Intra-tumoral heterogeneity confounds molecular taxonomy, fuels metastasis, and increases the chances of treatment failure. Understanding the origins of intra-tumoral heterogeneity and developing effective countermeasures should improve cancer outcomes. This proposal focuses on the cellular and molecular origins of intra-tumoral heterogeneity in basal-like breast cancer (BLBC), as these cancers frequently resist chemotherapy and currently lack molecular targets for drug development. BLBC is distinguishable from other breast cancer subtypes, as it exhibits a gene expression signature that is associated with fetal mammary stem cells (fMaSCs) generated during embryogenesis. Importantly, fMaSC-like cancer cells are very tumorigenic and differ significantly from the breast cancer stem cells that have received much recent attention. This project will determine the molecular programs that drive embryonic mammary cells into the stem cell state, and use gene editing technologies to generate a new mouse model that will enable the lab to identify fMaSCs in real time based on the cytokeratins they express. This experimental approach will allow the lab to selectively eliminate these cells to determine unambiguously if these are the only stem cells within the mammary gland, and whether other cells can acquire stemness in response to wounding, inflammation, obesity, etc. p53 mutations are frequently found in BLBC and contribute to both genetic heterogeneity and increased reprogramming efficiency. This project will induce p53 mutations in fMaSCs or their differentiated progeny and ask whether different types of tumors arise, and assess cellular and molecular heterogeneity. This project will determine whether other BLBC relevant mutations, such as BRCA1 (alone or in combination with p53 mutations) or environmental challenges (such as inflammation or obesity) elicit the same effects. Gene expression signatures of resulting tumors will be compared to those of human BLBC to generate mouse models that reflect the human disease more faithfully. Finally, this project will apply single cell sequencing and sophisticated bioinformatic approaches to: 1) decipher the mechanisms by which the stem cell state is generated, 2) assess heterogeneity within the tumor cell population, and 3) determine whether fMaSC embryonic antigens are detectable in human BLBC. Such antigens, and the pathways discovered to drive the fMaSC state, will provide new targets for developing tumor-selective, immune- and molecularly targeted therapies. The fMaSC-like cells in BLBC resemble bona-fide multi-potent embryonic mammary stem cells, and comprise a new and understudied cell type in cancer. Cells with similar stem-like attributes have been described in diverse solid tumors, indicating that findings from these studies will likely have general relevance for cancer biology.
Tremendous strides have been made to reduce the incidence, death and suffering resulting from the many diseases aggregated under the single umbrella of cancer, but cancer is still predicted to be the leading killer in the US within the nex several years. The heterogeneity of the cells within each patient's tumor limits the effectiveness of personalized molecular medicines because such cell diversity is a breeding ground for the emergence of drug resistance, and interactions between different cells in the aberrant cancer cell society can facilitate malignant progression and metastasis. The goal of this grant is to use innovative approaches that integrate stem cell, developmental and cancer biology to identify the cellular and molecular underpinnings of cancer heterogeneity, and to derive new targets for more effective diagnosis and treatment.
| 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 |
| Giraddi, Rajshekhar R; Chung, Chi-Yeh; Heinz, Richard E et al. (2018) Single-Cell Transcriptomes Distinguish Stem Cell State Changes and Lineage Specification Programs in Early Mammary Gland Development. Cell Rep 24:1653-1666.e7 |
| Wahl, Geoffrey M; Spike, Benjamin T (2017) Cell state plasticity, stem cells, EMT, and the generation of intra-tumoral heterogeneity. NPJ Breast Cancer 3:14 |
| Trejo, Christy L; Luna, Gidsela; Dravis, Christopher et al. (2017) Lgr5 is a marker for fetal mammary stem cells, but is not essential for stem cell activity or tumorigenesis. NPJ Breast Cancer 3:16 |
