Lineage tracing 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. ChanNir Yosef, Tyler Jacks, Jonathan S. Weissman

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1905-1923.e25
JournalCell
Volume185
Issue number11
DOIs
StatePublished - May 26 2022

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Keywords

  • fitness
  • genetically engineered mouse model
  • lineage tracing
  • lung cancer
  • phylogenetics
  • plasticity
  • single cell
  • transcriptome heterogeneity
  • tumor evolution

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