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

1. Cell. 2020 Sep 3;182(5):1232-1251.e22. doi: 10.1016/j.cell.2020.07.017. Epub 2020 Aug 20. Therapy-Induced Evolution of Human Lung Cancer Revealed by Single-Cell RNA Sequencing. Maynard A(1), McCoach CE(2), Rotow JK(3), Harris L(1), Haderk F(4), Kerr DL(5), Yu EA(5), Schenk EL(6), Tan W(1), Zee A(7), Tan M(1), Gui P(2), Lea T(8), Wu W(5), Urisman A(9), Jones K(9), Sit R(1), Kolli PK(10), Seeley E(5), Gesthalter Y(5), Le DD(1), Yamauchi KA(1), Naeger DM(11), Bandyopadhyay S(12), Shah K(13), Cech L(5), Thomas NJ(5), Gupta A(5), Gonzalez M(5), Do H(5), Tan L(5), Bacaltos B(5), Gomez-Sjoberg R(1), Gubens M(2), Jahan T(2), Kratz JR(14), Jablons D(14), Neff N(1), Doebele RC(6), Weissman J(15), Blakely CM(16), Darmanis S(17), Bivona TG(18). Author information: (1)Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. (2)Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA. (3)Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (4)Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA. (5)Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA. (6)Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. (7)Chan Zuckerberg Biohub, San Francisco, CA 94158, USA; Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA. (8)Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA. (9)Department of Pathology University of California, San Francisco, San Francisco, CA 94143, USA. (10)Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94143 USA. (11)Denver Health Medical Center, Denver, CO 80204, USA; Department of Radiology, University of Colorado, Aurora, CO 80045, USA. (12)Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA. (13)Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA. (14)Department of Surgery, University of California, San Francisco, CA 94143, USA. (15)Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA. (16)Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: collin.blakely@ucsf.edu. (17)Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. Electronic address: spyros.darmanis@czbiohub.org. (18)Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: trever.bivona@ucsf.edu. 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. Copyright ©