Loss of BMPR1a in fibroblasts restricts breast cancer progression and alters the immune tumor microenvironment.

Abstract The Bone Morphogenetic Protein (BMP) pathway is a member of the TGFβ signaling family and has complex roles in cancer. The dichotomous role of BMPs as both tumor promoters and suppressors appears to be largely context based in both the cancer cell and the surrounding microenvironment. Fibroblasts who are activated in the tumor microenvironment to become cancer associated fibroblasts (CAFs) also carry out diverse functions to support tumor progression, including matrix generation and remodeling as well as angiogenesis and immune cell regulation. We found that conditional deletion of the BMP signaling receptor BMPR1a in mammary fat pad derived fibroblasts (via FSP-Cre) restricts tumor progression in a C57BL/6 syngeneic mammary fat pad MMTV-PyMT breast cancer mouse model. Specific changes in the architecture of collagen were found in the tumors with loss of BMPR1a signaling in CAFs. We analyzed these mammary fat pad tumors using Vectra multiplexed immunohistochemistry (mIHC) to evaluate differential cell phenotypes, spatial distribution, and high-dimensional cell clustering dependent on BMP signaling in CAFs. Vectra mIHC panels were designed to perform tumor and stromal cell classification, immune cell profiling, immune cell function, cell signaling and vascular analysis. Based on Vectra mIHC, changes in myeloid cell populations and immune cell interactions in the tumors were observed with differential BMPR1a expression in CAFs. We profiled the secretome of mammary fat pad fibroblasts and found distinct chemokine and cytokine secretion was altered related on BMPR1a loss. These results indicate a unique necessity for BMP signaling in fibroblasts during tumor progression to influence the stroma, matrix, and immune components of the tumor microenvironment. Citation Format: Claire Louise Ihle, Meredith D. Provera, Parvanee A. Karimpour, Desiree M. Straign, Erin Smith, Philip Owens. Loss of BMPR1a in fibroblasts restricts breast cancer progression and alters the immune tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 114.