Cancer-Associated Fibroblasts: Co-Migrating from Primary to Metastatic Tumor Sites

Breast tumors are characterized by an extensive desmoplastic stroma, abundantly populated by fibroblasts. Cancer-associated fibroblasts (CAFs) are the most abundant cell type in tumor stroma. CAFs are an essential component of the tumor microenvironment involved in many processes that promote tumor progression, including growth promoting, pro-angiogenic and pro-inflammatory signaling. In addition, CAFs were shown to support cancer cell invasion and metastasis via their extracellular matrix remodeling capacities. However, a direct active participation of CAFs in supporting the dissemination of cancer cells to secondary organs and supporting metastatic colonization is still largely obscure.

We show that fibroblasts from mammary tumors are capable of co-migrating with disseminated tumor cells to the lungs and are incorporated into ensuing pulmonary metastases. We utilized novel multi-transgenic mouse models of spontaneous breast carcinoma and lung metastasis (MMTV-PyMT) combined with transgenic mice in which fibroblasts are genetically labeled with fluorescent reporter genes, thus allowing their unbiased tracking and isolation during tumor progression and metastasis. By orthotopic transplantations of fluorescently labeled tumors we were able to detect CAFs derived from primary tumors in lung metastases. We plan to characterize the functional role of co-migrating CAFs by analyzing the transcriptional changes that migrating CAFs undergo in the process. We will seek to uncover specific molecular pathways which contribute to the reciprocal interactions between migrating CAFs and cancer cells which serve to promote and enhance the metastatic process.

In summary, we were able to uncover a novel role for mammary CAFs in which they co-migrate with cancer cells from the primary tumor to metastatic sites in the lungs.