Journal
CELL
Volume 182, Issue 5, Pages 1232-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2020.07.017
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Funding
- NIH/NCI [R01CA227807, U54CA224081, R01CA204302, R01CA211052, R01CA231300, R01CA169338, U01CA217882]
- Van Auken Foundation
- Novartis Pharmaceuticals
- Pfizer
- University of California Cancer League (United States)
- Damon Runyon Cancer Research Foundation [P0528804]
- Doris Duke Charitable Foundation [P2018110]
- V Foundation [P0530519]
- Mildred Scheel postdoctoral fellowship fromthe German Cancer Aid
- NHLBI [T32 HL007185]
- AstraZeneca (United Kingdom)
- [K12 CA086913]
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Lung cancer, the leading cause of cancer mortality, exhibits heterogeneity that enables adaptability, limits therapeutic success, and remains incompletely understood. Single-cell RNA sequencing (scRNA-seq) of metastatic lung cancer was performed using 49 clinical biopsies obtained from 30 patients before and during targeted therapy. Over 20,000 cancer and tumor microenvironment (TME) single-cell profiles exposed a rich and dynamic tumor ecosystem. scRNA-seq of cancer cells illuminated targetable oncogenes beyond those detected clinically. Cancer cells surviving therapy as residual disease (RD) expressed an alveolar-regenerative cell signature suggesting a therapy-induced primitive cell-state transition, whereas those present at on-therapy progressive disease (PD) upregulated kynurenine, plasminogen, and gap-junction pathways. Active T-lymphocytes and decreased macrophages were present at RD and immunosuppressive cell states characterized PD. Biological features revealed by scRNA-seq were biomarkers of clinical outcomes in independent cohorts. This study highlights how therapy-induced adaptation of the multi-cellular ecosystem of metastatic cancer shapes clinical outcomes.
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