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

被引：468

作者：

Maynard, Ashley ^{[1
]}

McCoach, Caroline E. ^{[2
,3
]}

Rotow, Julia K. ^{[4
]}

Harris, Lincoln ^{[1
]}

Haderk, Franziska ^{[2
,3
,5
]}

Kerr, D. Lucas ^{[2
]}

Yu, Elizabeth A. ^{[2
]}

Schenk, Erin L. ^{[6
]}

Tan, Weilun ^{[1
]}

Zee, Alexander ^{[1
,7
]}

Tan, Michelle ^{[1
]}

Gui, Philippe ^{[2
,3
]}

Lea, Tasha ^{[3
]}

Wu, Wei ^{[2
]}

Urisman, Anatoly ^{[8
]}

Jones, Kirk ^{[8
]}

Sit, Rene ^{[1
]}

Kolli, Pallav K. ^{[9
]}

Seeley, Eric ^{[2
]}

Gesthalter, Yaron ^{[2
]}

Le, Daniel D. ^{[1
]}

Yamauchi, Kevin A. ^{[1
]}

Naeger, David M. ^{[10
,11
]}

Bandyopadhyay, Sourav ^{[3
,12
]}

Shah, Khyati ^{[12
]}

Cech, Lauren ^{[2
]}

Thomas, Nicholas J. ^{[2
]}

Gupta, Anshal ^{[2
]}

Gonzalez, Mayra ^{[2
]}

Do, Hien ^{[2
]}

Tan, Lisa ^{[2
]}

Bacaltos, Bianca ^{[2
]}

Gomez-Sjoberg, Rafael ^{[1
]}

Gubens, Matthew ^{[2
,3
]}

Jahan, Thierry ^{[2
,3
]}

Kratz, Johannes R. ^{[13
]}

Jablons, David ^{[13
]}

Neff, Norma ^{[1
]}

Doebele, Robert C. ^{[6
]}

Weissman, Jonathan ^{[5
,14
]}

Blakely, Collin M. ^{[2
,3
]}

Darmanis, Spyros ^{[1
]}

Bivona, Trever G. ^{[2
,3
,5
]}

机构：

[1] Chan Zuckerberg Biohub, San Francisco, CA 94158 USA

[2] Univ Calif San Francisco, Dept Med, San Francisco, CA 94158 USA

[3] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA

[4] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02215 USA

[5] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA

[6] Univ Colorado, Dept Med, Anschutz Med Campus, Aurora, CO 80045 USA

[7] Univ Calif San Francisco, Dept Biomol Engn, Santa Cruz, CA 95064 USA

[8] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA

[9] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA

[10] Denver Hlth Med Ctr, Denver, CO 80204 USA

[11] Univ Colorado, Dept Radiol, Aurora, CO 80045 USA

[12] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA

[13] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA

[14] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA

来源：

CELL | 2020年 / 182卷 / 05期

关键词：

PLASMINOGEN-ACTIVATOR INHIBITOR-1; TUMOR-ASSOCIATED MACROPHAGES; GENE-EXPRESSION; M2; MACROPHAGES; BETA-CATENIN; PROMOTES; PATHWAY; RESISTANCE; SEQ; HETEROGENEITY;

D O I：

10.1016/j.cell.2020.07.017

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1232 / +

页数：42

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