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

TitleSingle-cell lineages reveal the rates, routes, and drivers of metastasis in cancer xenografts.
Publication TypeJournal Article
Year of Publication2021
AuthorsQuinn, JJ, Jones, MG, Okimoto, RA, Nanjo, S, Chan, MM, Yosef, N, Bivona, TG, Weissman, JS
JournalScience
Volume371
Issue6532
Date Published2021/02/26
ISSN1095-9203
KeywordsAnimals, Cell Line, Tumor, Cell Lineage, Clone Cells, CRISPR-Cas Systems, Gene Expression Regulation, Neoplastic, Humans, Keratin-17, Lung Neoplasms, Mice, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasm Seeding, Neoplasm Transplantation, Phenotype, RNA-Seq, Single-Cell Analysis, Transcriptome, Transplantation, Heterologous
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 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.

DOI10.1126/science.abc1944
Alternate JournalScience
PubMed ID33479121
PubMed Central IDPMC7983364
Grant ListU19 AI090023 / AI / NIAID NIH HHS / United States
K08 CA222625 / CA / NCI NIH HHS / United States
R01 DA036858 / DA / NIDA NIH HHS / United States
F32 GM125247 / GM / NIGMS NIH HHS / United States
R01 CA204302 / CA / NCI NIH HHS / United States
U54 CA224081 / CA / NCI NIH HHS / United States
RM1 HG009490 / HG / NHGRI NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
R01 CA211052 / CA / NCI NIH HHS / United States
R01 CA231300 / CA / NCI NIH HHS / United States
R01 CA169338 / CA / NCI NIH HHS / United States