Abstract IA11: Dissecting cancer through the lens of development

Abstract

Abstract Mammary stem cells (MaSCs) self-renew and generate the different epithelial cell types of the breast. Impressively, a single MaSC can regenerate an entire functional mouse mammary gland when transplanted into a cleared fat pad. Intriguingly, stem-like cells have been identified in some types of breast cancer using bioinformatic strategies. These observations raise a number of important questions: Do some breast cancers arise by mutations occurring in mammary stem cells, as such cells have a high capacity for self-renewal, proliferation and differentiation? Or, do breast cancers arise by de-differentiation of cells to a stem-like state, as such cells may be particularly able to generate the heterogeneity that fuels tumor progression? If stem cells contribute to cancer, what is the nature of such cells, and can we use this information to devise better treatment strategies or prognostic molecular signatures? Finally, cancer cells that seem particularly competent at generating tumors upon xenografting into nude mice have also been suggested to exhibit stem cell characteristics such as multi-lineage differentiation and self-renewal. Are these “cancer stem cells” mutant stem cells, or a different type of cell that is particularly tumorigenic in the xenograft assay? Here, we integrate approaches involving developmental, stem cell, and cancer biology to gain insight into these challenging questions. We took a new direction to isolate and characterize MaSCs during fetal mammogenesis when undifferentiated cells are expected to be enriched. We microdissected and dissociated fetal mammary cells across different stages of development and conducted limiting dilution, orthotopic mammary transplantation analyses to determine fetal MaSC (fMaSC) frequency. We found that the fMaSCs are not measurable until mid-gestation, when an elongating duct that invades through the adjacent mesenchyme is formed. We used flow sorting to significantly enrich fMaSCs, and then used microarray and single cell RNA-seq to begin to interrogate the molecular pathways that drive their proliferation. We find that the pathways they express, and that are expressed by the fetal stroma that surround them, are enriched in several very aggressive types of human breast cancer, as well as in several genetically engineered mouse models. These data and powerful experimental strategies are opening new ways of understanding cancer from a developmental perspective, and for using this knowledge to develop new diagnostic and treatment strategies. Citation Format: Geoffrey Myles Wahl, Christopher Dravis, Claire Johns, Rose Rodewald, Benjamin T. Spike, Christy Trejo. Dissecting cancer through the lens of development. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr IA11.