Lineage tracing reveals the phylodynamics, plasticity, and paths of tumor evolution. Author Dian Yang, Matthew Jones, Santiago Naranjo, William Rideout, Kyung Min, Raymond Ho, Wei Wu, Joseph Replogle, Jennifer Page, Jeffrey Quinn, Felix Horns, Xiaojie Qiu, Michael Chen, William Freed-Pastor, Christopher McGinnis, David Patterson, Zev Gartner, Eric Chow, Trever Bivona, Michelle Chan, Nir Yosef, Tyler Jacks, Jonathan Weissman Publication Year 2022 Type Journal Article 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 Animals, Mice, Phylogeny, Neoplasms, Genes, ras, Exome Sequencing Journal Cell Volume 185 Issue 11 Pages 1905-1923.e25 Date Published 2022 May 26 ISSN Number 1097-4172 DOI 10.1016/j.cell.2022.04.015 Alternate Journal Cell PMCID PMC9452598 PMID 35523183 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML