Intratumor heterogeneity in BRCA1-mutated breast cancer metastasis

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Abstract Metastasis continues to cause the vast majority of breast cancer related deaths because the metastatic process is poorly understood and therapies for effectively inhibiting it do not exist. Women with BRCA1 mutations develop the most aggressive, and highly metastatic basal-like breast cancer at a high rate. Despite resembling basal epithelial cells, recent studies have identified the luminal progenitor as the cell type which undergoes malignant transformation in basal-like breast cancer. Preliminary sequencing data included in this proposal, from same-cell gene expression and chromatin accessibility epigenetics assay in a mouse model of basal-like breast cancer, reveal the presence of several differentiation states of luminal progenitor cells within the tumor. Additionally, several tumor cell states appear to have unique DNA copy-number mutational signatures. These observations prompt the questions of whether a particular differentiation state is involved in metastasis and if mutations drive the differentiation and metastasis trajectory. To investigate the metastatic potentials of the cellular differentiation states and mutational cell subpopulations in the tumors, the proposed study will consist of the following methodological steps: 1) harvesting spontaneously generated Brca1&p53-mutant mouse tumors, 2) injection of tumor cells into mice to generate metastasis replicates, 3) isolation of metastatic cells using mouse strain-specific antibodies, 4) splitting of metastatic cells and original mammary tumor cells for parallel single cell profiling with a) gene expression and chromatin accessibility assay and b) custom-built high-resolution mutation panel, 5) data integration to incorporate the contribution of mutations, epigenetic chromatin states, and gene expression, 6) computational comparison of metastatic cells to original tumor cells. This study is expected to reveal the molecular markers which define metastatic cells in Brca1&p53-mutant tumors to inspire metastasis inhibiting therapy. This study will be carried out by a student with substantial training in molecular pathology and systems biology who wishes to further her cancer genomics and bioinformatics training. Laboratory animal personnel will assist with animal work, the bioinformatics director will guide the computational analysis and statistical tests, and the faculty advisor/sponsor will oversee experiments and interpretations of results. The student will work closely with the sponsor and the bioinformatics collaborator to learn the proper use of cutting edge genomics and bioinformatics tools to advance the breast cancer metastasis field. Additionally, the student will be given professional development opportunities such as attending conferences, mentoring undergraduates, and teaching a summer course to prepare her for a post-doctoral position in a cancer-related field.