A Caltech Library Service

Lineage Recording Reveals the Phylodynamics, Plasticity and Paths of Tumor Evolution

Yang, Dian and Jones, Matthew G. and Naranjo, Santiago and Rideout, William M., III and Min, Kyung Hoi Joseph and Ho, Raymond and Wu, Wei and Replogle, Joseph M. and Page, Jennifer L. and Quinn, Jeffrey J. and Horns, Felix and Qiu, Xiaojie and Chen, Michael Z. and Freed-Pastor, William A. and McGinnis, Christopher S. and Patterson, David M. and Gartner, Zev J. and Chow, Eric D. and Bivona, Trever G. and Chan, Michelle M. and Yosef, Nir and Jacks, Tyler and Weissman, Jonathan S. (2021) Lineage Recording Reveals the Phylodynamics, Plasticity and Paths of Tumor Evolution. Cold Spring Harbor Laboratory . (Unpublished)

[img] PDF - Submitted Version
Creative Commons Attribution Non-commercial No Derivatives.

[img] PDF (Supplementary Figures) - Supplemental Material
Creative Commons Attribution Non-commercial No Derivatives.


Use this Persistent URL to link to this item:


Tumor evolution is driven by the progressive acquisition of genetic and epigenetic alterations that enable uncontrolled growth, expansion to neighboring and distal tissues, and therapeutic resistance. The study of phylogenetic relationships between cancer cells provides key insights into these processes. Here, we introduced an evolving lineage-tracing system with a single-cell RNA-seq readout into a mouse model of Kras;Trp53(KP)-driven lung adenocarcinoma which enabled us to track tumor evolution from single transformed cells to metastatic tumors at unprecedented resolution. We found that loss of the initial, stable alveolar-type2-like state was accompanied by transient increase in plasticity. This was followed by adoption of distinct fitness associated transcriptional programs which enable rapid expansion and ultimately clonal sweep of rare, stable subclones capable of metastasizing to distant sites. Finally, we showed that tumors develop through stereotypical evolutionary trajectories, and perturbing additional tumor suppressors accelerates tumor progression by creating novel evolutionary paths. Overall, our study elucidates the hierarchical nature of tumor evolution, and more broadly enables the in-depth study of tumor progression.

Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper
Yang, Dian0000-0002-8455-0047
Jones, Matthew G.0000-0002-0363-4493
Yosef, Nir0000-0001-9004-1225
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. We thank Marco Jost, Jeffrey Hussmann, Luke Koblan, Yocef Ouadah, Lindsay LaFave, Luke Gilbert, Julien Sage, Xin Ye, Brittany Adamson and all members of the Weissman, Jacks and Yosef labs for helpful discussions. We thank Liming Tao, Demi Sandel, Caterina Colon, Laura Liao, Danielle Dionne, Toni Delorey, Jenna Pfiffner-Borges, Orit Rozenblatt-Rosen and Aviv Regev for technical help. We thank Joan Kanter, Cristen Muresan, Karen Yee, Judy Teixeira for administrative support. We thank Michelle Tan, the UCSF Center for Advanced Technology and the Chan Zuckerberg Biohub for assistance with high-throughput sequencing. We thank UCSF Flow Cytometry Facility, UCSF Cell and Genome Engineering Core, UCSF Center for Advanced Technology, MIT Koch Institute Animal Facility, MIT Swanson Biotechnology Center Flow Cytometry Facility. Research reported in this publication was supported in part by the NCI Cancer Target Discovery And Development (CTD^2) and the NIH Centers of Excellence in Genomic Science (CEGS), the NCI Cancer Center Support (core) grant P30-CA14051, the Howard Hughes Medical Institute, and the Ludwig Center at MIT. D.Y. is supported by a Damon Runyon Cancer Research Foundation Postdoctoral Fellowship (DRG-2238-18). M.G.J. is supported by a UCSF Discovery Fellowship. S.N. is supported by a pre-doctoral Training Grant T32GM007287 and a Howard Hughes Medical Institute Gilliam Award. J.M.R. is supported by the NIH F31NS115380. J.J.Q. is supported by a NIH NIGMS F32GM125247. F.H. is supported by a Helen Hay Whitney Foundation Fellowship. C.S.M. is supported by the NIH-NCI F31CA257349. D.M.P. is supported by the NIH-NIGMS F32GM128366. M.M.C. is a Gordon and Betty Moore fellow of the Life Sciences Research Foundation. J.S.W. and T.J. were supported by the Howard Hughes Medical Institute and the Ludwig Center at MIT. T.J. is supported by the Break Through Cancer Foundation. T.G.B received funding support from the National Institutes of Health (R01CA231300, U54CA224081, R01CA204302, R01CA211052 and R01CA169338). AUTHOR CONTRIBUTIONS. D.Y., M.G.J., T.J. N.Y. and J.S.W. conceived of, designed and led the analysis of the KP-tracer project. D.Y. constructed lineage tracing targeting vectors and engineered the mouse ES cells with the help from J.L.P. and W.F-P.. W.M.R III generated the KP-Tracer chimeric mice and S.N. transduced the mice. D.Y. and S.N. harvested tumors. D.Y. generated the single-cell RNA-seq data with help from C.S.M., D.M.P., Z.J.G. and E.D.C.. W.W. and T.G.B analyzed the TCGA data. M.G.J. and N.Y. conceived of the expansion-detection, Phylotime, and Evolutionary Coupling statistics and M.G.J. implemented these approaches with supervision from N.Y.. M.G.J., K.H.M. and D.Y. analyzed the data with help from F.H., X.Q., J.J.Q., R.H., M.Z.C., and M.M.C.. D.Y., M.G.J., N.Y., T.J., J.S.W. interpreted results. D.Y., M.G.J., T.J., N.Y. and J.S.W. wrote the manuscript, with input from all authors. J.S.W., T.J. and N.Y. supervised the project. Competing Interest Statement. J.S.W. declares outside interest in 5 AM Venture, Amgen, Chroma Medicine, KSQ Therapeutics, Maze Therapeutics, Tenaya Therapeutics, Tessera Therapeutics and Third Rock Ventures. T.J. is a member of the Board of Directors of Amgen and Thermo Fisher Scientific. He is also a co-Founder of Dragonfly Therapeutics and T2 Biosystems. T.J. serves on the Scientific Advisory Board of Dragonfly Therapeutics, SQZ Biotech, and Skyhawk Therapeutics. He is the President of Break Through Cancer. None of these affiliations represent a conflict of interest with respect to the design or execution of this study or interpretation of data presented in this manuscript. T.J. laboratory currently also receives funding from the Johnson & Johnson Lung Cancer Initiative and The Lustgarten Foundation for Pancreatic Cancer Research, but this funding did not support the research described in this manuscript. T.G.B. is an advisor to Array Biopharma, Revolution Medicines, Novartis, AstraZeneca, Takeda, Springworks, Jazz Pharmaceuticals, Relay Therapeutics, Rain Therapeutics, Engine Biosciences, and receives research funding from Novartis, Strategia, Kinnate, and Revolution Medicines. J.M.R. consults for Maze Therapeutics and Waypoint Bio. Z.J.G. is an equity holder in Scribe biosciences and Provenance bio, and a member of the SAB of Serotiny Bio.
Funding AgencyGrant Number
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Massachusetts Institute of Technology (MIT)UNSPECIFIED
Damon Runyon Cancer Research FoundationDRG-2238-18
University of California, San FranciscoUNSPECIFIED
NIH Predoctoral FellowshipT32GM007287
NIH Postdoctoral FellowshipF31NS115380
NIH Postdoctoral FellowshipF32GM125247
Helen Hay Whitney FoundationUNSPECIFIED
NIH Postdoctoral FellowshipF31CA257349
NIH Postdoctoral FellowshipF32GM128366
Life Sciences Research FoundationUNSPECIFIED
Break Through Cancer FoundationUNSPECIFIED
Subject Keywords:Lineage Tracing; Tumor Evolution; Phylogenetics; Single Cell; Fitness; Plasticity; Transcriptome Heterogeneity; Genetically Engineered Mouse Model; Lung Cancer
Record Number:CaltechAUTHORS:20211015-222206199
Persistent URL:
Official Citation:Lineage Recording Reveals the Phylodynamics, Plasticity and Paths of Tumor Evolution Dian Yang, Matthew G Jones, Santiago Naranjo, William M Rideout, Kyung Hoi Joseph Min, Raymond Ho, Wei Wu, Joseph M Replogle, Jennifer L Page, Jeffrey J Quinn, Felix Horns, Xiaojie Qiu, Michael Z Chen, William A Freed-Pastor, Christopher S McGinnis, David M Patterson, Zev J Gartner, Eric D Chow, Trever G Bivona, Michelle M Chan, Nir Yosef, Tyler Jacks, Jonathan S Weissman bioRxiv 2021.10.12.464111; doi:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:111484
Deposited By: George Porter
Deposited On:18 Oct 2021 17:01
Last Modified:18 Oct 2021 17:01

Repository Staff Only: item control page