Myeloid cell-derived TGF-beta signaling regulates ECM deposition in mammary carcinoma via adenosine-dependent mechanisms

Abstract

TGFβ plays a crucial role in the tumor microenvironment by regulating cell-cell and cell-stroma interactions. We previously demonstrated that TGFβ signaling on myeloid cells regulates expression of CD73, a key enzyme for production of adenosine, a pro-tumorigenic metabolite implicated in regulation of tumor cell behaviors, immune response, and angiogenesis. Here, using an MMTV-PyMT mouse mammary tumor model, we discovered that deletion of TGFβ signaling on myeloid cells (PyMT/TGFβRII ^LysM) affects ECM formation in tumor tissue, specifically increasing collagen and decreasing fibronectin deposition. These changes were associated with mitigated tumor growth and reduced metastases. Reduced TGFβ signaling on fibroblasts was associated with their proximity to CD73 ⁺ myeloid cells in tumor tissue. Consistent with these findings, adenosine significantly downregulated TGFβ signaling on fibroblasts, an effect regulated by A _2A and A _2B adenosine receptors. METABRIC data set analysis revealed that patients with triple-negative breast cancer and basal type harbored a similar signature of adenosine and ECM profiles: high expression of A _2B adenosine receptors correlated with decreased expression of Col1 and was associated with poor outcome. Taken together, our studies reveal a new role for TGFβ signaling on myeloid cells in tumorigenesis. This discovered crosstalk between TGFβ/CD73 on myeloid cells and TGFβ signaling on fibroblasts can contribute to ECM remodeling and pro-tumorigenic actions of CAF.