Cancer discovery最新文献_第2页

Insights on Future Directions in Cancer Research from the 2025 AACR NextGen Stars.

IF 29.7 1区医学

Cancer discovery Pub Date : 2025-04-02 DOI: 10.1158/2159-8290.CD-25-0239

Edmond M Chan, Yash Chhabra, Karen O Dixon, Adam D Durbin, Anniina Färkkilä, Anand D Jeyasekharan, Zuzana Keckesova, John R Prensner, Elvin Wagenblast, Stephanie Z Xie, Di Zhao

引用次数: 0

High-Purity CTC RNA Sequencing Identifies Prostate Cancer Lineage Phenotypes Prognostic for Clinical Outcomes.

IF 29.7 1区医学

Cancer discovery Pub Date : 2025-04-01 DOI: 10.1158/2159-8290.CD-24-1509

Marina N Sharifi, Jamie M Sperger, Amy K Taylor, Katharine E Tippins, Shannon R Reese, Viridiana Carreno, Katherine R Kaufmann, Alex H Chang, Luke A Nunamaker, Charlotte Linebarger, Leilani Mora-Rodriguez, Jennifer L Schehr, Hannah M Krause, Kyle T Helzer, Matthew L Bootsma, Grace C Blitzer, John M Floberg, Christos E Kyriakopoulos, Hamid Emamekhoo, Elisabeth I Heath, Meghan Wells, Scott T Tagawa, Martin Sjöström, Atish D Choudhury, Menggang Yu, Andrew J Armstrong, Dana E Rathkopf, Himisha Beltran, Peter S Nelson, Felix Y Feng, Scott M Dehm, David Kosoff, Xiao X Wei, Rana R McKay, Shuang G Zhao, Joshua M Lang

引用次数: 0

Somatic uniparental disomy of PTEN in endothelial cells causes vascular malformations in patients with PTEN Hamartoma Tumor Syndrome.

IF 29.7 1区医学

Cancer discovery Pub Date : 2025-03-28 DOI: 10.1158/2159-8290.CD-24-0807

Sandra D Castillo, Xabier Perosanz, Andrew K Ressler, Marta Ivars, Jairo Rodriguez, Carlota Rovira, Emanuele M Nola, Judith Llena, Joaquim Grego-Bessa, Monica Roldan, Raquel Arnau, Anabel Martínez-Romero, Ignasi Barber, Miguel Bejarano, Asuncion Vicente, Veronica Celis, Héctor Salvador, Jaume Mora, Douglas A Marchuk, Eulalia Baselga, Mariona Graupera

{"title":"Somatic uniparental disomy of PTEN in endothelial cells causes vascular malformations in patients with PTEN Hamartoma Tumor Syndrome.","authors":"Sandra D Castillo, Xabier Perosanz, Andrew K Ressler, Marta Ivars, Jairo Rodriguez, Carlota Rovira, Emanuele M Nola, Judith Llena, Joaquim Grego-Bessa, Monica Roldan, Raquel Arnau, Anabel Martínez-Romero, Ignasi Barber, Miguel Bejarano, Asuncion Vicente, Veronica Celis, Héctor Salvador, Jaume Mora, Douglas A Marchuk, Eulalia Baselga, Mariona Graupera","doi":"10.1158/2159-8290.CD-24-0807","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0807","url":null,"abstract":"PTEN Hamartoma Tumor Syndrome (PHTS) is a rare tumor risk disorder caused by germline loss-of-function mutations in PTEN. Half of these patients develop vascular malformations, a hamartoma characterized by overgrowth of vessels. Here, we harness biopsies and patient-derived endothelial cells (ECs) to study the genetic etiology of PHTS-related vascular malformations. We discover that these lesions are generated by the somatic loss of the PTEN wild-type allele through copy-neutral loss of heterozygosity, leading to somatic uniparental disomy of the PTEN mutated allele in ECs. We established a mouse model of PHTS-related vascular malformations and identified that the mTOR inhibitor rapamycin and AKT inhibitor capivasertib block vascular lesion growth. As proof-of-concept for clinical activity, off-label treatment with rapamycin of two patients with PHTS reduced vascular overgrowth and abrogated lesion-associated pain. Overall, our results uncover the genetic cause of vascular malformations in patients with PHTS and open new avenues for therapeutic intervention.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728708","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}

引用次数: 0

Cytosolic Phospholipase A2 determines Intercellular Heterogeneity of Stress Granules and Chemotherapy Response

IF 28.2 1区医学

Cancer discovery Pub Date : 2025-03-18 DOI: 10.1158/2159-8290.cd-24-1144

Alexandra Redding, Guillaume Fonteneau, Stefan Heinrich, Matthias M. Gaida, Elda Grabocka

{"title":"Cytosolic Phospholipase A2 determines Intercellular Heterogeneity of Stress Granules and Chemotherapy Response","authors":"Alexandra Redding, Guillaume Fonteneau, Stefan Heinrich, Matthias M. Gaida, Elda Grabocka","doi":"10.1158/2159-8290.cd-24-1144","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1144","url":null,"abstract":"Cancer cell heterogeneity is a major therapeutic challenge. Here, we identify that individual cells within cancer cell populations show significant heterogeneity in the levels of the stress-adaptive organelles, stress granules (SGs), and demonstrate that SG heterogeneity is dictated by cell-cycle state. Specifically, SG-formation is distinctively heightened in cells in G2-phase due to the interplay between a non-apoptotic function of Caspase 3 and calcium-dependent phospholipase A2 (cPLA2)-mediated production of the SG-promoting molecule, 15-deoxy-delta-prostaglandin-J2 (15d-PGJ2). We demonstrate that in G1/S phase, Caspase 3 cleaves and inactivates cPLA2, whereas in G2-phase, Caspase 3 activity is suppressed, resulting in enhanced cPLA2 activity and 15d-PGJ2 upregulation. We show that cell-cycle-dependent SG heterogeneity is a property of pancreatic ductal adenocarcinoma (PDAC) and targeting G2-SGs by inhibiting cPLA2 sensitizes PDAC to G2-arrest-inducing chemotherapeutics. Our findings highlight cell-cycle-dependent SG formation as a fundamental property of SGs, a key aspect of cancer heterogeneity, and a target for cancer treatment.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"59 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653398","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}

引用次数: 0

PGV001, a multi-peptide personalized neoantigen vaccine platform: Phase I study in patients with solid and hematological malignancies in the adjuvant setting

IF 28.2 1区医学

Cancer discovery Pub Date : 2025-03-17 DOI: 10.1158/2159-8290.cd-24-0934

Mansi Saxena, Thomas U. Marron, Julia Kodysh, John P. Finnigan, Sayali Onkar, Anna Kaminska, Kevin Tuballes, Ruiwei Guo, Rachel Lubong. Sabado, Marcia Meseck, Timothy J. O'Donnell, Robert P. Sebra, Samir Parekh, Matthew D. Galsky, Ana Blasquez, Gustavo Gimenez, Mesude Bicak, Cansu Cimen Bozkus, Daniela Delbeau-Zagelbaum, Denise Rodriguez, Ana Acuna-Villaorduna, Krzysztof J. Misiukiewicz, Marshall R. Posner, Brett A. Miles, Hanna Y. Irie, Amy Tiersten, Deborah B. Doroshow, Andrea Wolf, John Mandeli, Rachel Brody, Andres M. Salazar, Sacha Gnjatic, Jeff Hammerbacher, Eric Schadt, Philip Friedlander, Alexander Rubinsteyn, Nina Bhardwaj

{"title":"PGV001, a multi-peptide personalized neoantigen vaccine platform: Phase I study in patients with solid and hematological malignancies in the adjuvant setting","authors":"Mansi Saxena, Thomas U. Marron, Julia Kodysh, John P. Finnigan, Sayali Onkar, Anna Kaminska, Kevin Tuballes, Ruiwei Guo, Rachel Lubong. Sabado, Marcia Meseck, Timothy J. O'Donnell, Robert P. Sebra, Samir Parekh, Matthew D. Galsky, Ana Blasquez, Gustavo Gimenez, Mesude Bicak, Cansu Cimen Bozkus, Daniela Delbeau-Zagelbaum, Denise Rodriguez, Ana Acuna-Villaorduna, Krzysztof J. Misiukiewicz, Marshall R. Posner, Brett A. Miles, Hanna Y. Irie, Amy Tiersten, Deborah B. Doroshow, Andrea Wolf, John Mandeli, Rachel Brody, Andres M. Salazar, Sacha Gnjatic, Jeff Hammerbacher, Eric Schadt, Philip Friedlander, Alexander Rubinsteyn, Nina Bhardwaj","doi":"10.1158/2159-8290.cd-24-0934","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0934","url":null,"abstract":"Immunotherapies like immune checkpoint inhibitors (ICIs) have changed the standard of care for cancer patients, often leading to durable responses. However, many patients remain or become refractory to ICIs owing to factors such as a lack of primed neoantigen-reactive T cells. We developed a peptide-based vaccination platform that utilizes fully personalized genome vaccines (PGV) and targets neoantigens predicted by our OpenVax computational pipeline. Here we report results from PGV001 study (NCT02721043) targeting up to 10 neoantigens, administered in the adjuvant setting to patients with both solid and hematological malignancies who have high risk of recurrence. Our data indicates that PGV001 is feasible and safe, with 13 out of 14 enrolled patients receiving the vaccine and 11 completing the treatment. 100% of vaccinated patients developed targeted T cell and B cell responses highlighting the capacity of OpenVax to predict immunogenic neoantigens and the potential of PGV001 for safely inducing targeted immunity.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"137 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635276","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}

引用次数: 0

Activated T cells break tumor immunosuppression by macrophage re-education

IF 28.2 1区医学

Cancer discovery Pub Date : 2025-03-17 DOI: 10.1158/2159-8290.cd-24-0415

Rosa Trotta, Silvia Rivis, Shikang Zhao, Marie-Pauline Orban, Sarah Trusso Cafarello, Iris Charatsidou, Joanna Pozniak, Jonas Dehairs, Lotte Vanheer, Carlos A. Pulido Vicuna, Veerle Boecxstaens, Oliver Bechter, Francesca M. Bosisio, Johannes V. Swinnen, Jean-Christophe Marine, Massimiliano Mazzone

{"title":"Activated T cells break tumor immunosuppression by macrophage re-education","authors":"Rosa Trotta, Silvia Rivis, Shikang Zhao, Marie-Pauline Orban, Sarah Trusso Cafarello, Iris Charatsidou, Joanna Pozniak, Jonas Dehairs, Lotte Vanheer, Carlos A. Pulido Vicuna, Veerle Boecxstaens, Oliver Bechter, Francesca M. Bosisio, Johannes V. Swinnen, Jean-Christophe Marine, Massimiliano Mazzone","doi":"10.1158/2159-8290.cd-24-0415","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0415","url":null,"abstract":"Here, we observe that in human and murine melanomas, T-cell activation abates hematopoietic prostaglandin-D2 synthase (HPGDS) transcription in tumor-associated macrophages (TAMs) through TNFα signaling. Mechanistically, HPGDS installs a Prostaglandin-D2 (PGD2) autocrine loop in TAMs via DP1 and DP2 activation that sustains their pro-tumoral phenotype and promotes paracrine inhibition of CD8+ T cells via a PGD2-DP1 axis. Genetic or pharmacologic HPGDS targeting induces anti-tumoral features in TAMs and favors CD8+ T-cell recruitment, activation, and cytotoxicity, altogether sensitizing tumors to αPD1. Conversely, HPGDS overexpression in TAMs or systemic TNFα blockade sustains a pro-tumoral environment and αPD1-resistance, preventing the downregulation of HPGDS by T cells. Congruently, patients and mice resistant to αPD1 fail to suppress HPGDS in TAMs, reinforcing the evidence that circumventing HPGDS is necessary for efficient αPD1 treatment. Overall, we disclose a mechanism whereby T-cell activation controls the innate immune system, and we suggest HPGDS/PGD2 targeting to overcome immunotherapy resistance.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"69 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143640637","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}

引用次数: 0

Aged and BRCA mutated stromal cells drive epithelial cell transformation.

IF 29.7 1区医学

Cancer discovery Pub Date : 2025-03-14 DOI: 10.1158/2159-8290.CD-24-0805

Geyon L Garcia, Taylor Orellana, Grace Gorecki, Leonard Frisbie, Roja Baruwal, Swathi Suresh, Ester Goldfeld, Ian Beddows, Ian P MacFawn, Ananya K Britt, Macy M Hale, Amal Taher Elhaw, Brian R Isett, Nadine Hempel, Riyue Bao, Hui Shen, Ronald J Buckanovich, Toren Finkel, Ronny Drapkin, T Rinda Soong, Tullia C Bruno, Huda I Atiya, Lan G Coffman

{"title":"Aged and BRCA mutated stromal cells drive epithelial cell transformation.","authors":"Geyon L Garcia, Taylor Orellana, Grace Gorecki, Leonard Frisbie, Roja Baruwal, Swathi Suresh, Ester Goldfeld, Ian Beddows, Ian P MacFawn, Ananya K Britt, Macy M Hale, Amal Taher Elhaw, Brian R Isett, Nadine Hempel, Riyue Bao, Hui Shen, Ronald J Buckanovich, Toren Finkel, Ronny Drapkin, T Rinda Soong, Tullia C Bruno, Huda I Atiya, Lan G Coffman","doi":"10.1158/2159-8290.CD-24-0805","DOIUrl":"10.1158/2159-8290.CD-24-0805","url":null,"abstract":"The fundamental steps in high-grade serous ovarian cancer (HGSOC) initiation are unclear presenting critical barriers in prevention and early detection of this deadly disease. Current models propose that fallopian tube epithelial (FTE) cells transform into serous tubal intraepithelial carcinoma (STIC) precursor lesions and subsequently HGSOC. Here we report that an epigenetically altered mesenchymal stem cell niche, termed high risk MSC (hrMSC), exists prior to STIC lesion formation. hrMSCs are enriched in STIC stroma and contribute to a stromal 'field effect' extending beyond the borders of STIC lesion. hrMSCs promote DNA damage in FTE cells while also fostering FTE cell survival. hrMSCs induce malignant transformation of FTE resulting in metastatic cancer in vivo, indicating hrMSCs promote cancer initiation. hrMSCs are significantly enriched in BRCA1/2 mutation carriers and increase with age. Combined, these findings indicate that hrMSCs can incite ovarian cancer initiation and have important implications for ovarian cancer detection and prevention.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623621","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}

引用次数: 0

Long term latency of highly mutated cells in normal mouse skin is reversed by exposure to tumor promoters and chronic tissue damage.

IF 28.2 1区医学

Cancer discovery Pub Date : 2025-03-12 DOI: 10.1158/2159-8290.cd-24-1379

Yun Rose. Li, Eve Kandyba, Kyle Halliwill, Reyno Delrosario, Quan Tran, Nora Bayani, Di Wu, Olga K. Mirzoeva, Melissa Quino. Reeves, S M Ashiqul Islam, Laura Riva, Erik N. Bergstrom, Kavya Achanta, John DiGiovanni, Ludmil B. Alexandrov, Allan Balmain

{"title":"Long term latency of highly mutated cells in normal mouse skin is reversed by exposure to tumor promoters and chronic tissue damage.","authors":"Yun Rose. Li, Eve Kandyba, Kyle Halliwill, Reyno Delrosario, Quan Tran, Nora Bayani, Di Wu, Olga K. Mirzoeva, Melissa Quino. Reeves, S M Ashiqul Islam, Laura Riva, Erik N. Bergstrom, Kavya Achanta, John DiGiovanni, Ludmil B. Alexandrov, Allan Balmain","doi":"10.1158/2159-8290.cd-24-1379","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1379","url":null,"abstract":"Historical studies performed nearly a century ago using mouse skin models identified two key steps in cancer evolution: initiation, a likely mutational event, and promotion, driven by inflammation and cell proliferation. Initiation was proposed to be permanent, with promotion as the critical rate-limiting step for cancer development. Here, we carried out whole genome sequencing to demonstrate that initiated cells with thousands of mutagen-induced mutations can persist for long periods and are not removed by cell competition or by immune intervention, thus mimicking the persistence of cells with cancer driver mutations in normal human tissues. In the mouse, these cells do not give rise to tumors unless exposed to the tumor promoter TPA. Tissue damage and regenerative proliferation, but not normal cell turnover, consistently trigger tumor formation. Wounding, promoter treatment, and obesity enhance promotion without increasing mutational burden, supporting the possibility of future cancer prevention efforts directed at promotional risk factors.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"32 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607898","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}

引用次数: 0

Spatial-Temporal Diversity of Extrachromosomal DNA Shapes Urothelial Carcinoma Evolution and Tumor-Immune Microenvironment.

IF 29.7 1区医学

Cancer discovery Pub Date : 2025-03-11 DOI: 10.1158/2159-8290.CD-24-1532

Wei Lv, Yuchen Zeng, Conghui Li, Yuan Liang, Huiying Tao, Yanfen Zhu, Xiaolong Sui, Yue Li, Shiqi Jiang, Qingqing Gao, Elias Rodriguez-Fos, Gino Prasad, Yuanmei Wang, Run Zhou, Zhe Xu, Xiaoguang Pan, Linlin Chen, Xi Xiang, Huajing Teng, Chaoyang Sun, Tianyu Qin, Wei Dong, Yongwei Li, Xun Lan, Xuesong Li, Lin Lin, Lars Bolund, Huanming Yang, Roel G W Verhaak, Bishoy M Faltas, Jacob B Hansen, Sihan Wu, Paul S Mischel, Anton G Henssen, Vineet Bafna, Jens Luebeck, Birgitte Regenberg, Yonglun Luo, Chunhua Lin, Peng Han

{"title":"Spatial-Temporal Diversity of Extrachromosomal DNA Shapes Urothelial Carcinoma Evolution and Tumor-Immune Microenvironment.","authors":"Wei Lv, Yuchen Zeng, Conghui Li, Yuan Liang, Huiying Tao, Yanfen Zhu, Xiaolong Sui, Yue Li, Shiqi Jiang, Qingqing Gao, Elias Rodriguez-Fos, Gino Prasad, Yuanmei Wang, Run Zhou, Zhe Xu, Xiaoguang Pan, Linlin Chen, Xi Xiang, Huajing Teng, Chaoyang Sun, Tianyu Qin, Wei Dong, Yongwei Li, Xun Lan, Xuesong Li, Lin Lin, Lars Bolund, Huanming Yang, Roel G W Verhaak, Bishoy M Faltas, Jacob B Hansen, Sihan Wu, Paul S Mischel, Anton G Henssen, Vineet Bafna, Jens Luebeck, Birgitte Regenberg, Yonglun Luo, Chunhua Lin, Peng Han","doi":"10.1158/2159-8290.CD-24-1532","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-1532","url":null,"abstract":"Extrachromosomal DNA (ecDNA) presents a promising target for cancer therapy; however, its spatial-temporal diversity and influence on tumor evolution and the immune microenvironment remain largely unclear. We apply computational methods to analyze ecDNA from whole-genome sequencing data of 595 urothelial carcinoma (UC) patients. We demonstrate that ecDNA drives clonal evolution through structural rearrangements during malignant transformation and recurrence of UC. This supports a model wherein tumors evolve via the selective expansion of ecDNA-bearing cells. Through multi-regional sampling of tumors, we demonstrate that ecDNA contributes to the evolution of multifocality and increased intratumoral heterogeneity. EcDNA is present in 36% of UC tumors and correlates with an immunosuppressive phenotype and poor prognosis. Single-cell RNA sequencing analyses reveal that ecDNA+ malignant cells exhibit diminished expression of major histocompatibility complex class I molecules, enabling them to evade T-cell immunity. Finally, we show that sequencing of urinary sediment-derived DNA has excellent specificity in detecting ecDNA.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584738","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}

引用次数: 0

RORγ bridges cancer-driven lipid dysmetabolism and myeloid immunosuppression

IF 28.2 1区医学

Cancer discovery Pub Date : 2025-03-11 DOI: 10.1158/2159-8290.cd-24-0199

Augusto Bleve, Martina Incerti, Francesca Maria. Consonni, Valentina Garlatti, Giulia Ballerini, Chiara Pandolfo, Marta Noemi. Monari, Simone Serio, Daniela Pistillo, Marina Sironi, Chiara Alì, Marcello Manfredi, Elettra Barberis, Giovanna Finocchiaro, Marco Antonio. Cassatella, Cristina Panico, Gianluigi Condorelli, Antonio Sica

{"title":"RORγ bridges cancer-driven lipid dysmetabolism and myeloid immunosuppression","authors":"Augusto Bleve, Martina Incerti, Francesca Maria. Consonni, Valentina Garlatti, Giulia Ballerini, Chiara Pandolfo, Marta Noemi. Monari, Simone Serio, Daniela Pistillo, Marina Sironi, Chiara Alì, Marcello Manfredi, Elettra Barberis, Giovanna Finocchiaro, Marco Antonio. Cassatella, Cristina Panico, Gianluigi Condorelli, Antonio Sica","doi":"10.1158/2159-8290.cd-24-0199","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0199","url":null,"abstract":"Despite well-documented metabolic and hematopoietic alterations during tumor development, the mechanisms underlying this crucial immunometabolic intersection remain elusive. Of particular interest is the connection between lipid metabolism and the retinoic-acid-related orphan receptor (RORC1/RORγ), whose transcriptional activity modulates cancer-related emergency myelopoiesis and is boosted by cholesterol metabolites, while hypercholesterolemia itself is associated with dysregulated myelopoiesis. Here, we show that cancer and hypercholesterolemic diet independently or cooperatively activate RORγ-dependent expansion of myeloid-derived suppressor cells (MDSCs) and M2-polarized tumor-associated macrophages (TAMs), supporting cancer spread. Moreover, we report that tumor-induced expression of IL-1b and IL-6 promotes hepatic expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) in preclinical models and patients. Importantly, lowering cholesterol levels, by genetic or pharmacological inhibition of PCSK9, prevents MDSC expansion, M2 TAM accumulation and tumor progression in a RORγ-dependent manner, unleashing specific anti-tumor immunity. Overall, we identify RORγ as a key sensor of lipid disorders, bridging hypercholesterolemia and pro-tumor myelopoiesis.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"56 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143599815","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}

引用次数: 0