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Lineage tracing 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. (2022) Lineage tracing reveals the phylodynamics, plasticity, and paths of tumor evolution. Cell, 185 (11). pp. 1905-1923. ISSN 0092-8674. doi:10.1016/j.cell.2022.04.015. https://resolver.caltech.edu/CaltechAUTHORS:20220513-557902000

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[img] MS Excel (Table S2. Differential expression gene lists of individual Leiden clusters, related to Figures 3 and 6) - Supplemental Material
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[img] MS Excel (Table S3. Phylogenetic fitness majority vote gene association signatures and modules, related to Figures 3 and 6) - Supplemental Material
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Abstract

Tumor evolution is driven by the progressive acquisition of genetic and epigenetic alterations that enable uncontrolled growth and expansion to neighboring and distal tissues. 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 and tracked tumor evolution from single-transformed cells to metastatic tumors at unprecedented resolution. We found that the loss of the initial, stable alveolar-type2-like state was accompanied by a transient increase in plasticity. This was followed by the adoption of distinct transcriptional programs that enable rapid expansion and, ultimately, clonal sweep of stable subclones capable of metastasizing. Finally, tumors develop through stereotypical evolutionary trajectories, and perturbing additional tumor suppressors accelerates progression by creating novel trajectories. Our study elucidates the hierarchical nature of tumor evolution and, more broadly, enables in-depth studies of tumor progression.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.cell.2022.04.015DOIArticle
https://ars.els-cdn.com/content/image/1-s2.0-S0092867422004627-mmc1.xlsxPublisherTable S1. Tumor sample information, tree reconstruction parameters, and quality-control statistics, related to Figure 1
https://ars.els-cdn.com/content/image/1-s2.0-S0092867422004627-mmc2.xlsxPublisherTable S2. Differential expression gene lists of individual Leiden clusters, related to Figures 3 and 6
https://ars.els-cdn.com/content/image/1-s2.0-S0092867422004627-mmc3.xlsxPublisherTable S3. Phylogenetic fitness majority vote gene association signatures and modules, related to Figures 3 and 6
https://ars.els-cdn.com/content/image/1-s2.0-S0092867422004627-mmc4.xlsxPublisherTable S4. Evolutionary coupling and Leiden cluster proportions for individual tumors (including all KP, KPL, and KPA tumors) analyzed for Figures 5 and 6
https://ars.els-cdn.com/content/image/1-s2.0-S0092867422004627-mmc5.xlsxPublisherTable S5. Phylotime differential gene expression analysis, related to Figure 5. This table contains the differentially expressed genes following early to late Phylotime in tumors from Fate Cluster 1 and 2
https://ars.els-cdn.com/content/image/1-s2.0-S0092867422004627-mmc6.xlsxPublisherTable S6. Primers and plasmids used in this manuscript, related to STAR Methods
https://github.com/mattjones315/KPTracer-releaseRelated ItemCode
ORCID:
AuthorORCID
Yang, Dian0000-0002-8455-0047
Jones, Matthew G.0000-0002-0363-4493
Rideout, William M., III0000-0001-7376-5248
Min, Kyung Hoi (Joseph)0000-0003-0894-4017
Ho, Raymond0000-0002-6043-4287
Wu, Wei0000-0002-6556-067X
Replogle, Joseph M.0000-0003-1832-919X
Page, Jennifer L.0000-0002-5822-0298
Quinn, Jeffrey J.0000-0001-6497-1605
Qiu, Xiaojie0000-0002-7881-5395
Chen, Michael Z.0000-0002-2998-9014
Freed-Pastor, William A.0000-0002-7377-2111
McGinnis, Christopher S.0000-0001-6923-9341
Gartner, Zev J.0000-0001-7803-1219
Chow, Eric D.0000-0001-8079-918X
Bivona, Trever G.0000-0001-5734-4128
Yosef, Nir0000-0001-9004-1225
Jacks, Tyler0000-0001-5785-8911
Weissman, Jonathan S.0000-0003-2445-670X
Additional Information:© 2022 The Authors. Published by Elsevier Under a Creative Commons license. Attribution 4.0 International (CC BY 4.0). Received 21 September 2021, Revised 9 February 2022, Accepted 8 April 2022, Available online 5 May 2022. We thank Marco Jost, Jeffrey Hussmann, Luke Koblan, Yocef Ouadah, Lindsay LaFave, Luke Gilbert, Julien Sage, Xin Ye, Brittany Adamson, Sebastian Prillo, and all members of the Weissman, Jacks, and Yosef labs for helpful discussions. We thank Liming Tao, Demi Sandel, Caterina Colon, Laura Liao, Kieren Marini, Alejandro Sweet-Cordero, Danielle Dionne, Toni Delorey, Jenna Pfiffner-Borges, Orit Rozenblatt-Rosen, and Aviv Regev for technical help. We thank Joan Kanter, Cristen Muresan, Karen Yee, and Judy Teixeira for administrative support. We thank 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, MIT Koch Institute Animal Facility, and 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 predoctoral 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, Johnson & Johnson Lung Cancer Initiative, and The Lustgarten 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 computational approaches, and M.G.J. implemented these approaches. M.G.J., K.H.(J.)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., and 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. Declaration of interests. J.S.W. declares outside interest in 5 AM Venture, Amgen, Chroma Medicine, KSQ Therapeutics, Maze Therapeutics, Tenaya Therapeutics, and Tessera Therapeutics. T.J. is a member of the Board of Directors of Amgen and Thermo Fisher Scientific, is a co-founder of Dragonfly Therapeutics and T2 Biosystems, and is the president of Break Through Cancer. T.J. serves on the Scientific Advisory Board of Dragonfly Therapeutics, SQZ Biotech, and Skyhawk Therapeutics. None of these affiliations represent a conflict of interest with respect to this study. T.G.B. is an advisor to Array BioPharma, Revolution Medicines, Novartis, AstraZeneca, Takeda, Springworks, Jazz Pharmaceuticals, Relay Therapeutics, Rain Therapeutics, and 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. Inclusion and diversity One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. One or more of the authors of this paper received support from a program designed to increase minority representation in science. Data and code availability. Raw single-cell RNA-sequencing data has been deposited at the NCBI Sequence Read Archive database and are publicly available as of the date of the publication. Accession numbers are listed in the key resources table. Processed single-cell data, reconstructed phylogenies, derived statistics, interactive VISION (DeTomaso et al., 2019) and PhyloVision (Jones et al., 2022) reports have been deposited at Zenodo and are publicly available as of the date of the publication. DOIs are listed in the key resources table. All original code is available on Github (https://github.com/mattjones315/KPTracer-release) and has been deposited at Zenodo and is publicly available as of the date of the publication. DOIs are listed in the key resources table. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.
Funders:
Funding AgencyGrant Number
NIHP30-CA14051
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
Johnson & Johnson Lung Cancer InitiativeUNSPECIFIED
Lustgarten FoundationUNSPECIFIED
NIHR01CA231300
NIHU54CA224081
NIHR01CA204302
NIHR01CA211052
NIHR01CA169338
Subject Keywords:lineage tracing; tumor evolution; phylogenetics; single cell; fitness; plasticity; transcriptome heterogeneity; genetically engineered mouse model; lung cancer
Issue or Number:11
DOI:10.1016/j.cell.2022.04.015
Record Number:CaltechAUTHORS:20220513-557902000
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20220513-557902000
Official Citation: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, Lineage tracing reveals the phylodynamics, plasticity, and paths of tumor evolution, Cell, Volume 185, Issue 11, 2022, Pages 1905-1923.e25, ISSN 0092-8674, https://doi.org/10.1016/j.cell.2022.04.015. (https://www.sciencedirect.com/science/article/pii/S0092867422004627)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:114739
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:16 May 2022 16:50
Last Modified:08 Jun 2022 18:03

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