Pan-cancer single-cell analysis reveals the heterogeneity and plasticity of cancer-associated fibroblasts in the tumor microenvironment

Abstract

Cancer-associated fibroblasts (CAFs) are the predominant components of the tumor microenvironment (TME) and influence cancer hallmarks, but without systematic investigation on their ubiquitous characteristics across different cancer types. Here, we perform pan-cancer analysis on 226 samples across 10 solid cancer types to profile the TME at single-cell resolution, illustrating the commonalities/plasticity of heterogenous CAFs. Activation trajectory of the major CAF types is divided into three states, exhibiting distinct interactions with other cell components, and relating to prognosis of immunotherapy. Moreover, minor CAF components represent the alternative origin from other TME components (e.g., endothelia and macrophages). Particularly, the ubiquitous presentation of endothelial-to-mesenchymal transition CAF, which may interact with proximal SPP1+ tumor-associated macrophages, is implicated in endothelial-to-mesenchymal transition and survival stratifications. Our study comprehensively profiles the shared characteristics and dynamics of CAFs, and highlight their heterogeneity and plasticity across different cancer types. Browser of integrated pan-cancer single-cell information is available at https://gist-fgl.github.io/sc-caf-atlas/.

Cancer-associated fibroblasts, and clinicopathological characteristics and prognosis of gastric cancer: A systematic review and meta-analysis

“…Inflammatory CAFs and ECM CAFs show enhanced invasive activity and mobilize surrounding immune cells to construct a tumor-friendly microenvironment, which is associated with poor prognosis of GC. Recently, a pan-cancer single-cell analysis reveal the heterogeneity of CAF and revealed their different activation pathways and roles (46). The article proposed that a high proportion of FAP+ CAFs was significantly associated with poor OS, which was similar to the conclusion obtained in our study.…”

A Cancer-Associated Fibroblast Classification Framework for Single-Cell Data

“…The fact that we were able to define almost all CAF phenotypes in datasets from multiple cancer types, both when analysed individually and when analysed as an integrated dataset, strongly suggests that CAF phenotypes are generalizable across cancer types. A recent pan-cancer study has compared plasticity of fibroblasts and showed that distinct features are shared between the different tumour sites 39 .This may extend also to subtypes; for example, our breast cancer dataset mainly consisted of luminal B cancer, but the CAF phenotypes we defined were also present in samples of the other subtypes. Still, our data also indicate that different cancer types may be dominated by different CAF types.…”

Phase-specific signatures of wound fibroblasts and matrix patterns define cancer-associated fibroblast subtypes

“…Since we showed that time-resolved wound signatures could act as markers for whole tumor states, it is possible that genes that are overexpressed in wound fibroblasts at different phases of healing could act as markers for CAF subtypes, which are highly heterogeneous within and across tumor types [22, 23]. Therefore, we first correlated the inflammatory, proliferative and resolution phase wound genes with the gene expression signatures of wound fibroblasts from different phases of healing by re-analyzing the transcriptomes of wound fibroblasts from early- and late-stage large excisional mouse wounds [24] (Table S1).…”