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

• Published in: Cell 2022-05, Vol.185 (11), p.1905-1923.e25
• Main Authors: Yang, Dian, Jones, Matthew G., Naranjo, Santiago, Rideout, William M., Min, Kyung Hoi (Joseph), Ho, Raymond, Wu, Wei, Replogle, Joseph M., Page, Jennifer L., Quinn, Jeffrey J., Horns, Felix, Qiu, Xiaojie, Chen, Michael Z., Freed-Pastor, William A., McGinnis, Christopher S., Patterson, David M., Gartner, Zev J., Chow, Eric D., Bivona, Trever G., Chan, Michelle M., Yosef, Nir, Jacks, Tyler, Weissman, Jonathan S.
• Format: Article
• Language: English
• Subjects: Animals; Exome Sequencing; fitness; Genes, ras; genetically engineered mouse model; lineage tracing; lung cancer; Mice; Neoplasms - genetics; phylogenetics; Phylogeny; plasticity; single cell; transcriptome heterogeneity; tumor evolution
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2022.04.015

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. [Display omitted] •KP-tracer mice enable continuous, high-resolution in vivo cancer lineage tracing•Rare subclones with distinct expression programs expand during tumor evolution•Lineage tracing reveals cellular plasticity and evolutionary paths•Metastases are derived from spatially localized, expanding subclones of the tumor Yang et al. developed a genetically engineered mouse model of lung cancer capable of continuous lineage tracing with single-cell RNA-seq readout. They identified the subclonal dynamics of tumors, gene modules underlying expansion, transient increases in cellular plasticity, stereotypical evolutionary paths to aggressiveness across tumor genotypes, and the spatial and phylogenetic origins of metastases.