Abstract 173: Tumor proximal mesenchymal stem cells initiate a pro-metastatic microRNA regulatory network which acts via convergent targeting of the speech-associated transcriptional repressor FOXP2

Abstract

Abstract Tumor progression to metastasis is largely responsible for breast cancer mortalities, but the mechanisms underlying this process remain among the least understood in oncology. Cell-intrinsic mechanisms, such as accumulating genetic lesions, are well appreciated drivers of malignant progression; however, substantial evidence now supports a similarly critical role for cell-extrinsic stimuli, driving pro-malignant gene expression changes through epigenetic mechanisms. Such external stimuli derive from interactions with the tumor-associated stroma, a distinctive milieu of non-transformed stromal cells recruited to the tumor site by the growing neoplasm. Proximal interactions between cancer cells and components of this tumor-associated stroma have been demonstrated to drive angiogenesis, invasion and metastasis. Understanding these interactions will inform our knowledge of tumor progression and metastasis in general, and presents potential for developing therapeutic approaches based on interdicting the tumor-stroma crosstalk. Mesenchymal stem cells (MSCs) are ambulatory stromal progenitor cells that are normally dispatched to wound sites to aid in the repair of damaged tissues. MSCs similarly home with great affinity to tissues perturbed growing epithelial neoplasms, where they have been found to serve as stromal catalysts of carcinoma progression and metastasis in multiple experimental tumor models of a variety of human cancer contexts including lung, breast, melanoma, prostate, and colon. Despite expanding knowledge of how tumor-associated MSCs contribute to tumor malignancy, the programs and pathways deregulated in cancer cells as a consequence of their interactions with MSCs remain incompletely understood. We conducted genome-wide microRNA (miRNA) profiling analyses on MSC-exposed breast cancer cells (BCCs) to investigate how miRNA deregulation might contribute to malignant breast cancer progression. Our investigation revealed that MSCs cause aberrant expression of a distinct set of miRNAs that accelerate metastasis and are sufficient to provide cancer cells with enhanced tumor initiation capacities, including phenotypes and markers characteristic of putative cancer stem cells. We demonstrate that these miRNAs collectively constitute a regulatory network whose members converge upon a common target: the speech-associated transcriptional repressor FOXP2. FOXP2 knockdown phenocopied increases in metastasis and tumor-initiating ability of BCCs, including CSC-consistent markers, genes and phenotypes. Importantly, elevated MSC-induced miRNA levels and depressed FOXP2 levels were observed in human breast cancers as correlating with increased malignancy. Altogether, our results implicate FOXP2 and its MSC-induced miRNA regulators as novel determinants of malignant breast cancer progression. Citation Format: Benjamin Cuiffo, Antoine Campagne, George W. Bell, Evan Lien, Manoj K. Bhasin, Odette Mariani, Anne Vincent-Salomon, Antoine Karnoub. Tumor proximal mesenchymal stem cells initiate a pro-metastatic microRNA regulatory network which acts via convergent targeting of the speech-associated transcriptional repressor FOXP2. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 173. doi:10.1158/1538-7445.AM2014-173