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  • Therapy-Induced Evolution of Human Lung Cancer Revealed by Single-Cell RNA Sequencing.

Therapy-Induced Evolution of Human Lung Cancer Revealed by Single-Cell RNA Sequencing.

Cell (2020-08-22)
Ashley Maynard, Caroline E McCoach, Julia K Rotow, Lincoln Harris, Franziska Haderk, D Lucas Kerr, Elizabeth A Yu, Erin L Schenk, Weilun Tan, Alexander Zee, Michelle Tan, Philippe Gui, Tasha Lea, Wei Wu, Anatoly Urisman, Kirk Jones, Rene Sit, Pallav K Kolli, Eric Seeley, Yaron Gesthalter, Daniel D Le, Kevin A Yamauchi, David M Naeger, Sourav Bandyopadhyay, Khyati Shah, Lauren Cech, Nicholas J Thomas, Anshal Gupta, Mayra Gonzalez, Hien Do, Lisa Tan, Bianca Bacaltos, Rafael Gomez-Sjoberg, Matthew Gubens, Thierry Jahan, Johannes R Kratz, David Jablons, Norma Neff, Robert C Doebele, Jonathan Weissman, Collin M Blakely, Spyros Darmanis, Trever G Bivona
ABSTRACT

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.

MATERIALS
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Product Description

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