Journal
CELL
Volume 185, Issue 11, Pages 1905-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2022.04.015
Keywords
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Categories
Funding
- NCI Cancer Target Discovery And Development (CTD<^>2)
- NIH Centers of Excellence in Genomic Science (CEGS)
- NCI Cancer Center Support (core) grant [P30-CA14051]
- Howard Hughes Medical Institute
- Ludwig Center at MIT
- Damon Runyon Cancer Research Foundation Postdoctoral Fellowship [DRG-2238-18]
- UCSF Discovery Fellowship
- Howard Hughes Medical Institute Gilliam Award
- NIH [F31NS115380]
- NIH NIGMS [F32GM125247, F32GM128366]
- Helen Hay Whitney Foundation Fellowship
- NIH-NCI [F31CA257349]
- Break Through Cancer Foundation
- Johnson & Johnson Lung Cancer Initiative
- Lustgarten Foundation
- National Institutes of Health [R01CA231300, U54CA224081, R01CA204302, R01CA211052, R01CA169338]
- [T32GM007287]
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Tumor evolution is driven by progressive genetic and epigenetic alterations, enabling unrestricted growth and expansion. This study provides insights into the hierarchical nature of tumor evolution through tracking phylogenetic relationships between cancer cells, allowing for in-depth studies of tumor progression.
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.
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