Grant: Travel Awards - Institute Community Support

To date, occurrence of metastasis accounts for over 90% of breast cancer deaths, meaning that the invasion and development of metastasis are the most life threatening aspects of this disease. Despite the promising advances, the majority (if not all) of the breast cancer therapies fail in the metastatic setting. Therefore, there is a dire need to better understand the biology of metastasis in order to develop new therapeutic approaches that will be effective for combating this lethal process. We know only rare tumour cells shed into the circulation have the capacity to colonize distal sites. The recent characterization of the mammary epithelium developmental hierarchy in both mice and humans shows that even in the adult, stem and progenitor cells are present in the breast. Elucidation of the cellular and molecular mechanisms responsible for metastatic dissemination is of broad interest and paramount to the design of more effective treatments for breast cancer. However, analysis of the properties and regulation of tumor cell seeding has been limited by a lack of methods for their prospective isolation. Here we report the use of multiparameter cell sorting and modified experimental metastasis approach to demonstrate the purification of a rare subset of adult mouse normal breast that are able individually to seed and persist at the ectopic site. This subpopulation (Lin-CD29HiEpCAMInt) is highly enriched for lung colonizing cells (LCCs) by intravenous injection. In support of a potential role for LCCs in breast cancer, the LCC-enriched subpopulation was exclusively capable of giving rise to metastatic tumors upon activation of potent human oncogenes. The ability to isolate LCCs as a distinct population enables us to study how colonization by epithelial cells is regulated under normal conditions and perturbed during oncogenesis.