ELF3 mediates IL-1α induced differentiation of mesenchymal stem cells to inflammatory iCAFs

Stem Cells. 2021 Sep 14. doi: 10.1002/stem.3455. Online ahead of print.

Abstract

Stromal cells in the tumor microenvironment regulate the immune landscape and tumor progression. Yet, the ontogeny and heterogeneity of reactive stromal cells within tumors is not well understood. Carcinoma-associated fibroblasts exhibiting an inflammatory phenotype (iCAFs) have been identified within multiple cancers, however mechanisms that lead to their recruitment and differentiation also remain undefined. Targeting these mechanisms therapeutically may be important in managing cancer progression. Here, we identify the ELF3 transcription factor as the canonical mediator of IL-1α-induced differentiation of prostate mesenchymal stem cells to an iCAF phenotype, typical of the tumor microenvironment. Furthermore, IL-1α-induced iCAFs were subsequently refractive to TGF-β1 induced trans-differentiation to a myofibroblast phenotype (myCAF), another key carcinoma-associated fibroblast subtype typical of reactive stroma in cancer. Restricted trans-differentiation was associated with phosphorylation of the YAP protein, indicating that interplay between ELF3 action and activation of the Hippo pathway are critical for restricting trans-differentiation of iCAFs. Together, these data show that the IL-1α / ELF3 / YAP pathways are coordinate for regulating inflammatory carcinoma-associated fibroblast differentiation. © AlphaMed Press 2021 SIGNIFICANCE STATEMENT: The mechanisms determining the heterogeneity of stromal populations in the tumor microenvironment are poorly understood. The present study identifies ELF3 as an essential transcription factor in the differentiation of a key pro-inflammatory stromal cell type and identifies mesenchymal stem cells as a progenitor of inflammatory carcinoma-associated fibroblasts.

Keywords: ELF3 transcription factor; Hippo pathway; carcinoma-associated fibroblast; interleukin 1 alpha; pro-inflammatory fibroblast; prostate cancer; reactive stroma; tumor microenvironment.