Lineage tracing reveals the phylodynamics, plasticity, and paths of tumor evolution

Dian Yang; Matthew G Jones; Santiago Naranjo; William M Rideout 3rd; 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

doi:10.1016/j.cell.2022.04.015

Lineage tracing reveals the phylodynamics, plasticity, and paths of tumor evolution

Cell. 2022 May 26;185(11):1905-1923.e25. doi: 10.1016/j.cell.2022.04.015. Epub 2022 May 5.

Authors

Dian Yang¹, Matthew G Jones², Santiago Naranjo³, William M Rideout 3rd⁴, Kyung Hoi Joseph Min⁵, Raymond Ho¹, Wei Wu⁶, Joseph M Replogle⁷, Jennifer L Page⁸, Jeffrey J Quinn⁹, Felix Horns¹⁰, Xiaojie Qiu¹, Michael Z Chen¹¹, William A Freed-Pastor¹², Christopher S McGinnis¹³, David M Patterson¹⁴, Zev J Gartner¹⁵, Eric D Chow¹⁶, Trever G Bivona⁶, Michelle M Chan¹⁷, Nir Yosef¹⁸, Tyler Jacks¹⁹, Jonathan S Weissman²⁰

Affiliations

¹ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
² Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Biological and Medical Informatics Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA; Integrative Program in Quantitative Biology, University of California, San Francisco, San Francisco, CA 94158, USA; Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
³ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁴ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁵ Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁶ Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
⁷ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA 94158, USA; Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.
⁸ Cell and Genome Engineering Core, University of California San Francisco, San Francisco, CA 94158, USA.
⁹ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
¹⁰ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
¹¹ Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Medical Scientist Training Program, Harvard Medical School, Boston, MA 02115, USA.
¹² David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
¹³ Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
¹⁴ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
¹⁵ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA; Chan Zuckerberg BioHub Investigator, University of California, San Francisco, San Francisco, CA 94158, USA; Center for Cellular Construction, University of California, San Francisco, San Francisco, CA 94158, USA.
¹⁶ Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; Center for Advanced Technology, University of California, San Francisco, San Francisco, CA 94158, USA.
¹⁷ Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
¹⁸ Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Chan Zuckerberg BioHub Investigator, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Electrical Engineering and Computer Science, University of California Berkeley, Berkeley, CA 94720, USA; Ragon Institute of Massachusetts General Hospital, MIT and Harvard University, Cambridge, MA, USA. Electronic address: [email protected].
¹⁹ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address: [email protected].
²⁰ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address: [email protected].

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.

Keywords: fitness; genetically engineered mouse model; lineage tracing; lung cancer; phylogenetics; plasticity; single cell; transcriptome heterogeneity; tumor evolution.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Exome Sequencing
Genes, ras
Mice
Neoplasms* / genetics
Phylogeny

Abstract

Publication types

MeSH terms

Grants and funding