αSMA + fibroblasts suppress Lgr5 + cancer stem cells and restrain colorectal cancer progression.

The development and progression of solid tumors is dependent on cancer cell autonomous drivers and the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) in the TME possess both tumor-promoting and tumor-restraining functions. In the current study, we interrogated the role of αSMA ⁺ CAFs in a genetic mouse model of metastatic colorectal cancer (CRC). Selective depletion of αSMA ⁺ CAFs resulted in increased tumor invasiveness, lymph node metastasis, and reduced overall survival. Depletion of αSMA ⁺ CAFs reduced BMP4 and increased TGFβ1 secretion from stromal cells, and was associated with increased Lgr5 ⁺ cancer stem-like cells (CSCs) and the generation of an immunosuppressive TME with increased frequency of Foxp3 ⁺ regulatory T cells and suppression of CD8 ⁺ T cells. This study demonstrates that αSMA ⁺ CAFs in CRC exert tumor-restraining functions via BMP4/TGFβ1 paracrine signaling that serves to suppress Lgr5 ⁺ CSCs and promote anti-tumor immunity, ultimately limiting CRC progression.