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 pro-vided 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 immuno-modulatory (IM) CAFs. These superclusters are recapitulated across multiple tissue types and species. Se-lective 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.

Automated summary

This study investigates the heterogeneity of cancer-associated fibroblasts (CAFs) using a comprehensive multiomics approach, identifying three superclusters of CAFs. The study finds that disrupting mechanical force or immune checkpoint inhibition therapy leads to changes in the distribution of CAF subpopulations and affects tumor growth. The results of this research are important for expanding our understanding of CAF biology, identifying regulatory pathways in CAF differentiation, and discovering therapeutic targets for tumor treatment.