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

The heterogeneity of mammalian tumors has been well documented, but it remains unknown how differences between individual cells lead to metastasis and spread throughout the body. Quinn et al. created a Cas9-based lineage tracer and used single-cell sequencing to generate phylogenies and follow the m...

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Bibliographic Details
Published inScience (American Association for the Advancement of Science) Vol. 371; no. 6532
Main Authors Quinn, Jeffrey J., Jones, Matthew G., Okimoto, Ross A., Nanjo, Shigeki, Chan, Michelle M., Yosef, Nir, Bivona, Trever G., Weissman, Jonathan S.
Format Journal Article
LanguageEnglish
Published United States The American Association for the Advancement of Science 26.02.2021
Subjects
Animals
Biology
Cancer
Cell Line, Tumor
Cell Lineage
Clone Cells
CRISPR-Cas Systems
Drug resistance
Gene expression
Gene Expression Regulation, Neoplastic
Heterogeneity
Humans
Keratin-17 - genetics
Lung cancer
Lung Neoplasms - genetics
Lung Neoplasms - pathology
Metastases
Metastasis
Mice
Neoplasm Invasiveness - genetics
Neoplasm Metastasis - genetics
Neoplasm Metastasis - pathology
Neoplasm Seeding
Neoplasm Transplantation
Phenotype
Phylogenetics
RNA-Seq
Single-Cell Analysis
Subpopulations
Tissues
Transcriptome
Transplantation, Heterologous
Tumors
Xenografts
Online AccessGet full text
ISSN0036-8075
1095-9203
1095-9203
DOI10.1126/science.abc1944

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Summary:The heterogeneity of mammalian tumors has been well documented, but it remains unknown how differences between individual cells lead to metastasis and spread throughout the body. Quinn et al. created a Cas9-based lineage tracer and used single-cell sequencing to generate phylogenies and follow the movement of metastatic human cancer cells implanted in the lung of a mouse xenograph model. Using this model, they found that within the same cell line, cancer cells exhibited diverse metastatic phenotypes. These subclones exhibited differential gene expression profiles, some of which were previously associated with metastasis. Science , this issue p. eabc1944 A Cas9-based lineage tracer elucidates the process of cancer metastasis. 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.
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The authors contributed equally to this work.
Author contributions: All authors contributed to the design of experiments and analysis. J.J.Q. engineered cell lines, processed tissues, and prepared sequencing libraries. R.A.O. performed mouse surgeries and imaging. M.G.J. and J.J.Q. processed lineage tracing sequencing data. S.N. and J.J.Q. performed invasion assays. M.G.J. performed phylogenetic reconstruction and analyzed the trees and single-cell RNA-sequencing data. M.G.J. and N.Y. conceived and implemented the FitchCount algorithm. All authors aided in the interpretation of the analyses. J.J.Q., M.G.J., and J.S.W. wrote the manuscript, and all authors read and approved the final manuscript.
ISSN:0036-8075
1095-9203
1095-9203
DOI:10.1126/science.abc1944