Cooperative Invasion Between Tumor Cell Subpopulations

Breast cancer is responsible for over 40,000 deaths each year in the United States. The majority of these deaths are not attributable to the primary breast tumor, but to metastases in vital organs. Tumor cell invasion is an early step in the metastatic cascade which can occur collectively by multiple cells cooperatively invading into the surrounding stroma. Primary patient breast tumors and patient-derived breast cancer cells can collectively invade yet how cells collectively invade is still largely unknown. It is well known that tumors contain heterogenous populations of cells yet traditional metastasis models focus on the ability of a rare population of neoplastic cells to autonomously invade past the basement membrane surrounding the tumor, intravasate into blood vessels and disseminate throughout the body to colonize foreign tissues. We hypothesized that there is a stable subpopulation of tumor cells that is capable of initiating the invasion of another population. Using organotypic culture models, which provide a three dimensional environment that models stromal conditions, and real-time imaging, a technique in which cell behavior can be imaged in real time at a single cell resolution, we determined that breast cancer cell lines can contain populations of cells with differential invasive potential. Furthermore, we concluded that one population of invasvie cells is sufficient to induce the invasion of other noninvasvie cells. This suggests a new mechanism for breast cancer metastasis, in which subpopulations of cells can cooperate with each other as opposed to competing against each other, to invade and potentially metastasize. Future studies will focus on determining the requirements for the leader cells to induce invasion and the follower cells to migrate behind the leader cells, with the eventual goal of targeting specific tumor populations for diagnostic and therapeutic treatment.