ELF3 Mediates IL-1α Induced Differentiation of Mesenchymal Stem Cells to Inflammatory iCAFs
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 07, 2021
- Source ID
- 10.1002/stem.3455
Entities
People
- David R. Rowley
- Linda Tran
- Rintu Thomas
- Truong Dang
Organizations
- Baylor College of Medicine
- Cancer Prevention and Research Institute of Texas
- Foundation for the National Institutes of Health
- United States Department of Defense