Pub Date : 2024-11-01DOI: 10.1158/2159-8290.CD-23-0017
Bruno Giotti, Komal Dolasia, William Zhao, Peiwen Cai, Robert Sweeney, Elliot Merritt, Evgeny Kiner, Grace S Kim, Atharva Bhagwat, Thinh Nguyen, Samarth Hegde, Bailey G Fitzgerald, Sanjana Shroff, Travis Dawson, Monica Garcia-Barros, Jamshid Abdul-Ghafar, Rachel Chen, Sacha Gnjatic, Alan Soto, Rachel Brody, Seunghee Kim-Schulze, Zhihong Chen, Kristin G Beaumont, Miriam Merad, Raja M Flores, Robert P Sebra, Amir Horowitz, Thomas U Marron, Anna Tocheva, Andrea Wolf, Alexander M Tsankov
Immunotherapies have shown great promise in pleural mesothelioma (PM), yet most patients still do not achieve significant clinical response, highlighting the importance of improving the understanding of the tumor microenvironment (TME). Here, we utilized high-throughput, single-cell RNA sequencing (scRNA-seq) to de novo identify 54 expression programs and construct a comprehensive cellular catalog of the PM TME. We found four cancer-intrinsic programs associated with poor disease outcome and a novel fetal-like, endothelial cell population that likely responds to VEGF signaling and promotes angiogenesis. Across cellular compartments, we observe substantial difference in the TME associated with a cancer-intrinsic sarcomatoid signature, including enrichment in fetal-like endothelial cells, CXCL9+ macrophages, and cytotoxic, exhausted, and regulatory T cells, which we validated using imaging and bulk deconvolution analyses on independent cohorts. Finally, we show, both computationally and experimentally, that NKG2A:HLA-E interaction between NK and tumor cells represents an important new therapeutic axis in PM, especially for epithelioid cases. Significance: This manuscript presents the first single-cell RNA sequencing atlas of PM tumor microenvironment. Findings of translational relevance, validated experimentally and using independent bulk cohorts, include identification of gene programs predictive of survival, a fetal-like endothelial cell population, and NKG2A blockade as a promising new immunotherapeutic intervention in PM.
免疫疗法在胸膜间皮瘤(PM)中显示出了巨大的前景,但大多数患者仍未获得明显的临床反应,这凸显了加深了解肿瘤微环境(TME)的重要性。在这里,我们利用高通量单细胞RNA测序技术从新识别了54种表达程序,并构建了胸膜间皮瘤TME的综合细胞目录。我们发现了四种与不良疾病预后相关的癌症内在程序,以及一种新型胎儿样内皮细胞群,这种细胞群可能会对血管内皮生长因子信号做出反应并促进血管生成。在整个细胞分区中,我们观察到与癌症内在肉瘤特征相关的 TME 存在巨大差异,包括胎儿样内皮细胞、CXCL9+ 巨噬细胞、细胞毒性 T 细胞、衰竭 T 细胞和调节性 T 细胞的富集。最后,我们通过计算和实验表明,NK 和肿瘤细胞之间的 NKG2A-HLA-E 相互作用代表了 PM 重要的新治疗轴,尤其是对于上皮样病例。
{"title":"Single-Cell View of Tumor Microenvironment Gradients in Pleural Mesothelioma.","authors":"Bruno Giotti, Komal Dolasia, William Zhao, Peiwen Cai, Robert Sweeney, Elliot Merritt, Evgeny Kiner, Grace S Kim, Atharva Bhagwat, Thinh Nguyen, Samarth Hegde, Bailey G Fitzgerald, Sanjana Shroff, Travis Dawson, Monica Garcia-Barros, Jamshid Abdul-Ghafar, Rachel Chen, Sacha Gnjatic, Alan Soto, Rachel Brody, Seunghee Kim-Schulze, Zhihong Chen, Kristin G Beaumont, Miriam Merad, Raja M Flores, Robert P Sebra, Amir Horowitz, Thomas U Marron, Anna Tocheva, Andrea Wolf, Alexander M Tsankov","doi":"10.1158/2159-8290.CD-23-0017","DOIUrl":"10.1158/2159-8290.CD-23-0017","url":null,"abstract":"<p><p>Immunotherapies have shown great promise in pleural mesothelioma (PM), yet most patients still do not achieve significant clinical response, highlighting the importance of improving the understanding of the tumor microenvironment (TME). Here, we utilized high-throughput, single-cell RNA sequencing (scRNA-seq) to de novo identify 54 expression programs and construct a comprehensive cellular catalog of the PM TME. We found four cancer-intrinsic programs associated with poor disease outcome and a novel fetal-like, endothelial cell population that likely responds to VEGF signaling and promotes angiogenesis. Across cellular compartments, we observe substantial difference in the TME associated with a cancer-intrinsic sarcomatoid signature, including enrichment in fetal-like endothelial cells, CXCL9+ macrophages, and cytotoxic, exhausted, and regulatory T cells, which we validated using imaging and bulk deconvolution analyses on independent cohorts. Finally, we show, both computationally and experimentally, that NKG2A:HLA-E interaction between NK and tumor cells represents an important new therapeutic axis in PM, especially for epithelioid cases. Significance: This manuscript presents the first single-cell RNA sequencing atlas of PM tumor microenvironment. Findings of translational relevance, validated experimentally and using independent bulk cohorts, include identification of gene programs predictive of survival, a fetal-like endothelial cell population, and NKG2A blockade as a promising new immunotherapeutic intervention in PM.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141497228","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}
Pub Date : 2024-11-01DOI: 10.1158/2159-8290.CD-23-1165
Alina Bollhagen, Bernd Bodenmiller
Precision oncology tailors treatment strategies to a patient's molecular and health data. Despite the essential clinical value of current diagnostic methods, hematoxylin and eosin morphology, immunohistochemistry, and gene panel sequencing offer an incomplete characterization. In contrast, highly multiplexed tissue imaging allows spatial analysis of dozens of markers at single-cell resolution enabling analysis of complex tumor ecosystems; thereby it has the potential to advance our understanding of cancer biology and supports drug development, biomarker discovery, and patient stratification. We describe available highly multiplexed imaging modalities, discuss their advantages and disadvantages for clinical use, and potential paths to implement these into clinical practice. Significance: This review provides guidance on how high-resolution, multiplexed tissue imaging of patient samples can be integrated into clinical workflows. It systematically compares existing and emerging technologies and outlines potential applications in the field of precision oncology, thereby bridging the ever-evolving landscape of cancer research with practical implementation possibilities of highly multiplexed tissue imaging into routine clinical practice.
{"title":"Highly Multiplexed Tissue Imaging in Precision Oncology and Translational Cancer Research.","authors":"Alina Bollhagen, Bernd Bodenmiller","doi":"10.1158/2159-8290.CD-23-1165","DOIUrl":"10.1158/2159-8290.CD-23-1165","url":null,"abstract":"<p><p>Precision oncology tailors treatment strategies to a patient's molecular and health data. Despite the essential clinical value of current diagnostic methods, hematoxylin and eosin morphology, immunohistochemistry, and gene panel sequencing offer an incomplete characterization. In contrast, highly multiplexed tissue imaging allows spatial analysis of dozens of markers at single-cell resolution enabling analysis of complex tumor ecosystems; thereby it has the potential to advance our understanding of cancer biology and supports drug development, biomarker discovery, and patient stratification. We describe available highly multiplexed imaging modalities, discuss their advantages and disadvantages for clinical use, and potential paths to implement these into clinical practice. Significance: This review provides guidance on how high-resolution, multiplexed tissue imaging of patient samples can be integrated into clinical workflows. It systematically compares existing and emerging technologies and outlines potential applications in the field of precision oncology, thereby bridging the ever-evolving landscape of cancer research with practical implementation possibilities of highly multiplexed tissue imaging into routine clinical practice.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528208/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557240","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}
Pub Date : 2024-11-01DOI: 10.1158/2159-8290.CD-24-0740
Anupriya Singhal, Hannah C Styers, Jonathan Rub, Zhuxuan Li, Stefan R Torborg, Jung Yun Kim, Olivera Grbovic-Huezo, Huijin Feng, Zeynep Cagla Tarcan, Hulya Sahin Ozkan, Jill Hallin, Olca Basturk, Rona Yaeger, James G Christensen, Doron Betel, Yan Yan, Iok In Christine Chio, Elisa de Stanchina, Tuomas Tammela
Intratumoral heterogeneity in pancreatic ductal adenocarcinoma (PDAC) is characterized by a balance between basal and classical epithelial cancer cell states, with basal dominance associating with chemoresistance and a dismal prognosis. Targeting oncogenic KRAS, the primary driver of pancreatic cancer, shows early promise in clinical trials, but efficacy is limited by acquired resistance. Using genetically engineered mouse models and patient-derived xenografts, we find that basal PDAC cells are highly sensitive to KRAS inhibitors. Employing fluorescent and bioluminescent reporter systems, we longitudinally track cell-state dynamics in vivo and reveal a rapid, KRAS inhibitor-induced enrichment of the classical state. Lineage tracing uncovers that these enriched classical PDAC cells are a reservoir for disease relapse. Genetic or chemotherapy-mediated ablation of the classical cell state is synergistic with KRAS inhibition, providing a preclinical proof of concept for this therapeutic strategy. Our findings motivate combining classical state-directed therapies with KRAS inhibitors to deepen responses and counteract resistance in pancreatic cancer. Significance: KRAS inhibitors hold promise in pancreatic cancer, but responses are limited by acquired resistance. We find that a classical epithelial cancer cell state is acutely resistant to KRAS inhibition and serves as a reservoir for disease relapse. Targeting the classical state alongside KRAS inhibition deepens responses, revealing a potent therapeutic strategy. See related commentary by Marasco and Misale, p. 2018.
{"title":"A Classical Epithelial State Drives Acute Resistance to KRAS Inhibition in Pancreatic Cancer.","authors":"Anupriya Singhal, Hannah C Styers, Jonathan Rub, Zhuxuan Li, Stefan R Torborg, Jung Yun Kim, Olivera Grbovic-Huezo, Huijin Feng, Zeynep Cagla Tarcan, Hulya Sahin Ozkan, Jill Hallin, Olca Basturk, Rona Yaeger, James G Christensen, Doron Betel, Yan Yan, Iok In Christine Chio, Elisa de Stanchina, Tuomas Tammela","doi":"10.1158/2159-8290.CD-24-0740","DOIUrl":"10.1158/2159-8290.CD-24-0740","url":null,"abstract":"<p><p>Intratumoral heterogeneity in pancreatic ductal adenocarcinoma (PDAC) is characterized by a balance between basal and classical epithelial cancer cell states, with basal dominance associating with chemoresistance and a dismal prognosis. Targeting oncogenic KRAS, the primary driver of pancreatic cancer, shows early promise in clinical trials, but efficacy is limited by acquired resistance. Using genetically engineered mouse models and patient-derived xenografts, we find that basal PDAC cells are highly sensitive to KRAS inhibitors. Employing fluorescent and bioluminescent reporter systems, we longitudinally track cell-state dynamics in vivo and reveal a rapid, KRAS inhibitor-induced enrichment of the classical state. Lineage tracing uncovers that these enriched classical PDAC cells are a reservoir for disease relapse. Genetic or chemotherapy-mediated ablation of the classical cell state is synergistic with KRAS inhibition, providing a preclinical proof of concept for this therapeutic strategy. Our findings motivate combining classical state-directed therapies with KRAS inhibitors to deepen responses and counteract resistance in pancreatic cancer. Significance: KRAS inhibitors hold promise in pancreatic cancer, but responses are limited by acquired resistance. We find that a classical epithelial cancer cell state is acutely resistant to KRAS inhibition and serves as a reservoir for disease relapse. Targeting the classical state alongside KRAS inhibition deepens responses, revealing a potent therapeutic strategy. See related commentary by Marasco and Misale, p. 2018.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554211","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}
Pub 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
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.
铜(Cu)是细胞色素 c 氧化酶(CuCOX)的辅助因子,是有氧线粒体呼吸不可或缺的物质。这项研究发现,晚期透明细胞肾细胞癌(ccRCC)会积累铜,并将其分配给CuCOX。我们采用了一系列正交方法,包括代谢组学、脂质组学、同位素标记的葡萄糖和谷氨酰胺通量分析以及肿瘤样本、细胞系、异种移植和 PDX 模型的转录组学,并结合基因和药物干预,探讨了 Cu 在 ccRCC 中的作用。Cu水平升高会刺激CuCOX的生物生成,提供生物能和生物合成益处,从而促进肿瘤生长。葡萄糖依赖性谷胱甘肽的产生补充了这一作用,促进了解毒并减轻了 Cu-H2O2 的毒性。单细胞 RNA 测序(scRNA-seq)和空间转录组学揭示了 ccRCC 进展过程中氧化代谢增加、谷胱甘肽和铜代谢改变以及 HIF 活性降低。因此,铜推动了生物能、生物合成和氧化还原平衡的综合致癌重塑,助长了ccRCC的生长,而这可以成为新治疗方法的靶点。
{"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":null,"pages":null},"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}
Pub 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
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.
{"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":null,"pages":null},"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}
Pub 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
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 (<1.3%), the Rodrigues fruit bat (<1.6%), the black-footed penguin (<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.
{"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":null,"pages":null},"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}
Pub 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
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.
{"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":null,"pages":null},"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}
Pub 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
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.
{"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":null,"pages":null},"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}
Pub 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
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.
{"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":null,"pages":null},"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}
Pub Date : 2024-10-04DOI: 10.1158/2159-8290.CD-24-1020
Elmira Khabusheva, Margaret A Goodell
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.
{"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":null,"pages":null},"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}