Single-cell lineages reveal the rates, routes, and drivers of metastasis in cancer xenografts

Science. 2021 Feb 26;371(6532):eabc1944. doi: 10.1126/science.abc1944. Epub 2021 Jan 21.


Detailed phylogenies of tumor populations can recount the history and chronology of critical events during cancer progression, such as metastatic dissemination. We applied a Cas9-based, single-cell lineage tracer to study the rates, routes, and drivers of metastasis in a lung cancer xenograft mouse model. We report deeply resolved phylogenies for tens of thousands of cancer cells traced over months of growth and dissemination. This revealed stark heterogeneity in metastatic capacity, arising from preexisting and heritable differences in gene expression. We demonstrate that these identified genes can drive invasiveness and uncovered an unanticipated suppressive role for KRT17 We also show that metastases disseminated via multidirectional tissue routes and complex seeding topologies. Overall, we demonstrate the power of tracing cancer progression at subclonal resolution and vast scale.

Publication types

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

MeSH terms

  • Animals
  • CRISPR-Cas Systems
  • Cell Line, Tumor
  • Cell Lineage
  • Clone Cells
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Keratin-17 / genetics
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology*
  • Mice
  • Neoplasm Invasiveness / genetics
  • Neoplasm Metastasis* / genetics
  • Neoplasm Metastasis* / pathology
  • Neoplasm Seeding
  • Neoplasm Transplantation
  • Phenotype
  • RNA-Seq
  • Single-Cell Analysis
  • Transcriptome
  • Transplantation, Heterologous


  • KRT17 protein, human
  • Keratin-17