Bone Marrow-Derived Fibroblasts are a Functionally Distinct Stromal Cell Population in Breast Cancer and Lung Metastases

Breast tumors are characterized by an extensive desmoplastic stroma, abundantly populated by fibroblasts. Cancer-associated fibroblasts (CAFs) are a heterogeneous cell population found in the microenvironment of solid tumors, shown to promote tumor growth in various mechanisms, including stimulation of tumor cell proliferation and enhancement of angiogenesis. We previously uncovered a novel role for CAFs in mediating tumor-promoting inflammation in several tumor types, including breast cancer. Here we set out to characterize the various subpopulations of fibroblastic cells during progression of mammary carcinoma and lung metastasis utilizing the MMTV-PyMT transgenic mouse model of human breast carcinogenesis. Using adaptive bone marrow transplantations (BMT), we show that BM-derived mesenchymal stromal cells are specifically recruited to breast tumors and to spontaneous lung metastases, where they differentiate to CAFs, but not to normal mammary glands or lungs. Detailed analysis of this unique population revealed that BM-derived CAFs express α-SMA, but do not express PDGFRα, implying that the later is a marker of resident tissue fibroblasts. Furthermore, we show that BM-derived CAFs are functionally distinct from resident fibroblasts in various tumor promoting activities. We isolated the different CAF subpopulations from primary tumors and lung metastases and analyzed their immunological transcriptome. This analysis revealed distinct gene expression signatures of resident and BM-derived CAFs, as well as genes that are commonly expressed by both subpopulations. Interestingly, the distinct inflammatory profile exhibited by BM-derived depended on the location to which they were recruited. Furthermore, BM-derived CAFs induced significantly more angiogenesis compared to resident mammary CAFs in a plug assay in vivo. Characterization of specific CAF populations in the tumor microenvironment can form the mechanistic basis for novel therapeutic manipulations and co-targeting of BM-derived CAFs.