Pan-cancer single-cell RNA-seq identifies recurring programs of cellular heterogeneity

Cultured cell lines are the workhorse of cancer research, but the extent to which they recapitulate the heterogeneity observed among malignant cells in tumors is unclear. Here researchers from the Weizmann Institute of Science used multiplexed single-cell RNA-seq to profile 198 cancer cell lines from 22 cancer types. They identified 12 expression programs that are recurrently heterogeneous within multiple cancer cell lines. These programs are associated with diverse biological processes, including cell cycle, senescence, stress and interferon responses, epithelial–mesenchymal transition and protein metabolism. Most of these programs recapitulate those recently identified as heterogeneous within human tumors. The researchers prioritized specific cell lines as models of cellular heterogeneity and used them to study subpopulations of senescence-related cells, demonstrating their dynamics, regulation and unique drug sensitivities, which were predictive of clinical response. This work describes the landscape of heterogeneity within diverse cancer cell lines and identifies recurrent patterns of heterogeneity that are shared between tumors and specific cell lines.

Characterizing expression heterogeneity within cell lines by multiplexed scRNA-seq

Fig. 1

a, Workflow of the multiplexing strategy used to profile multiple cell lines simultaneously. Cell lines were pooled and profiled by droplet-based scRNA-seq. We used reference CCLE data to assign cells to the most similar cell line based on their overall gene expression and SNP pattern. Expr., expression; endo., endometrial; esoph., eshophageal. b, t-SNE plot of a representative pool demonstrating the robustness of cell line assignment. Cells with inconsistent assignments (by gene expression and SNPs) are denoted and were excluded from further analyses. c, Distribution of the cancer types that were profiled.

Kinker GS, Greenwald AC, Tal R, Orlova Z, Cuoco MS, McFarland JM, Warren A, Rodman C, Roth JA, Bender SA, Kumar B, Rocco JW, Fernandes PACM, Mader CC, Keren-Shaul H, Plotnikov A, Barr H, Tsherniak A, Rozenblatt-Rosen O, Krizhanovsky V, Puram SV, Regev A, Tirosh I. (2020) Pan-cancer single-cell RNA-seq identifies recurring programs of cellular heterogeneity. Nat Genet 52(11):1208-1218. [abstract]

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