Cancer discoveryPub Date : 2024-10-31DOI: 10.1158/2159-8290.CD-24-0187
Megan E Bischoff, Behrouz Shamsaei, Juechen Yang, Dina Secic, Bhargav Vemuri, Julie A Reisz, Angelo D'Alessandro, Caterina Bartolacci, Rafal Adamczak, Lucas Schmidt, Jiang Wang, Amelia Martines, Jahnavi Venkat, Vanina Toffessi Tcheuyap, Jacek Biesiada, Catherine A Behrmann, Katherine E Vest, James Brugarolas, Pier Paolo Scaglioni, David R Plas, Krushna C Patra, Shuchi Gulati, Julio A Landero Figueroa, Jarek Meller, John T Cunningham, Maria F Czyzyk-Krzeska
{"title":"Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma.","authors":"Megan E Bischoff, Behrouz Shamsaei, Juechen Yang, Dina Secic, Bhargav Vemuri, Julie A Reisz, Angelo D'Alessandro, Caterina Bartolacci, Rafal Adamczak, Lucas Schmidt, Jiang Wang, Amelia Martines, Jahnavi Venkat, Vanina Toffessi Tcheuyap, Jacek Biesiada, Catherine A Behrmann, Katherine E Vest, James Brugarolas, Pier Paolo Scaglioni, David R Plas, Krushna C Patra, Shuchi Gulati, Julio A Landero Figueroa, Jarek Meller, John T Cunningham, Maria F Czyzyk-Krzeska","doi":"10.1158/2159-8290.CD-24-0187","DOIUrl":"10.1158/2159-8290.CD-24-0187","url":null,"abstract":"<p><p>Copper (Cu) is a cofactor of cytochrome c oxidase (CuCOX), indispensable for aerobic mitochondrial respiration. This study reveals that advanced clear cell renal cell carcinomas (ccRCCs) accumulate Cu, allocating it to CuCOX. Using a range of orthogonal approaches, including metabolomics, lipidomics, isotope-labeled glucose and glutamine flux analysis, and transcriptomics across tumor samples, cell lines, xenografts, and PDX models, combined with genetic and pharmacological interventions, we explored Cu's role in ccRCC. Elevated Cu levels stimulate CuCOX biogenesis, providing bioenergetic and biosynthetic benefits that promote tumor growth. This effect is complemented by glucose-dependent glutathione production, which facilitates detoxification and mitigates Cu-H2O2 toxicity. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics reveal increased oxidative metabolism, altered glutathione and Cu metabolism, and diminished HIF activity during ccRCC progression. Thus, Cu drives an integrated oncogenic remodeling of bioenergetics, biosynthesis, and redox homeostasis, fueling ccRCC growth, which can be targeted for new therapeutic approaches.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543875","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}
Cancer discoveryPub Date : 2024-10-29DOI: 10.1158/2159-8290.CD-24-0897
Ziren Kong, Zhu Li, Xi-Yang Cui, Jian Wang, Mengxin Xu, Yang Liu, Junyi Chen, Song Ni, Zongmin Zhang, Xiaowei Fan, Jiazhao Huang, Yansong Lin, Yuning Sun, Yuqin He, Xinfeng Lin, Tianyu Meng, Han Li, Yixuan Song, Boshizhang Peng, Changming An, Chenyan Gao, Nan Li, Chen Liu, Yiming Zhu, Zhi Yang, Zhibo Liu, Shaoyan Liu
{"title":"CTR-FAPI PET enables precision management of medullary thyroid carcinoma.","authors":"Ziren Kong, Zhu Li, Xi-Yang Cui, Jian Wang, Mengxin Xu, Yang Liu, Junyi Chen, Song Ni, Zongmin Zhang, Xiaowei Fan, Jiazhao Huang, Yansong Lin, Yuning Sun, Yuqin He, Xinfeng Lin, Tianyu Meng, Han Li, Yixuan Song, Boshizhang Peng, Changming An, Chenyan Gao, Nan Li, Chen Liu, Yiming Zhu, Zhi Yang, Zhibo Liu, Shaoyan Liu","doi":"10.1158/2159-8290.CD-24-0897","DOIUrl":"10.1158/2159-8290.CD-24-0897","url":null,"abstract":"<p><p>Medullary thyroid carcinoma (MTC) can only be cured through the excision of all metastatic lesions, but 29-60% patients failed to localize the disease in the current clinical practice. Previously, we developed a fibroblast activation protein inhibitor (FAPI)-based covalent targeted radioligand (CTR) for improved detection sensitivity and accuracy. In this first-in-class clinical trial, we head-to-head compared [68Ga]Ga-CTR-FAPI PET-CT and [18F]FDG PET-CT in 50 MTC patients. The primary endpoint was the patient-based detection rate, with [68Ga]Ga-CTR-FAPI exhibiting higher detection than [18F]FDG (98% vs. 66%, p=0.0002). This improved detection was attributed to increased tumor uptake (SUVmax 11.71±9.16 vs. 2.55±1.73, p<0.0001). Diagnostic accuracy, validated on lesions with gold-standard pathology, was greater for [68Ga]Ga-CTR-FAPI compared to [18F]FDG (96.7% vs. 43.3%, p<0.0001). Notably, 32% patients altered management following [68Ga]Ga-CTR-FAPI PET-CT, and 66.7% patients changed their surgical plan. Overall, [68Ga]Ga-CTR-FAPI PET-CT provided superior detection and diagnostic accuracy compared to [18F]FDG PET-CT, enabling precision management of MTC patients.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521077","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}
Cancer discoveryPub Date : 2024-10-24DOI: 10.1158/2159-8290.cd-24-0573
Zachary T. Compton, Walker Mellon, Valerie K. Harris, Shawn Rupp, Diego Mallo, Stefania E. Kapsetaki, Mallory Wilmot, Ryan Kennington, Kathleen Noble, Cristina Baciu, Lucia N. Ramirez, Ashley Peraza, Brian Martins, Sushil Sudhakar, Selin Aksoy, Gabriela Furukawa, Orsolya Vincze, Mathieu Giraudeau, Elizabeth G. Duke, Simon Spiro, Edmund Flach, Hannah Davidson, Christopher I. Li, Ashley Zehnder, Trevor A. Graham, Brigid V. Troan, Tara M. Harrison, Marc Tollis, Joshua D. Schiffman, C. Athena Aktipis, Lisa M. Abegglen, Carlo C. Maley, Amy M. Boddy
{"title":"Cancer Prevalence across Vertebrates","authors":"Zachary T. Compton, Walker Mellon, Valerie K. Harris, Shawn Rupp, Diego Mallo, Stefania E. Kapsetaki, Mallory Wilmot, Ryan Kennington, Kathleen Noble, Cristina Baciu, Lucia N. Ramirez, Ashley Peraza, Brian Martins, Sushil Sudhakar, Selin Aksoy, Gabriela Furukawa, Orsolya Vincze, Mathieu Giraudeau, Elizabeth G. Duke, Simon Spiro, Edmund Flach, Hannah Davidson, Christopher I. Li, Ashley Zehnder, Trevor A. Graham, Brigid V. Troan, Tara M. Harrison, Marc Tollis, Joshua D. Schiffman, C. Athena Aktipis, Lisa M. Abegglen, Carlo C. Maley, Amy M. Boddy","doi":"10.1158/2159-8290.cd-24-0573","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0573","url":null,"abstract":"Cancer is pervasive across multicellular species, but what explains the differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades of tetrapods (amphibians, sauropsids, and mammals), we found that neoplasia and malignancy prevalence increases with adult mass (contrary to Peto’s paradox) and somatic mutation rate but decreases with gestation time. The relationship between adult mass and malignancy prevalence was only apparent when we controlled for gestation time. Evolution of cancer susceptibility appears to have undergone sudden shifts followed by stabilizing selection. Outliers for neoplasia prevalence include the common porpoise (&lt;1.3%), the Rodrigues fruit bat (&lt;1.6%), the black-footed penguin (&lt;0.4%), ferrets (63%), and opossums (35%). Discovering why some species have particularly high or low levels of cancer may lead to a better understanding of cancer syndromes and novel strategies for the management and prevention of cancer. Significance: Evolution has discovered mechanisms for suppressing cancer in a wide variety of species. By analyzing veterinary necropsy records, we can identify species with exceptionally high or low cancer prevalence. Discovering the mechanisms of cancer susceptibility and resistance may help improve cancer prevention and explain cancer syndromes.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"97 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489809","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}
Cancer discoveryPub Date : 2024-10-23DOI: 10.1158/2159-8290.cd-24-0708
Raffaele Colombo,Paolo Tarantino,Jamie R Rich,Patricia M LoRusso,Elisabeth G E de Vries
{"title":"The Journey of Antibody-Drug Conjugates: Lessons Learned from 40 Years of Development.","authors":"Raffaele Colombo,Paolo Tarantino,Jamie R Rich,Patricia M LoRusso,Elisabeth G E de Vries","doi":"10.1158/2159-8290.cd-24-0708","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0708","url":null,"abstract":"Antibody-drug conjugates (ADC) represent one of the most rapidly expanding treatment modalities in oncology, with 11 ADCs approved by the FDA and more than 210 currently being tested in clinical trials. Spanning over 40 years, ADC clinical development has enhanced our understanding of the multifaceted mechanisms of action for this class of therapeutics. In this article, we discuss key insights into the toxicity, efficacy, stability, distribution, and fate of ADCs. Furthermore, we highlight ongoing challenges related to their clinical optimization, the development of rational sequencing strategies, and the identification of predictive biomarkers. Significance: The development and utilization of ADCs have allowed for relevant improvements in the prognosis of multiple cancer types. Concomitantly, the rise of ADCs in oncology has produced several challenges, including the prediction of their activity, their utilization in sequence, and minimization of their side effects, that still too often resemble those of the cytotoxic molecule that they carry. In this review, we retrace 40 years of development in the field of ADCs and delve deep into the mechanisms of action of these complex therapeutics and reasons behind the many achievements and failures observed in the field to date.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"145 1","pages":"OF1-OF20"},"PeriodicalIF":28.2,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488205","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}
Cancer discoveryPub Date : 2024-10-08DOI: 10.1158/2159-8290.cd-23-1541
Katelyn M. Mullen, Jungeui Hong, Marc A. Attiyeh, Akimasa Hayashi, Hitomi Sakamoto, Zachary A. Kohutek, Caitlin A. McIntyre, Haochen Zhang, Alvin P. Makohon-Moore, Amanda Zucker, Laura D. Wood, Matthew A. Myers, Brian J. Arnold, Simone Zaccaria, Joanne F. Chou, Marinela Capanu, Nicholas D. Socci, Benjamin J. Raphael, Christine A. Iacobuzio-Donahue
{"title":"The Evolutionary Forest of Pancreatic Cancer","authors":"Katelyn M. Mullen, Jungeui Hong, Marc A. Attiyeh, Akimasa Hayashi, Hitomi Sakamoto, Zachary A. Kohutek, Caitlin A. McIntyre, Haochen Zhang, Alvin P. Makohon-Moore, Amanda Zucker, Laura D. Wood, Matthew A. Myers, Brian J. Arnold, Simone Zaccaria, Joanne F. Chou, Marinela Capanu, Nicholas D. Socci, Benjamin J. Raphael, Christine A. Iacobuzio-Donahue","doi":"10.1158/2159-8290.cd-23-1541","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-23-1541","url":null,"abstract":"The genomic features of pancreatic ductal adenocarcinoma (PDAC) have been well described, yet the evolutionary contexts within which those features occur remains unexplored. We studied the genome landscapes, phylogenies and clonal compositions of 91 PDACs in relation to clinicopathologic features. There was no difference in the number of driver mutations or the evolutionary timing that each mutation occurred. High truncal density, a metric of the accumulation of somatic mutations in the lineage that gave rise to each PDAC, was significantly associated with worse overall survival. Polyclonal, monoclonal or mixed polyclonal/monoclonal metastases were identified across the cohort highlighting multiple forms of inter-tumoral heterogeneity. Advanced stage and treated PDACs had higher odds of being polyclonal, whereas oligometastatic PDACs had fewer driver alterations, a lower fractional allelic loss and increased likelihood of being monoclonal. In sum, our findings reveal novel insights into the dynamic nature of the PDAC genome beyond established genetic paradigms.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"46 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385205","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}
Cancer discoveryPub Date : 2024-10-07DOI: 10.1158/2159-8290.CD-23-1336
Vamsi Mangena, Rony Chanoch-Myers, Rafaela Sartore, Bruna Paulsen, Simon Gritsch, Hannah Weisman, Toshiro Hara, Xandra O Breakefield, Koen Breyne, Aviv Regev, Kwanghun Chung, Paola Arlotta, Itay Tirosh, Mario L Suva
{"title":"Glioblastoma-cortical organoids recapitulate cell state heterogeneity and intercellular transfer.","authors":"Vamsi Mangena, Rony Chanoch-Myers, Rafaela Sartore, Bruna Paulsen, Simon Gritsch, Hannah Weisman, Toshiro Hara, Xandra O Breakefield, Koen Breyne, Aviv Regev, Kwanghun Chung, Paola Arlotta, Itay Tirosh, Mario L Suva","doi":"10.1158/2159-8290.CD-23-1336","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-23-1336","url":null,"abstract":"<p><p>Glioblastoma is characterized by heterogeneous malignant cells that are functionally integrated within the neuroglial microenvironment. Here, we model this ecosystem by growing glioblastoma into long-term cultured human cortical organoids that contain the major neuroglial cell types found in the cerebral cortex. Single-cell RNA-seq analysis suggests that, compared to matched gliomasphere models, glioblastoma cortical organoids (GCO) more faithfully recapitulate the diversity and expression programs of malignant cell states found in patient tumors. Additionally, we observe widespread transfer of glioblastoma transcripts and GFP proteins to non-malignant cells in the organoids. Mechanistically, this transfer involves extracellular vesicles and is biased towards defined glioblastoma cell states and astroglia cell types. These results extend previous glioblastoma-organoid modeling efforts and suggest widespread intercellular transfer in the glioblastoma neuroglial microenvironment.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380088","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}
Cancer discoveryPub Date : 2024-10-04DOI: 10.1158/2159-8290.CD-23-1379
Raghuvaran Shanmugam, Prativa Majee, Wei Shi, Mert B Ozturk, Thamil S Vaiyapuri, Khaireen Idzham, Anandhkumar Raju, Seung H Shin, Kerem Fidan, Joo-Leng Low, Joelle Y H Chua, Yap C Kong, Ong Y Qi, Emile Tan, Aik Y Chok, Isaac Seow-En, Ian Wee, Dominique C Macalinao, Dawn Q Chong, Hong Y Chang, Fiona Lee, Wei Q Leow, Maki Murata-Hori, Zhang Xiaoqian, Chia Shumei, Chris S H Tan, Ramanuj Dasgupta, Iain B Tan, Vinay Tergaonkar
{"title":"Iron-(Fe3+)-Dependent Reactivation of Telomerase Drives Colorectal Cancers.","authors":"Raghuvaran Shanmugam, Prativa Majee, Wei Shi, Mert B Ozturk, Thamil S Vaiyapuri, Khaireen Idzham, Anandhkumar Raju, Seung H Shin, Kerem Fidan, Joo-Leng Low, Joelle Y H Chua, Yap C Kong, Ong Y Qi, Emile Tan, Aik Y Chok, Isaac Seow-En, Ian Wee, Dominique C Macalinao, Dawn Q Chong, Hong Y Chang, Fiona Lee, Wei Q Leow, Maki Murata-Hori, Zhang Xiaoqian, Chia Shumei, Chris S H Tan, Ramanuj Dasgupta, Iain B Tan, Vinay Tergaonkar","doi":"10.1158/2159-8290.CD-23-1379","DOIUrl":"10.1158/2159-8290.CD-23-1379","url":null,"abstract":"<p><p>Over-consumption of iron-rich red meat and hereditary or genetic iron overload are associated with an increased risk of colorectal carcinogenesis, yet the mechanistic basis of how metal-mediated signaling leads to oncogenesis remains enigmatic. Using fresh colorectal cancer samples we identify Pirin, an iron sensor, that overcomes a rate-limiting step in oncogenesis, by reactivating the dormant human telomerase reverse transcriptase (hTERT) subunit of the telomerase holoenzyme in an iron-(Fe3+)-dependent manner and thereby drives colorectal cancers. Chemical genetic screens combined with isothermal dose-response fingerprinting and mass spectrometry identified a small molecule SP2509 that specifically inhibits Pirin-mediated hTERT reactivation in colorectal cancers by competing with iron-(Fe3+) binding. Our findings, first to document how metal ions reactivate telomerase, provide a molecular mechanism for the well-known association between red meat and increased incidence of colorectal cancers. Small molecules like SP2509 represent a novel modality to target telomerase that acts as a driver of 90% of human cancers and is yet to be targeted in clinic. Significance: We show how iron-(Fe3+) in collusion with genetic factors reactivates telomerase, providing a molecular mechanism for the association between iron overload and increased incidence of colorectal cancers. Although no enzymatic inhibitors of telomerase have entered the clinic, we identify SP2509, a small molecule that targets telomerase reactivation and function in colorectal cancers.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"1940-1963"},"PeriodicalIF":29.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11450372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141417873","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}
Cancer discoveryPub Date : 2024-10-04DOI: 10.1158/2159-8290.CD-24-1020
Elmira Khabusheva, Margaret A Goodell
{"title":"Can Ruxolitinib Crash TET2- and IDH2-Driven Clonal Hematopoiesis?","authors":"Elmira Khabusheva, Margaret A Goodell","doi":"10.1158/2159-8290.CD-24-1020","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-1020","url":null,"abstract":"<p><p>In this issue, Waarts and colleagues developed an advanced ex vivo CRISPR screening platform to identify vulnerabilities in clonal hematopoiesis (CH). This unique system allowed the authors to identify a link between IDH2 and TET2 CH mutations, histone demethylases, and altered cytokine signaling, which enabled targeting by ruxolitinib leading to the elimination of CH clones, offering a possible path for preventing the development of malignancy. See related article by Waarts et al., p. 1860.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"14 10","pages":"1768-1770"},"PeriodicalIF":29.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370979","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}
Cancer discoveryPub Date : 2024-10-04DOI: 10.1158/2159-8290.CD-24-1012
Hannah Noelle Bell, Weiping Zou
{"title":"Ironing Out the Kinks: Arming Natural Killer Cells against Ovarian Cancer.","authors":"Hannah Noelle Bell, Weiping Zou","doi":"10.1158/2159-8290.CD-24-1012","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-1012","url":null,"abstract":"<p><p>Ameliorating the tumor immune microenvironment is a key strategy to improve the therapeutic outcomes of patients with cancer. Sandoval and colleagues demonstrate that iron chelation enhances type I IFN production, promotes NK cell tumor trafficking and activation, and synergizes with chemotherapy drug cisplatin to reduce metastatic ovarian cancer progression in murine models. See related article by Sandoval et al., p. 1901.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"14 10","pages":"1771-1773"},"PeriodicalIF":29.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370981","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}
Cancer discoveryPub Date : 2024-10-04DOI: 10.1158/2159-8290.CD-23-1092
Michael R Waarts, Shoron Mowla, Meaghan Boileau, Anthony R Martinez Benitez, Junya Sango, Maya Bagish, Inés Fernández-Maestre, Yufan Shan, Shira E Eisman, Young C Park, Matthew Wereski, Isabelle Csete, Kavi O'Connor, Angelica C Romero-Vega, Linde A Miles, Wenbin Xiao, Xiaodi Wu, Richard P Koche, Scott A Armstrong, Alan H Shih, Eirini P Papapetrou, Jason M Butler, Sheng F Cai, Robert L Bowman, Ross L Levine
{"title":"CRISPR Dependency Screens in Primary Hematopoietic Stem Cells Identify KDM3B as a Genotype-specific Vulnerability in IDH2- and TET2-mutant Cells.","authors":"Michael R Waarts, Shoron Mowla, Meaghan Boileau, Anthony R Martinez Benitez, Junya Sango, Maya Bagish, Inés Fernández-Maestre, Yufan Shan, Shira E Eisman, Young C Park, Matthew Wereski, Isabelle Csete, Kavi O'Connor, Angelica C Romero-Vega, Linde A Miles, Wenbin Xiao, Xiaodi Wu, Richard P Koche, Scott A Armstrong, Alan H Shih, Eirini P Papapetrou, Jason M Butler, Sheng F Cai, Robert L Bowman, Ross L Levine","doi":"10.1158/2159-8290.CD-23-1092","DOIUrl":"10.1158/2159-8290.CD-23-1092","url":null,"abstract":"<p><p>Clonal hematopoiesis (CH) is a common premalignant state in the blood and confers an increased risk of blood cancers and all-cause mortality. Identification of therapeutic targets in CH has been hindered by the lack of an ex vivo platform amenable for studying primary hematopoietic stem and progenitor cells (HSPCs). Here, we utilize an ex vivo co-culture system of HSPCs with bone marrow endothelial cells to perform CRISPR/Cas9 screens in mutant HSPCs. Our data reveal that loss of the histone demethylase family members Kdm3b and Jmjd1c specifically reduces the fitness of Idh2- and Tet2-mutant HSPCs. Kdm3b loss in mutant cells leads to decreased expression of critical cytokine receptors including Mpl, rendering mutant HSPCs preferentially susceptible to inhibition of downstream JAK2 signaling. Our study nominates an epigenetic regulator and an epigenetically regulated receptor signaling pathway as genotype-specific therapeutic targets and provides a scalable platform to identify genetic dependencies in mutant HSPCs. Significance: Given the broad prevalence, comorbidities, and risk of malignant transformation associated with CH, there is an unmet need to identify therapeutic targets. We develop an ex vivo platform to perform CRISPR/Cas9 screens in primary HSPCs. We identify KDM3B and downstream signaling components as genotype-specific dependencies in CH and myeloid malignancies. See related commentary by Khabusheva and Goodell, p. 1768.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"1860-1878"},"PeriodicalIF":29.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141179115","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}
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