Single-cell lineages reveal the rates, routes, and drivers of metastasis in cancer xenografts

Jeffrey J Quinn; Matthew G Jones; Ross A Okimoto; Shigeki Nanjo; Michelle M Chan; Nir Yosef; Trever G Bivona; Jonathan S Weissman

doi:10.1126/science.abc1944

Single-cell lineages reveal the rates, routes, and drivers of metastasis in cancer xenografts

Science. 2021 Feb 26;371(6532):eabc1944. doi: 10.1126/science.abc1944. Epub 2021 Jan 21.

Authors

Jeffrey J Quinn^#^{1

2

3}, Matthew G Jones^#^{1

2

4

5

6}, Ross A Okimoto^{7

8}, Shigeki Nanjo^{7

8}, Michelle M Chan^{1

2

9}, Nir Yosef^{10

11

12

13}, Trever G Bivona^{14

7

8}, Jonathan S Weissman^{14

2

15

16}

Affiliations

¹ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
² Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA, USA.
³ Inscripta, Inc., Boulder, CO, USA.
⁴ Biological and Medical Informatics Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
⁵ Integrative Program in Quantitative Biology, University of California, San Francisco, San Francisco, CA, USA.
⁶ Center for Computational Biology, University of California, Berkeley, Berkeley, CA, USA.
⁷ UCSF Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
⁸ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
⁹ Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
¹⁰ Center for Computational Biology, University of California, Berkeley, Berkeley, CA, USA. weissman@wi.mit.edu trever.bivona@ucsf.edu niryosef@berkeley.edu.
¹¹ Department of Electrical Engineering and Computer Science, University of California, Berkeley, Berkeley, CA, USA.
¹² Chan Zuckerberg Biohub Investigator, San Francisco, CA, USA.
¹³ Ragon Institute of Massachusetts General Hospital, MIT and Harvard University, Cambridge, MA, USA.
¹⁴ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA. weissman@wi.mit.edu trever.bivona@ucsf.edu niryosef@berkeley.edu.
¹⁵ Whitehead Institute, Cambridge, MA, USA.
¹⁶ Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.

^# Contributed equally.

Abstract

Detailed phylogenies of tumor populations can recount the history and chronology of critical events during cancer progression, such as metastatic dissemination. We applied a Cas9-based, single-cell lineage tracer to study the rates, routes, and drivers of metastasis in a lung cancer xenograft mouse model. We report deeply resolved phylogenies for tens of thousands of cancer cells traced over months of growth and dissemination. This revealed stark heterogeneity in metastatic capacity, arising from preexisting and heritable differences in gene expression. We demonstrate that these identified genes can drive invasiveness and uncovered an unanticipated suppressive role for KRT17 We also show that metastases disseminated via multidirectional tissue routes and complex seeding topologies. Overall, we demonstrate the power of tracing cancer progression at subclonal resolution and vast scale.

Publication types

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

MeSH terms

Animals
CRISPR-Cas Systems
Cell Line, Tumor
Cell Lineage
Clone Cells
Gene Expression Regulation, Neoplastic
Humans
Keratin-17 / genetics
Lung Neoplasms / genetics
Lung Neoplasms / pathology*
Mice
Neoplasm Invasiveness / genetics
Neoplasm Metastasis* / genetics
Neoplasm Metastasis* / pathology
Neoplasm Seeding
Neoplasm Transplantation
Phenotype
RNA-Seq
Single-Cell Analysis
Transcriptome
Transplantation, Heterologous

Substances

KRT17 protein, human
Keratin-17

Abstract

Publication types

MeSH terms

Substances

Grants and funding