Cancer research最新文献

{"title":"Correction: Mathematical Model-Driven Deep Learning Enables Personalized Adaptive Therapy.","authors":"Kit Gallagher, Maximilian A R Strobl, Derek S Park, Fabian C Spoendlin, Robert A Gatenby, Philip K Maini, Alexander R A Anderson","doi":"10.1158/0008-5472.CAN-24-4438","DOIUrl":"10.1158/0008-5472.CAN-24-4438","url":null,"abstract":"","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"85 2","pages":"399"},"PeriodicalIF":12.5,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733530/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Senescent cell-derived extracellular vesicles inhibit cancer recurrence by coordinating immune surveillance","authors":"Tahereh Ziglari, Nicholas L. Calistri, Jennifer M. Finan, Daniel S. Derrick, Ernesto S. Nakayasu, Meagan C. Burnet, Jennifer E. Kyle, Matthew Hoare, Laura M. Heiser, Ferdinando Pucci","doi":"10.1158/0008-5472.can-24-0875","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0875","url":null,"abstract":"Senescence is a non-proliferative, survival state that cancer cells can enter to escape therapy. In addition to soluble factors, senescence cells secrete extracellular vesicles (EVs), which are important mediators of intercellular communication. To explore the role of senescent cell-derived EVs (senEVs) in inflammatory responses to senescence, we developed an engraftment-based senescence model in wild-type mice and genetically blocked senEV release in vivo, without significantly affecting soluble mediators. SenEVs were both necessary and sufficient to trigger immune-mediated clearance of senescent cells, thereby suppressing tumor growth. In the absence of senEVs, the recruitment of MHC-II+ antigen-presenting cells to the senescence microenvironment was markedly impaired. Blocking senEV release redirected the primary target of senescent cell signaling from antigen-presenting cells to neutrophils. Comprehensive transcriptional and proteomic analyses identified six ligands specific to senEVs, highlighting their role in promoting antigen-presenting cell–T cell adhesion and synapse formation. Antigen-presenting cells activated CCR2+CD4+ TH17 cells, which appeared to inhibit B cell activation, and CD4+ T cells were essential for preventing tumor recurrence. These findings suggest that senEVs complement the activity of secreted inflammatory mediators by recruiting and activating distinct immune cell subsets, thereby enhancing the efficient clearance of senescent cells. These conclusions may have implications not only for tumor recurrence but also for understanding senescence during de novo carcinogenesis. Consequently, this work could inform the development of early detection strategies for cancer based on the biology of cellular senescence.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"27 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142974776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ZNFX1 functions as a master regulator of epigenetically induced pathogen mimicry and inflammasome signaling in cancer","authors":"Lora Stojanovic, Rachel Abbotts, Kaushelendra Tripathi, Collin M. Coon, Saranya Rajendran, Elnaz Abbasi Farid, Galen Hostetter, Joseph W. Guarnieri, Douglas C. Wallace, Sheng Liu, Jun Wan, Gennaro Calendo, Rebecca Marker, Zahra Gohari, Mohammed M.A. Inayatullah, Vijay K. Tiwari, Tanjina Kader, Sandro Santagata, Ronny Drapkin, Stefan Kommoss, Jacobus Pfisterer, Gottfried E. Konecny, Ryan Coopergard, Jean-Pierre J. Issa, Boris J.N. Winterhoff, Michael J. Topper, George E. Sandusky, Kathy D. Miller, Stephen B. Baylin, Kenneth P. Nephew, Feyruz V. Rassool","doi":"10.1158/0008-5472.can-24-1286","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1286","url":null,"abstract":"DNA methyltransferase and poly (ADP-ribose) polymerase inhibitors (DNMTis, PARPis) induce a stimulator of interferon genes (STING)-dependent pathogen mimicry response (PMR) in ovarian and other cancers. Here, we showed that combining DNMTis and PARPis upregulates expression of the nucleic-acid sensor NFX1-type zinc finger-containing 1 protein (ZNFX1). ZNFX1 mediated induction of PMR in mitochondria, serving as a gateway for STING-dependent interferon/inflammasome signaling. Loss of ZNFX1 in ovarian cancer cells promoted proliferation and spheroid formation in vitro and tumor growth in vivo. In patient ovarian cancer databases, expression of ZNFX1 was elevated in advanced stage disease, and ZNFX1 expression alone significantly correlated with an increase in overall survival in a phase 3 trial for therapy-resistant ovarian cancer patients receiving bevacizumab in combination with chemotherapy. RNA-sequencing revealed an association between inflammasome signaling through ZNFX1 and abnormal vasculogenesis. Together, this study identified that ZNFX1 as a tumor suppressor that controls PMR signaling through mitochondria and may serve as a biomarker to facilitate personalized therapy in ovarian cancer patients.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"128 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myeloid Cells Induce Infiltration and Activation of B Cells and CD4+ T Follicular Helper Cells to Sensitize Brain Metastases to Combination Immunotherapy","authors":"Toshifumi Ninomiya, Naoya Kemmotsu, Fumiaki Mukohara, Masaki Magari, Ai Miyamoto, Youki Ueda, Takamasa Ishino, Joji Nagasaki, Tomohiro Fujiwara, Hidetaka Yamamoto, Hidetoshi Hayashi, Kota Tachibana, Joji Ishida, Yoshihiro Otani, Shota Tanaka, Shinichi Toyooka, Isamu Okamoto, Yosuke Togashi","doi":"10.1158/0008-5472.can-24-2274","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2274","url":null,"abstract":"Brain metastasis (BM) is a poor prognostic factor in cancer patients. Despite showing efficacy in many extracranial tumors, immunotherapy with anti-PD-1 monoclonal antibody (mAb) or anti-CTLA-4 mAb appears to be less effective against intracranial tumors. Promisingly, recent clinical studies have reported that combination therapy with anti-PD-1 and anti-CTLA-4 mAbs has a potent antitumor effect on BM, highlighting the need to elucidate the detailed mechanisms controlling the intracranial tumor microenvironment (TME) to develop effective immunotherapeutic strategies. Here, we analyzed the tumor-infiltrating lymphocytes in murine models of BM that responded to anti-CTLA-4 mAb to anti-PD-1 mAb. Activated CD4+ T follicular helper (TFH) cells with high CTLA-4 expression characteristically infiltrated the intracranial TME, which were activated by the combination anti-CTLA-4 and anti-PD-1 treatment. Loss of TFH cells suppressed the additive effect of CTLA-4 blockade on anti-PD-1 mAb. B cell-activating factor belonging to the TNF family (BAFF) and a proliferation-inducing ligand (APRIL) produced by abundant myeloid cells, particularly CD80hiCD206lo pro-inflammatory M1-like macrophages, in the intracranial TME, induced B cell and TFH cell infiltration and activation. Furthermore, the intracranial TME of patients with non-small cell lung cancer featured TFH and B cell infiltration as tertiary lymphoid structures. Together, these findings provide insights into the immune cell crosstalk in the intracranial TME that facilitates an additive anti-tumor effect of CTLA-4 blockade with anti-PD-1 treatment, supporting the potential of a combination immunotherapeutic strategy for BM.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"26 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142974800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MTHFD2 Enhances cMYC O-GlcNAcylation to Promote Sunitinib Resistance in Renal Cell Carcinoma","authors":"Jinwen Liu, Gaowei Huang, Hao Lin, Rui Yang, Wenhao Zhan, Cheng Luo, Yukun Wu, Lingwu Chen, Xiaopeng Mao, Junxing Chen, Bin Huang","doi":"10.1158/0008-5472.can-24-0050","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0050","url":null,"abstract":"Sunitinib is a first-line targeted therapy for patients with renal cell carcinoma (RCC), but resistance represents a significant obstacle to the treatment of advanced and metastatic RCC. Metabolic reprogramming is a characteristic of RCC, and changes in metabolic processes might contribute to resistance to sunitinib. Here, we identified MTHFD2, a mitochondrial enzyme involved in one-carbon metabolism, as a critical mediator of sunitinib resistance in RCC. MTHFD2 was elevated in sunitinib resistant RCC cells, and loss of MTHDF2 conferred sensitivity to sunitinib. In patients, MTHFD2 was highly expressed in RCC and was associated with poor outcomes. Mechanistically, MTHFD2 stimulated UDP-GlcNAc biosynthesis and promoted cMYC O-GlcNAcylation by driving the folate cycle. O-GlcNAcylation enhanced cMYC stability and promoted MTHFD2 and CCND1 transcription. Targeting MTHFD2 or cyclin D1 sensitized tumor cells to sunitinib in vitro and in vivo. Consistently, development of a peptide drug capable of efficiently degrading MTHFD2 enabled reversal of sunitinib resistance in RCC. These findings identify a noncanonical metabolic function of MTHFD2 in cell signaling and response to therapy and reveal the interplay between one-carbon metabolism and sunitinib resistance in RCC. Targeting MTHFD2 could be an effective approach to overcome sunitinib resistance.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"28 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142975080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidative Phosphorylation is a Metabolic Vulnerability of Endocrine Therapy-Tolerant Persister Cells in ER+ Breast Cancer","authors":"Steven Tau, Mary D. Chamberlin, Huijuan Yang, Jonathan D. Marotti, Patricia C. Muskus, Alyssa M. Roberts, Melissa M. Carmichael, Lauren Cressey, Christo Philip C. Dragnev, Eugene Demidenko, Riley A. Hampsch, Shannon M. Soucy, Fred W. Kolling, Kimberley S. Samkoe, James V. Alvarez, Arminja N. Kettenbach, Todd W. Miller","doi":"10.1158/0008-5472.can-24-1204","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1204","url":null,"abstract":"Despite adjuvant treatment with endocrine therapies, estrogen receptor-positive (ER+) breast cancers recur in a significant proportion of patients. Recurrences are attributable to clinically undetectable endocrine-tolerant persister cancer cells that retain tumor-forming potential. Therefore, strategies targeting such persister cells may prevent recurrent disease. Using CRISPR-Cas9 genome-wide knockout screening in ER+ breast cancer cells, we identified a survival mechanism involving metabolic reprogramming with reliance upon mitochondrial respiration in endocrine-tolerant persister cells. Quantitative proteomic profiling showed reduced levels of glycolytic proteins in persisters. Metabolic tracing of glucose revealed an energy-depleted state in persisters where oxidative phosphorylation was required to generate ATP. A phase II clinical trial was conducted to evaluate changes in mitochondrial markers in primary ER+/HER2- breast tumors induced by neoadjuvant endocrine therapy (NCT04568616). In an analysis of tumor specimens from 32 patients, tumors exhibiting residual cell proliferation after aromatase inhibitor-induced estrogen deprivation with letrozole showed increased mitochondrial content. Genetic profiling and barcode lineage tracing showed that endocrine-tolerant persistence occurred stochastically without genetic predisposition. Pharmacological inhibition of mitochondrial complex I suppressed the tumor-forming potential of persisters in mice and synergized with the anti-estrogen fulvestrant to induce regression of patient-derived xenografts. These findings indicate that mitochondrial metabolism is essential in endocrine-tolerant persister ER+ breast cancer cells and warrant the development of treatment strategies to leverage this vulnerability for treating breast cancer.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"42 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142937611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"H4K20me3-Mediated Repression of Inflammatory Genes Is a Characteristic and Targetable Vulnerability of Persister Cancer Cells.","authors":"Valentina Ramponi, Laia Richart, Marta Kovatcheva, Camille Stephan-Otto Attolini, Jordi Capellades, Alice E Lord, Oscar Yanes, Gabriella Ficz, Manuel Serrano","doi":"10.1158/0008-5472.CAN-24-0529","DOIUrl":"10.1158/0008-5472.CAN-24-0529","url":null,"abstract":"<p><p>Anticancer therapies can induce cellular senescence or drug-tolerant persistence, two types of proliferative arrest that differ in their stability. While senescence is highly stable, persister cells efficiently resume proliferation upon therapy termination, resulting in tumor relapse. Here, we used an ATP-competitive mTOR inhibitor to induce and characterize persistence in human cancer cells of various origins. Using this model and previously described models of senescence, we compared the same cancer cell lines under the two types of proliferative arrest. Persister and senescent cancer cells shared an expanded lysosomal compartment and hypersensitivity to BCL-XL inhibition. However, persister cells lacked other features of senescence, such as loss of lamin B1, senescence-associated β-galactosidase activity, upregulation of MHC-I, and an inflammatory and secretory phenotype (senescence-associated secretory phenotype or SASP). A genome-wide CRISPR/Cas9 screening for genes required for the survival of persister cells revealed that they are hypersensitive to the inhibition of one-carbon (1C) metabolism, which was validated by the pharmacologic inhibition of serine hydroxymethyltransferase, a key enzyme that feeds methyl groups from serine into 1C metabolism. Investigation into the relationship between 1C metabolism and the epigenetic regulation of transcription uncovered the presence of the repressive heterochromatic mark H4K20me3 at the promoters of SASP and IFN response genes in persister cells, whereas it was absent in senescent cells. Moreover, persister cells overexpressed the H4K20 methyltransferases KMT5B/C, and their downregulation unleashed inflammatory programs and compromised the survival of persister cells. In summary, this study identifies distinctive features and actionable vulnerabilities of persister cancer cells and provides mechanistic insight into their low inflammatory activity. Significance: Cell persistence and senescence are distinct states of proliferative arrest induced by cancer therapy, with persister cells being characterized by the silencing of inflammatory genes through the heterochromatic mark H4K20me3. See related commentary by Schmitt, p. 7.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"32-51"},"PeriodicalIF":12.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7617193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor Heterogeneity and Cooperating Cancer Hallmarks Driven by Divergent EMT Programs.","authors":"Phoebe Carter, Yibin Kang","doi":"10.1158/0008-5472.CAN-24-4309","DOIUrl":"10.1158/0008-5472.CAN-24-4309","url":null,"abstract":"<p><p>Epithelial-to-mesenchymal transition (EMT) is known to play roles in orchestrating cellular plasticity across many physiological and pathological contexts. Partial EMT, wherein cells maintain both epithelial and mesenchymal features, is gaining recognition for its functional importance in cancer in recent years. There are many factors regulating both partial and full EMT, and the precise mechanisms underlying these processes vary depending on the biological context. Furthermore, how different EMT states cooperate to create a heterogeneous tumor population and promote different pro-malignant features remains largely undefined. In a recent study published in Nature Cancer, Youssef and colleagues described how two disparate EMT programs, active in either organ fibrosis or embryonic development, are utilized within different cells within the same murine mammary tumor model. This work provides mechanistic insight into the development of intratumoral heterogeneity, providing evidence for the cooperation between the two EMT trajectories.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"12-14"},"PeriodicalIF":12.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LSD1 and CoREST2 Potentiate STAT3 Activity to Promote Enteroendocrine Cell Differentiation in Mucinous Colorectal Cancer.","authors":"Christopher A Ladaika, Ahmed H Ghobashi, William C Boulton, Samuel A Miller, Heather M O'Hagan","doi":"10.1158/0008-5472.CAN-24-0788","DOIUrl":"10.1158/0008-5472.CAN-24-0788","url":null,"abstract":"<p><p>Neuroendocrine cells have been implicated in therapeutic resistance and worse overall survival in many cancer types. Mucinous colorectal cancer (mCRC) is uniquely enriched for enteroendocrine cells (EEC), the neuroendocrine cells of the normal colon epithelium, as compared with non-mCRC. Therefore, targeting EEC differentiation may have clinical value in mCRC. In this study, single-cell multiomics uncovered epigenetic alterations that accompany EEC differentiation, identified STAT3 as a regulator of EEC specification, and discovered a rare cancer-specific cell type with enteric neuron-like characteristics. Furthermore, lysine-specific demethylase 1 (LSD1) and CoREST2 mediated STAT3 demethylation and enhanced STAT3 chromatin binding. Knockdown of CoREST2 in an orthotopic xenograft mouse model resulted in decreased primary tumor growth and lung metastases. Collectively, these results provide a rationale for developing LSD1 inhibitors that target the interaction between LSD1 and STAT3 or CoREST2, which may improve clinical outcomes for patients with mCRC. Significance: STAT3 activity mediated by LSD1 and CoREST2 induces enteroendocrine cell specification in mucinous colorectal cancer, suggesting disrupting interaction among LSD1, CoREST2, and STAT3 as a therapeutic strategy to target neuroendocrine differentiation.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"52-68"},"PeriodicalIF":12.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stimulating Soluble Guanylyl Cyclase with the Clinical Agonist Riociguat Restrains the Development and Progression of Castration-Resistant Prostate Cancer.","authors":"Ling Zhang, Clara I Troccoli, Beatriz Mateo-Victoriano, Laura Misiara Lincheta, Erin Jackson, Ping Shu, Trisha Plastini, Wensi Tao, Deukwoo Kwon, Xi Steven Chen, Janaki Sharma, Merce Jorda, Surinder Kumar, David B Lombard, James L Gulley, Marijo Bilusic, Albert C Lockhart, Annie Beuve, Priyamvada Rai","doi":"10.1158/0008-5472.CAN-24-0133","DOIUrl":"10.1158/0008-5472.CAN-24-0133","url":null,"abstract":"<p><p>Castration-resistant prostate cancer (CRPC) is incurable and fatal, making prostate cancer the second leading cancer-related cause of death for American men. CRPC results from therapeutic resistance to standard-of-care androgen deprivation (AD) treatments, through incompletely understood molecular mechanisms, and lacks durable therapeutic options. In this study, we identified enhanced soluble guanylyl cyclase (sGC) signaling as a mechanism that restrains CRPC initiation and growth. Patients with aggressive, fatal CRPC exhibited significantly lower serum levels of the sGC catalytic product cyclic GMP (cGMP) compared with the castration-sensitive stage. In emergent castration-resistant cells isolated from castration-sensitive prostate cancer populations, the obligate sGC heterodimer was repressed via methylation of its β subunit. Genetically abrogating sGC complex formation in castration-sensitive prostate cancer cells promoted evasion of AD-induced senescence and concomitant castration-resistant tumor growth. In established castration-resistant cells, the sGC complex was present but in a reversibly oxidized and inactive state. Subjecting CRPC cells to AD regenerated the functional complex, and cotreatment with riociguat, an FDA-approved sGC agonist, evoked redox stress-induced apoptosis. Riociguat decreased castration-resistant tumor growth and increased apoptotic markers, with elevated cGMP levels correlating significantly with lower tumor burden. Riociguat treatment reorganized the tumor vasculature and eliminated hypoxic tumor niches, decreasing CD44+ tumor progenitor cells and increasing the radiosensitivity of castration-resistant tumors. Thus, this study showed that enhancing sGC activity can inhibit CRPC emergence and progression through tumor cell-intrinsic and extrinsic effects. Riociguat can be repurposed to overcome CRPC, with noninvasive monitoring of cGMP levels as a marker for on-target efficacy. Significance: Soluble guanylyl cyclase signaling inhibits castration-resistant prostate cancer emergence and can be stimulated with FDA-approved riociguat to resensitize resistant tumors to androgen deprivation, providing a strategy to prevent and treat castration resistance.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"134-153"},"PeriodicalIF":12.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}