulatory hub of cancer stemness and progression. The review highlights the importance and the potential utilities of characterizing ACTL6A, which may imply molecularly informed diagnostics and therapeutics to improve the outcome of patients with cancer.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"485-493"},"PeriodicalIF":4.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795833","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}