Integrated single‐cell RNA sequencing analyses suggest developmental paths of cancer‐associated fibroblasts with gene expression dynamics

Dear Editor, The origin and the phenotypic heterogeneity of cancer-associated fibroblasts (CAFs) are suggested by various models, but not completely understood.1–3 We used six publicly available single-cell RNA sequencing (scRNA-seq) datasets of five cancer types (except breast cancer) on CAFs and corresponding normal fibroblasts (NFs) (Figure 1A)4–6 and established a comprehensive model for CAF development and gene expression dynamics over time. SEE PDF] Based on the global gene expression patterns, breast cancer CAFs were markedly different from CAFs from other organs (Figure 1C). Furthermore, the known CAF-related genes in various functional categories were upregulated only in the CAF clusters with high PRRX1 activity (Figure 1F). [...]we labeled these CAFs as “perpetually activated CAFs” (paCAFs), which were constituted approximately 50%–80% of all CAFs in each dataset (Figure 1D). [...]as paCAFs were identified based on the expression of PRRX1 and other CAF-related markers, the results did not fully reflect the activation status of heterogeneous CAFs.