Deconstructing Breast Cancer
Deconstructing breast cancer, mammary stem cells and epithelial development at single cell resolution
We were the first to isolate and analyze mammary stem cells from the mouse embryonic context.
In that study, we found by transplanting mammary cells from mouse embryos (e.g.the three bright dots in the upper left image above) and scoring mammary ductal tree reconstitution in hosts (upper right), that mammary stem cell (MaSC) capacity is much higher in the embryo than in adult tissues. We also found that these cells have molecular expression profiles related to those found in certain types of breast cancer and particularly in those of the 'Triple Negative' designation that lack known molecular targets for therapy. We have been working with collaborators to leverage these transcriptional profiles for clinical decision making and are also working to deconstruct the various underlying molecular circuits that are shared between tumors and developmentally primitive cells.
In the course of these studies, we noticed something else intriguing. Despite the high number of cells with functional stem cell capacity in transplantation and other stem cell assays, there was considerable transcriptional heterogeneity from cell to cell. We have since been using single cell transcriptomic approaches to deconstruct the stem cell state and the larger multicellular system at single cell resolution. We are engaging this approach in a variety of normal and tumor settings to understand what gives rise to cellular heterogeneity and how the boundaries of cell states are defined molecularly, for instance the boundaries between stem cell and non stem cell, between a tumorigenic cell and benign one, between metastatic and locally restricted cells and between those that are sensitive to chemotherapeutic agents and those that are not. On the horizon are studies that model these states using non-parametric approaches and dynamics aimed at identifying new causative molecular and cellular relationships.