Abstract 3161: Non-cell autonomous regulation of collective invasion be an epigenetically distinct subpopulation of tumor cells

Abstract

Abstract Diverse genetic and epigenetic traits can promote variant behaviors in subpopulations of cells within primary tumors. In some cases, these heterogeneous subpopulations may compete against each other for clonal dominance to improve tumor fitness. By comparison, the extent to which tumor cell subpopulations cooperate during malignant progression is not well understood. Here, we find that a commensal relationship can exist between epigentically distinct subpopulations of tumor cells during collective invasion. Using quantitive phenotypic analysis and live-cell imaging, we discovered that a subpopulation of cells, termed trailblazer cells, has an enhanced ability to collectively invade. Trailblazer phenotype was heritable and trailblazer subpopulations were derived from 5 triple-negative breast cancer cell lines. The percentage of trailblazers cells within a population ranged from between 0.5% and 90% of the parental population. Gene expression profiling identified a 29-gene expression signature that distinguished trailblazer cells from non-trailblazer cells and identified patients with poor outcome, A cohort of genes trailblazer signature genes were necessary for the formation of actin-rich projections that facilitate path generation during collective invasion. In addition, the trailblazer gene DOCK10 was necessary for spontaneous metastasis to the lung. The path generating function of a small subpopulation of trailblazer cells was sufficient to induce the collective invasion of large population of naturally occurring non-trailblazer cells in organotypic culture. Trailblazer cells were also sufficient to induce the invasion of a mouse model of ductal carcinoma in situ. Taken together, our results suggest that a rare subpopulation of tumor cells with an enhanced ability to collectively invade can promote metastatic progression through cell autonomous and non-cell autonomous mechanisms. Thus, our results support a paradigm shift towards identifying both the cell autonomous and the non cell-autonomous regulatory mechanisms of cell biological processes within heterogeneous tumors to understand neoplastic progression and develop new intervention modalities. Citation Format: Amanda Prechtl, Jill Westcott, Tuyen Dang, Erin Maine, Gray Pearson. Non-cell autonomous regulation of collective invasion be an epigenetically distinct subpopulation of tumor cells. [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 3161. doi:10.1158/1538-7445.AM2014-3161