Molecular Cancer Research最新文献

{"title":"Targeting LAMP2A Enhances SELENBP1 Expression and Suppresses Malignant Behaviors in HNSCC.","authors":"Hongwei Cao, Dongsheng Xing, Hanbing Yu, Feifei Jiang, Li Qi, Kunrong Wang, Yan Wang, Aihui Yan","doi":"10.1158/1541-7786.MCR-25-0388","DOIUrl":"10.1158/1541-7786.MCR-25-0388","url":null,"abstract":"<p><p>Lysosome-associated membrane protein type 2A (LAMP2A) serves as the critical rate-limiting component of chaperone-mediated autophagy (CMA), governing substrate translocation into lysosomes. Accumulating studies indicate that LAMP2A downregulation leads to CMA impairment in multiple cancer malignancies. In this study, we found that LAMP2A is significantly upregulated in head and neck squamous cell carcinoma (HNSCC) compared with normal tissues. Cell functional studies performed on FaDu and CAL-27 cells showed that downregulation of LAMP2A inhibited cell proliferation and stemness and induced cell apoptosis. As CMA specifically targets proteins containing a pentapeptide motif (KFERQ-like motif) in a LAMP2A-dependent manner, we further employed an integrated proteomic-interactome approach combined with KFERQ motif analysis. This comprehensive strategy identified selenium-binding protein 1 (SELENBP1) as a novel putative CMA substrate in HNSCC. Subsequent validation confirmed that the knockdown of the CMA receptor LAMP2A significantly increased SELENBP1 protein levels both in vitro and in vivo. Coimmunoprecipitation assays confirmed that SELENBP1 interacts with the CMA chaperone protein heat shock cognate 71 kDa protein (HSPA8) in a KFERQ motif (\"EKVIQ\")-dependent manner. Overexpression of SELENBP1 attenuated HNSCC cell proliferation and viability. Most importantly, silencing of SELENBP1 partially rescued the tumor-suppressive phenotypes induced by LAMP2A knockdown, suggesting that SELENBP1 mediated the effects of LAMP2A knockdown on HNSCC. This study provides insights into the role of the LAMP2A-CMA-SELENBP1 axis in the development of novel therapies for HNSCC.</p><p><strong>Implications: </strong>This study provides a novel insight into the role of CMA during the pathogenesis of HNSCC.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"134-146"},"PeriodicalIF":4.7,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145401166","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":"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% to 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. In this study, 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 polycomb repressive complex 2 (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 ERG/PRC2 interaction. AKT-mediated degradation of FOXO1 and subsequent loss of the ERG/PRC2 interaction provide a mechanism for ERG synergy with PTEN deletion in prostate cancer.</p><p><strong>Implications: </strong>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":"48-59"},"PeriodicalIF":4.7,"publicationDate":"2026-01-02","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":"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":"10.1158/1541-7786.MCR-25-0471","url":null,"abstract":"<p><p>Molecular-based risk stratification of prostate cancer holds significant potential for guiding precision therapeutic strategies. Previous studies revealed that SOX4 activation drives prostate cancer 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 patients with prostate cancer with low PTEN levels, and the expression of SOX4 and PTEN is inversely correlated in patients with prostate cancer. Importantly, patients with prostate cancer exhibiting SOX4-high/PTEN-low (SOX4+/PTEN-) expression represent an aggressive prostate cancer subtype associated with an unfavorable prognosis. Mechanistically, we found that SOX4 downregulates PTEN protein expression at the post-transcriptional level. Through high-throughput miRNA profiling and bioinformatics analysis, we identified that SOX4 transcriptionally activates the expression of the miR-106b∼25 cluster, which directly targets PTEN. Furthermore, SOX4 overexpression combined with PTEN deficiency leads to hyperactivation of the PI3K-AKT pathway. Importantly, dual targeting of SOX4 and PI3K-AKT signaling effectively suppresses prostate cancer cell proliferation, migration, and invasion in vivo and in vitro. These data establish a novel SOX4/miR-106b∼25/PTEN pathway model in promoting prostate cancer progression and propose a potential therapeutic strategy for this high-risk subtype.</p><p><strong>Implications: </strong>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":"72-82"},"PeriodicalIF":4.7,"publicationDate":"2026-01-02","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":"Correction: Differential Control of Growth and Identity by HNF4α Isoforms in Pancreatic Ductal Adenocarcinoma.","authors":"Pengshu Fang, Emily R Wilson, Sydney N Larsen, Walter A Orellana, Margaret A Hall, Chris Stubben, Acramul Haque Kabir, Kajsa Affolter, Richard A Moffitt, Xiaoyang Zhang, Eric L Snyder","doi":"10.1158/1541-7786.MCR-25-1225","DOIUrl":"10.1158/1541-7786.MCR-25-1225","url":null,"abstract":"","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":"24 1","pages":"83"},"PeriodicalIF":4.7,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889766","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":"10.1158/1541-7786.MCR-25-0423","url":null,"abstract":"<p><p>Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a 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. In this study, 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, whereas 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 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 patients with GBM.</p><p><strong>Implications: </strong>The ACYP2-driven c-Myc/PARP1 signaling axis defines a critical pathway driving TMZ resistance and represents a translationally actionable target for therapeutic intervention in GBM.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"7-20"},"PeriodicalIF":5.8,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12757725/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of Regulator of G Protein Signaling 11 Promotes Protumorigenic Features in Pancreatic Cancer.","authors":"Tejinder Kaur, Debasis Nayak, Arnav Joshi, Junan Li, Amy Hite, Rajgopal Govindarajan","doi":"10.1158/1541-7786.MCR-25-0144","DOIUrl":"10.1158/1541-7786.MCR-25-0144","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy associated with early metastasis, drug resistance, and poor outcomes. We previously demonstrated a putative tumor-suppressive role for concentrative nucleoside transporter 1 (CNT1) in PDAC. In this study, we demonstrate the regulator of G protein signaling (RGS) 11 as a key target of CNT1, with potent tumor-suppressive properties in PDAC. Compared with normal human pancreas, RGS11 expression is diminished in human PDAC tissues which correspond with the reduced patient survival times. In addition, quasimesenchymal pancreatic tumor cell lines with accelerated growth, metastatic propensity, and innate resistance to nucleoside analogs showed relatively lower RGS11 expression than their epithelial counterparts. Interestingly, RGS11 levels reversibly modulated the epithelial-mesenchymal transition of human PDAC cell lines influencing the chemotherapeutic sensitivities of anti-PDAC drugs. Additionally, stable lentiviral-mediated RGS11 expression reduced the cellular proliferation and colony establishment, increased the apoptotic index, and decreased the migratory and invasive abilities in quasimesenchymal tumor cell lines, whereas RGS11 depletion in epithelial tumor cell lines showed opposite effects. Global transcriptomic analysis revealed RGS11 replenishment in PDAC cells to suppress CD44-directed stemness features with significant reprogramming of the PDAC oncogenic landscape. Furthermore, RGS11 reduced the primary tumor burden and metastatic occurrence in a mouse model of PDAC. Together, these findings uncover RGS11 as a key target of CNT1 that exhibits therapeutic potential for intervention of aggressive PDAC.</p><p><strong>Implications: </strong>RGS11 identified as a downstream target of a gemcitabine transporter CNT1 exerts potent antitumorigenic features in PDAC with therapeutic and prognostic values.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"34-47"},"PeriodicalIF":5.8,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12680025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145286250","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":"RAS Mutation-Specific Responses to Paralog- and State-Selective RAS Inhibitors.","authors":"Beau Baars, Ana Orive-Ramos, Matthew J Emmett, Bijaya Gaire, Mathieu Desaunay, Ziyue Kou, Guangyan Li, Christos Adamopoulos, Stuart A Aaronson, Shaomeng Wang, William R Sellers, Tiphaine Martin, Evripidis Gavathiotis, Poulikos I Poulikakos","doi":"10.1158/1541-7786.MCR-25-0319","DOIUrl":"10.1158/1541-7786.MCR-25-0319","url":null,"abstract":"<p><p>A high therapeutic index, defined as potent inhibition of oncogenic signaling in tumor cells with minimal effects on normal cells, is critical for effective cancer therapies. Recent advances have introduced diverse RAS-targeting inhibitors, including mutant-specific inhibitors such as KRAS G12C and KRAS G12D, as well as paralog- and state-selective inhibitors. Non-mutant-specific RAS inhibition can be achieved by: (i) guanine nucleotide exchange-OFF inhibitors that indirectly inactivate RAS by targeting SHP2 or SOS1, (ii) KRAS-OFF inhibitors that spare NRAS and HRAS, and (iii) active-state RAS(ON) inhibitors that directly block binding of effector RAF. However, the signaling inhibition index (SII)-the differential suppression of oncogenic signaling between RAS-mutant and normal cells-remains poorly defined for these approaches. We evaluated the SII for state- and paralog-selective RAS inhibitors across diverse RAS-mutant and RAS-wild-type models. Guanine nucleotide exchange-OFF inhibitors exhibited neutral or negative values, with reduced MAPK suppression in KRAS G12X cells compared with wild-type cells. KRAS G13D models, especially with NF1 loss, showed low sensitivity. SHP2 plus MEK inhibition resulted in low selectivity, and RAS Q61X models were resistant due to MEK inhibitor-induced NRAS reactivation and altered SHP2 conformations. KRAS-OFF inhibitors demonstrated higher selectivity, whereas active- state RAS(ON) inhibitors showed broader activity but narrow selectivity. Sensitivity to mutant-specific inhibitors largely overlapped with sensitivity to state-selective agents, suggesting that most RAS-mutant tumors will respond poorly to any currently available RAS inhibitor.</p><p><strong>Implications: </strong>Determining the SII can inform the design and clinical application of RAS-targeted therapies to improve tumor selectivity and therapeutic outcomes.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"60-71"},"PeriodicalIF":5.8,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12710464/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145302532","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: Differential Effects of Clinically Relevant N- versus C-Terminal Truncating CDKN1A Mutations on Cisplatin Sensitivity in Bladder Cancer.","authors":"Rahmat K Sikder, Moataz Ellithi, Robert N Uzzo, David J Weader, Alexander L Metz, Ali Behbahani, Erica R McKenzie, Wafik S El-Deiry, Philip H Abbosh","doi":"10.1158/1541-7786.MCR-25-1186","DOIUrl":"10.1158/1541-7786.MCR-25-1186","url":null,"abstract":"","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":"24 1","pages":"84"},"PeriodicalIF":5.8,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889827","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":"Combined MYC Activation and PTEN Loss Drives Molecular Features of Aggressive Preinvasive Lesions in Mouse Prostate.","authors":"Michael Rubenstein, Apurv Rege, Gretchen Hubbard, Danielle Cannady, Shreya Agarwal, Kevin Chen, Alex Estrada, Carolina Gomes-Alexandre, Jessica Hicks, Tracy Jones, Qizhi Zheng, Srinivasan Yegnasubramanian, Charles J Bieberich, Angelo M De Marzo","doi":"10.1158/1541-7786.MCR-24-1206","DOIUrl":"10.1158/1541-7786.MCR-24-1206","url":null,"abstract":"<p><p>Prostate cancer ranges from indolent to rapidly progressive. An elevated cell proliferation index portends poor outcomes, yet the molecular alterations essential for increased cell proliferation remain ill-defined. Gain of MYC combined with biallelic PTEN loss predicts prostate cancer mortality. Prior studies have shown that combined MYC overexpression and Pten loss, driven by the Hoxb13 locus, results in prostatic intraepithelial neoplastic (PIN) lesions that progress to metastatic disease (BMPC mice). Yet, single gene alterations in these mice result only in PIN lesions. In this study, we performed transcriptomic profiling of PIN lesions from each of the three genotypes. Whereas MYC alone resulted in increases in genes related to cell-cycle regulation/cell division, combined MYC and Pten loss led to a further and more consistent increase and a synergistic cell-cycle progression. Increased ribosome biogenesis/translation is required for cell proliferation. Whereas MYC alone increased 45S rRNA and most components of the translation machinery, these were more strongly induced in BMPC mice. Surprisingly, Pten loss alone resulted in a downregulation of translation machinery genes, which could explain the absence of biallelic PTEN loss in human PIN lesions and early carcinomas. Some MYC targets were increased only after Pten loss, indicating Pten loss increases MYC activity.</p><p><strong>Implications: </strong>Increased cell cycle and translational machinery gene induction may explain the synergy between MYC and PTEN loss for increasing prostate cancer cell proliferation and disease aggressiveness. These results provide further support for the therapeutic targeting of translation in prostate cancer.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"21-33"},"PeriodicalIF":5.8,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13482967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280905","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":"MDSCs in Breast Cancer: Metastasis, Lipid Metabolism, and Therapeutics.","authors":"Ukjin Kim, Rumela Chakrabarti","doi":"10.1158/1541-7786.MCR-24-0838","DOIUrl":"10.1158/1541-7786.MCR-24-0838","url":null,"abstract":"<p><p>Myeloid-derived suppressor cells (MDSC) are one of the major contributors to the immunosuppressive microenvironment of breast cancer. MDSCs have unique mechanisms for each breast cancer metastasis site, and lipid metabolism acts as an energy source necessary to perform the role of MDSCs. In addition, MDSCs show different characteristics depending on the breast cancer subtype. Currently, there is no clear understanding of MDSCs tailored to subtypes and metastatic sites in breast cancer. In this study, we reviewed the biology and function of MDSCs revealed in breast cancer, focusing on metastasis and lipid metabolism, and discussed treatments targeting MDSCs. Understanding MDSC properties and functions by breast cancer subtype and metastatic niche will be a prerequisite for taking the next step in subdividing patients with breast cancer and providing customized treatment.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"959-970"},"PeriodicalIF":5.8,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12742582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145286272","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}