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Continuous lineage recording reveals rapid, multidirectional metastasis in a lung cancer xenograft model in mouse

By Jeffrey J Quinn, Matthew G Jones, Ross A. Okimoto, Michelle M. Chan, Nir Yosef, Trever G. Bivona, Jonathan S. Weissman

Posted 17 Apr 2020
bioRxiv DOI: 10.1101/2020.04.16.045245

Consequential events in cancer progression are typically rare and occur in the unobserved past. Detailed cell phylogenies can capture the history and chronology of such transient events - including metastasis. Here, we applied our Cas9-based lineage tracer to study metastatic progression in a lung cancer xenograft mouse model, revealing the underlying rates, routes, and patterns 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 highly aggressive populations, and these differences are associated with characteristic changes in transcriptional state, including differential expression of metastasis-related genes like IFI27 and ID3. We further show that metastases transit via tissue routes that are diverse, complex, and multidirectional, and identify examples of reseeding, seeding cascades, and parallel seeding topologies. More broadly, we demonstrate the power of next-generation lineage tracers to record cancer evolution at high resolution and vast scale. ### Competing Interest Statement J.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.

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