Distinct cancer-associated fibroblast states drive clinical outcomes in high-grade serous ovarian cancer and are regulated by TCF21

Abstract

Recent studies indicate that cancer-associated fibroblasts (CAFs) are phenotypically and functionally heterogeneous. However, little is known about CAF subtypes and the roles they play in cancer progression. Here we identify and characterize two CAF subtypes that coexist within high grade serous ovarian cancers: Fibroblast activation protein (FAP)-high (FH) CAFs resemble the classical myofibroblast-type CAF, whereas FAP-low (FL) CAFs possesses a preadipocyte-like molecular signature. Patients with predominantly FH CAFs have significantly worse outcomes than patients with predominantly FL CAFs. FH CAFs contract collagen gels and aggressively promote proliferation, invasion and therapy resistance of cancer cells, whereas FL CAFs do not. Overexpression of the FL-specific transcription factor TCF21 in FH CAFs decreases their ability to promote gel contraction, invasion, and in vivo tumor growth. Understanding CAF subtypes in more detail could lead to better patient stratification and novel therapeutic strategies.