PT  - JOURNAL ARTICLE
AU  - Jeffrey J. Quinn
AU  - Matthew G. Jones
AU  - Ross A. Okimoto
AU  - Shigeki Nanjo
AU  - Michelle M. Chan
AU  - Nir Yosef
AU  - Trever G. Bivona
AU  - Jonathan S. Weissman
TI  - Single-cell lineages reveal the rates, routes, and drivers of metastasis in cancer xenografts
AID  - 10.1101/2020.04.16.045245
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.04.16.045245
4099  - http://biorxiv.org/content/early/2020/09/21/2020.04.16.045245.short
4100  - http://biorxiv.org/content/early/2020/09/21/2020.04.16.045245.full
AB  - Cancer progression is characterized by rare, transient events which are nonetheless highly consequential to disease etiology and mortality. Detailed cell phylogenies can recount the history and chronology of these critical events – including metastatic seeding. Here, we applied our Cas9-based lineage tracer to study the subclonal dynamics of metastasis in a lung cancer xenograft mouse model, revealing the underlying rates, routes, and drivers of metastasis. We report deeply resolved phylogenies for tens of thousands of metastatically disseminated cancer cells. We observe surprisingly diverse metastatic phenotypes, ranging from metastasis-incompetent to aggressive populations. These phenotypic distinctions result from pre-existing, heritable, and characteristic differences in gene expression, and we demonstrate that these differentially expressed genes can drive invasiveness. Furthermore, metastases transit via diverse, multidirectional tissue routes and seeding topologies. Our work demonstrates the power of tracing cancer progression at unprecedented resolution and scale.One Sentence Summary Single-cell lineage tracing and RNA-seq capture diverse metastatic behaviors and drivers in lung cancer xenografts in mice.Competing Interest StatementJ.S.W. is an advisor and/or has equity in KSQ Therapeutics, Maze Therapeutics, Amgen, Tenaya, and 5 AM Ventures. T.G.B. is an advisor to Novartis, Astrazeneca, Revolution Medicines, Array, Springworks, Strategia, Relay, Jazz, Rain and receives research funding from Novartis and Revolution Medicines.