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

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

doi:10.1016/j.cell.2020.07.017

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

Cell. 2020 Sep 3;182(5):1232-1251.e22. doi: 10.1016/j.cell.2020.07.017. Epub 2020 Aug 20.

Authors

Ashley Maynard¹, Caroline E McCoach², Julia K Rotow³, Lincoln Harris¹, Franziska Haderk⁴, D Lucas Kerr⁵, Elizabeth A Yu⁵, Erin L Schenk⁶, Weilun Tan¹, Alexander Zee⁷, Michelle Tan¹, Philippe Gui², Tasha Lea⁸, Wei Wu⁵, Anatoly Urisman⁹, Kirk Jones⁹, Rene Sit¹, Pallav K Kolli¹⁰, Eric Seeley⁵, Yaron Gesthalter⁵, Daniel D Le¹, Kevin A Yamauchi¹, David M Naeger¹¹, Sourav Bandyopadhyay¹², Khyati Shah¹³, Lauren Cech⁵, Nicholas J Thomas⁵, Anshal Gupta⁵, Mayra Gonzalez⁵, Hien Do⁵, Lisa Tan⁵, Bianca Bacaltos⁵, Rafael Gomez-Sjoberg¹, Matthew Gubens², Thierry Jahan², Johannes R Kratz¹⁴, David Jablons¹⁴, Norma Neff¹, Robert C Doebele⁶, Jonathan Weissman¹⁵, Collin M Blakely¹⁶, Spyros Darmanis¹⁷, Trever G Bivona¹⁸

Affiliations

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.

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.

Keywords: ALK; EGFR; lung cancer; single-cell RNA sequencing; targeted therapy.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers, Tumor / genetics
Cell Line
Ecosystem
Humans
Lung Neoplasms / genetics*
Lung Neoplasms / pathology
Macrophages / pathology
Sequence Analysis, RNA / methods
Single-Cell Analysis / methods
T-Lymphocytes / pathology
Tumor Microenvironment / genetics

Substances

Biomarkers, Tumor

Abstract

Publication types

MeSH terms

Substances

Grants and funding