The Role of Tumor-secreted miR-125b in Fibroblast Differentiation during Metastasis

Description

Every year, thousands of women around the world die of breast cancer (1). About 90% of breastcancer deaths are due to metastasis, a stage at which cancers have spread to distant sites andtreatments become ineffective (2,3). The development of effective therapies for cancer metastasisis an urgent unmet clinical need (2). This requires a thorough understanding of the evolvinginteraction between tumor cells and their environment at different stages of metastasis. Duringmetastasis, tumor cells release large quantities of small vesicles that can deliver proteins andnucleic acids to other cells (4). Recent studies demonstrated that these vesicles contain largeamounts of microRNAs (miRNAs), small RNAs that regulate gene expression (5,6). We illustratedthat a group of miRNAs in tumor vesicles, the miR-200 family, can propagate metastatic capabilityin tumor cells (7). Our preliminary data reveal that one of the most abundant miRNAs secreted bymetastatic breast cancer cells is miR-125b, which is also enriched in the circulation of mice bearinghuman metastatic tumors (unpublished data). Moreover, miR-125b levels are elevated in thecirculation of breast cancer patients with metastasis or chemotherapy resistance (8). However, itremains unclear whether the secretion of miR-125b contributes to metastasis. Do healthy cells takeup miR-125b, and can that alter the metastatic progression of disease?To identify host cells that naturally take up vesicles from tumor cells, we created breast cancercells that secrete fluorescent vesicles. These fluorescent vesicles were taken up the most byfibroblasts in the tumors (unpublished data). We also identified several putative targets of miR-125b, bound and repressed by miR-125b, that are potential suppressors of the signaling pathwaysinvolved in fibroblast differentiation (unpublished data). Recent studies have shown that miR-125bis essential for the differentiation of fibroblasts and endothelial cells to myofibroblasts in the heart(9). In tumors, fibroblasts and endothelial cells often give rise to cancer-associated fibroblasts(CAFs) that are similar to myofibroblasts in phenotype and gene expression (10). CAFs play a keyrole in supporting tumor growth and metastasis (11,12). We hypothesize that miR-125b transferredfrom tumor cells to fibroblasts via small vesicles promotes the conversion of fibroblasts into CAFs.We propose to quantify the uptake of tumor-secreted miR-125b by fibroblasts in primary breasttumors and in the lung, a major metastatic site for breast cancer cells (Aim 1). Subsequently, wewill examine the influence of miR-125b uptake on the differentiation of fibroblasts and identifythe targets of miR-125b that mediate this effect (Aim 2).The outcome of this study will illustrate the novel contribution of secreted miR-125b to thecrosstalk between cancer cells and stromal cells during metastasis. Such a mechanism couldsuggest therapeutic approaches to targeting miR-125b in tumor vesicles for the treatment of breastcancer metastasis.?