Pan-Cancer Single Cell RNA-Seq Uncovers Recurring Programs of Cellular Heterogeneity

Cultured cell lines are the workhorse of cancer research, although they do not model certain aspects of human tumors, such as their microenvironment. It is unclear to what extent cancer cell lines recapitulate the cellular heterogeneity that exists within tumors. Here, we used a multiplexing approach to profile ~200 cancer cell lines by single cell RNA-seq. We uncovered recurrent expression programs primarily driven by epigenetic plasticity that are associated with diverse biological processes. Many of the recurrent expression programs we identified, including senescence and epithelial-to-mesenchymal transitions (EMT), recapitulated in vivo expression programs observed in tumors.

Additionally, we prioritize certain cell lines as model systems of cellular plasticity, and demonstrate the dynamics, regulation and vulnerabilities of a novel cancer senescence program, EpiSen. Unlike classical senescence, EpiSen is dynamic and does not represent complete exit from cell cycle. We demonstrate differential drug sensitivity between the EpiSen high and EpiSen low states in two head and neck cancer cell lines and highlight clinically relevant vulnerabilities. Taken together, our work demonstrates that many cancer cell lines harbor significant transcriptional diversity in the absence of a tumor microenvironment and that an understanding of this diversity can be leveraged in the rational selection of optimal model systems.