Multiomic analysis reveals conservation of cancer-associated fibroblast phenotypes across species and tissue of origin.

Cancer-associated fibroblasts (CAFs) are integral to the solid tumor microenvironment. CAFs were once thought to be a relatively uniform population of matrix-producing cells, but single-cell RNA sequencing has revealed diverse CAF phenotypes. Here, we further probed CAF heterogeneity with a comprehensive multiomics approach. Using paired, same-cell chromatin accessibility and transcriptome analysis, we provided an integrated analysis of CAF subpopulations over a complex spatial transcriptomic and proteomic landscape to identify three superclusters: steady state-like (SSL), mechanoresponsive (MR), and immunomodulatory (IM) CAFs. These superclusters are recapitulated across multiple tissue types and species. Selective disruption of underlying mechanical force or immune checkpoint inhibition therapy results in shifts in CAF subpopulation distributions and affected tumor growth. As such, the balance among CAF superclusters may have considerable translational implications. Collectively, this research expands our understanding of CAF biology, identifying regulatory pathways in CAF differentiation and elucidating therapeutic targets in a species- and tumor-agnostic manner.
Competing Interests: Declaration of interests D.S.F., M.J., D.D., H.Y.C., J.A.N., and M.T.L. have applied for a provisional patent through Stanford University related to the research presented in this manuscript. H.Y.C. is a co-founder of Accent Therapeutics, Boundless Bio, and Cartography Biosciences, and an advisor of 10X Genomics, Arsenal Biosciences, and Spring Discovery. K.E.Y. is a consultant for Cartography Biosciences.
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