Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways

Cancer Discovery, Journal Year: 2023, Volume and Issue: 13(6), P. 1364 - 1385

Published: March 28, 2023

Abstract Understanding the evolutionary pathways to metastasis and resistance immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present most comprehensive intrapatient metastatic dataset assembled date as part of Posthumous Evaluation Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent doubling widespread loss heterozygosity, often involving antigen-presentation machinery. found KIT extrachromosomal DNA may have contributed lack response a KIT-driven melanoma. At lesion-level, MYC amplifications were enriched ICI nonresponders. Single-cell revealed polyclonal seeding metastases originating clones with different ploidy one patient. Finally, that brain diverged early molecular evolution emerge late disease. Overall, our study illustrates diverse landscape advanced Significance: Despite treatment advances, remains deadly disease at stage IV. Through dense sampling combined extensive multiomic profiling, elucidates many mechanisms melanomas use evade immune system, whether through mutations, copy-number alterations, or DNA. See related commentary by Shain, p. 1294. This article highlighted In Issue feature, 1275

Language: Английский

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Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites

Cancer Cell, Journal Year: 2023, Volume and Issue: 41(12), P. 2083 - 2099.e9

Published: Dec. 1, 2023

Neuroendocrine neoplasms (NENs) comprise well-differentiated neuroendocrine tumors (NETs) and poorly differentiated carcinomas (NECs). Treatment options for patients with NENs are limited, in part due to lack of accurate models. We establish patient-derived tumor organoids (PDTOs) from pulmonary NETs derive PDTOs an understudied subtype NEC, large cell carcinoma (LCNEC), arising multiple body sites. maintain the gene expression patterns, intra-tumoral heterogeneity, evolutionary processes parental tumors. Through hypothesis-driven drug sensitivity analyses, we identify ASCL1 as a potential biomarker response LCNEC treatment BCL-2 inhibitors. Additionally, discover dependency on EGF NET PDTOs. Consistent these findings, find that, independent cohort, approximately 50% express EGFR. This study identifies actionable vulnerability subset NETs, emphasizing utility PDTO

Language: Английский

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Cancer Evolution: A Multifaceted Affair

Cancer Discovery, Journal Year: 2023, Volume and Issue: 14(1), P. 36 - 48

Published: Dec. 4, 2023

Cancer cells adapt and survive through the acquisition selection of molecular modifications. This process defines cancer evolution. Building on a theoretical framework based heritable genetic changes has provided insights into mechanisms supporting However, hallmarks also emerge via nongenetic mechanisms, including epigenetic chromatin topological changes, interactions between tumor microenvironment. Recent findings evolutionary draw multifaceted picture where heterogeneous forces interact influence each other while shaping progression. A comprehensive characterization toolkit is required to improve personalized medicine biomarker discovery. Tumor evolution fueled by multiple enabling mechanisms. Importantly, instability, reprogramming, with microenvironment are neither alternative nor independent As demonstrated highlighted in this perspective, experimental approaches must account for their ultimately understand, predict, steer

Language: Английский

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Clinical and translational relevance of intratumor heterogeneity

Trends in cancer, Journal Year: 2023, Volume and Issue: 9(9), P. 726 - 737

Published: May 27, 2023

Language: Английский

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The evolutionary theory of cancer: challenges and potential solutions

Nature reviews. Cancer, Journal Year: 2024, Volume and Issue: 24(10), P. 718 - 733

Published: Sept. 10, 2024

Language: Английский

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