Cancer is increasingly viewed as a problem of developmental biology. Evidence now suggests the rapid growth and invasive properties of cancer cells are often driven by the aberrant re-activation of developmental pathways used in organogenesis. This concept appears particularly apt with breast cancer and development, where the initiation of a breast tumor and the development of the mammary gland invoke many of the same physical processes and use many of the same gene pathways. To explore this relation further, the Wahl laboratory has identified a novel population of mammary stem cells (MaSCs) within the developing embryo, which are termed fetal MaSCs. As few as 5-10 fMaSCs have the ability to generate a mammary gland, showing their potential to initiate tremendous growth. Importantly, the gene expression patterns in fMaSCs are similar to cancer cells taken from certain types of breast cancer, including the very aggressive basal-like triple negative breast cancers (TNBC). This shows that there are fMaSC-like cancer cells in these tumors, which may be reactivating some of the same programs that fMaSCs use in development to drive the formation of a mammary gland, to now drive progression of the tumor in these breast cancers. This shared biology offers hope to identify improved treatment for TNBCs, which do not have targeted therapies. Defining how fMaSCs respond to chemotherapeutic drugs illuminates how fMaSC-like cancer cells likely respond as well, and will allow researchers to design strategies that avoid chemo-resistant responses. Similarly, defining how growth and stem cell functions are regulated in fMaSCs provides excellent candidates to build the first targeted therapies around to eliminate those same functions in TNBCs. Profiling these newly identified cells has immediate clinical potential. This application presents a three-front approac to profile these important cells for the first time. First, the resistance of fMaSCs to chemotherap agents will be analyzed, to determine if there are ways to better target cancers that cover all stem-like functions in these cells. Next, the effects of signal inhibitors and different growth conditions on fMaSCs will be analyzed, to determine what factors are necessary for cancer-like behaviors in fMaSCs and identify candidates for new therapeutic pathways in TNBCs. Finally, a novel reporter system to better localize fMaSCs will be generated, to improve the enrichment of these cells. Improved isolation of fMaSCs results in stronger analysis of these cells and a means for clinicians to better personalize treatments. This reporter system also contains a novel inducible cell death system that will ascribe function (that is currently unknown) to fMaSC-like cells in TNBCs or other fMaSC-like cancers, which would be a significant advance for the field.
An emerging theme in cancer research is the shared biology between cancer cells and stem cells. We have identified a new set of mammary-specific stem cells that are very similar to types of breast cancers that are aggressive and poorly treated. We will characterize these mammary stem cells to find ways to better treat these similar breast cancer cells, to improve treatment options for patients.
| Dravis, Christopher; Chung, Chi-Yeh; Lytle, Nikki K et al. (2018) Epigenetic and Transcriptomic Profiling of Mammary Gland Development and Tumor Models Disclose Regulators of Cell State Plasticity. Cancer Cell 34:466-482.e6 |
| Dravis, Christopher; Spike, Benjamin T; Harrell, J Chuck et al. (2015) Sox10 Regulates Stem/Progenitor and Mesenchymal Cell States in Mammary Epithelial Cells. Cell Rep 12:2035-48 |
