Cancer research最新文献

{"title":"PHGDH Induction by MAPK Is Essential for Melanoma Formation and Creates an Actionable Metabolic Vulnerability.","authors":"Neel Jasani, Xiaonan Xu, Benjamin Posorske, Yumi Kim, Kaizhen Wang, Olga Vera, Kenneth Y Tsai, Gina M DeNicola, Florian A Karreth","doi":"10.1158/0008-5472.CAN-24-2471","DOIUrl":"10.1158/0008-5472.CAN-24-2471","url":null,"abstract":"<p><p>Overexpression of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in the serine synthesis pathway, promotes melanomagenesis, melanoma cell proliferation, and survival of metastases in serine-low environments such as the brain. Here, we found that PHGDH is universally increased in melanoma cells and required for melanomagenesis. Although PHGDH amplification explained PHGDH overexpression in a subset of melanomas, oncogenic BRAFV600E also promoted PHGDH transcription through mTORC1-mediated translation of ATF4. Importantly, depletion of PHGDH in genetic mouse melanoma models blocked tumor formation. In addition to BRAFV600E-mediated upregulation, PHGDH was further induced by exogenous serine restriction. Surprisingly, BRAFV600E inhibition diminished serine restriction-mediated PHGDH expression by preventing ATF4 induction. Consequently, melanoma cells could be specifically starved of serine by combining BRAFV600E inhibition with exogenous serine restriction, which promoted cell death in vitro and attenuated melanoma growth in vivo. In summary, this study identified that PHGDH is essential for melanomagenesis and regulated by BRAFV600E, revealing a targetable vulnerability in BRAFV600E-mutant melanoma. Significance: BRAFV600E promotes the expression of the serine synthesis enzyme PHGDH, which is required for melanoma formation, and can be targeted to sensitize melanoma to dietary serine restriction, providing a melanoma cell-specific treatment strategy.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"314-328"},"PeriodicalIF":12.5,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11735329/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566488","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":"ACE2 Enhances Sensitivity to PD-L1 Blockade by Inhibiting Macrophage-Induced Immunosuppression and Angiogenesis.","authors":"Peiyi Xie, Lei Guo, Qiang Yu, Yufei Zhao, Mincheng Yu, Hui Wang, Mengyuan Wu, Wenxin Xu, Min Xu, Xiao-Dong Zhu, Yongfeng Xu, Yong-Sheng Xiao, Cheng Huang, Jian Zhou, Jia Fan, Mien-Chie Hung, Huichuan Sun, Qing-Hai Ye, Bo Zhang, Hui Li","doi":"10.1158/0008-5472.CAN-24-0954","DOIUrl":"10.1158/0008-5472.CAN-24-0954","url":null,"abstract":"<p><p>Anti-PD-L1-based combination immunotherapy has become the first-line treatment for unresectable hepatocellular carcinoma (HCC). However, the objective response rate is lower than 40%, highlighting the need to identify mechanisms of tolerance to immune checkpoint inhibitors and accurate biomarkers of response. In this study, we used next-generation sequencing to analyze HCC samples from 10 patients receiving anti-PD-L1 therapy. Activation of the renin-angiotensin system was elevated in nonresponders compared with responders, and angiotensin-converting enzyme 2 (ACE2) expression was significantly downregulated in nonresponders. ACE2 deficiency promoted HCC development and anti-PD-L1 resistance, whereas ACE2 overexpression inhibited HCC progression in immune-competent mice. Mass cytometry by time of flight revealed that ACE2-deficient murine orthotopic tumor tissues featured elevated M2-like tumor-associated macrophages, displayed a CCR5+PD-L1+ immunosuppressive phenotype, and exhibited high VEGFα expression. ACE2 downregulated tumor-intrinsic chemokine (C-C motif) ligand 5 expression by suppressing NF-κB signaling through the ACE2/angiotensin-(1-7)/Mas receptor axis. The lower chemokine (C-C motif) ligand 5 levels led to reduced activation of the JAK-STAT3 pathway and suppressed PD-L1 and VEGFα expression in macrophages, blocking macrophage infiltration and M2-like polarization. Pharmacologic targeting of CCR5 using maraviroc enhanced the tumor-suppressive effect of anti-PD-L1 therapy. Together, these findings suggest that activation of the ACE2 axis overcomes the immunosuppressive microenvironment of HCC and may serve as an immunotherapeutic target and predictive biomarker of response to PD-L1 blockade. Significance: ACE2 regulates the immune landscape of hepatocellular carcinoma by abrogating M2-like macrophage polarization and sensitizes tumors to anti-PD-L1, suggesting that harnessing the ACE2 axis could be a promising strategy to improve immunotherapy efficacy.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"299-313"},"PeriodicalIF":12.5,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566331","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":"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}