Targeting intratumor heterogeneity in breast cancer

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PROJECT SUMMARY: Breast cancer is the most common cancer and the leading cause of cancer deaths in women world- wide. While targeted and immune therapies have improved patient outcomes, a significant fraction of patients fail to respond to treatment and die of their disease. Most of these therapeutic failures are due to extensive intratumor heterogeneity (ITH) driven by genetic and epigenetic heterogeneity of cancer cells in combination with selection forces of the local and systemic environment, such as immune cells. The focus of my laboratory is to understand breast tumor evolution using interdisciplinary approaches and improve the clinical management of breast cancer patients based on this knowledge. We have been at the forefront of studies analyzing tumors as a whole and emphasizing the importance of both cancer cell and stromal heterogeneity in disease progression and therapeutic resistance. In our recent work, we made advances in dissecting the clinical and functional relevance of ITH. We analyzed cellular genetic ITH in HER2+ breast cancer in relation to therapeutic responses. We identified epigenetic enzymes as regulators of transcriptional heterogeneity and linked this to treatment resistance. We showed that polyclonal tumors drive polyclonal metastases by altering the local and systemic immune environments and we described progressively suppressive immune milieu during breast tumor progression. Our proposed research will focus on three general areas: 1. Decipher the breast tumor ecosystem at the single cell level: we will assess ITH using genomic and computational tools to identify key cellular and spatial features of disease progression. We will focus on preinvasive to invasive transition and treatment-resistant tumors progressing to metastatic disease. 2. Conduct functional studies to gain mechanistic insights underlying ITH: we will apply single cell tracking and functional screens in experimental models to assess the impact of metabolic and microenvironmental stressors on ITH, especially epigenetic heterogeneity. 3. Design and test novel therapeutic approaches for heterogeneous breast tumors: we will follow up known and new targets and conduct large-scale screens to identify synthetic lethal interactions and understand mechanisms of synergy. Our recent findings also highlight the importance of tumor-host interactions that go beyond the tumor microenvironment. Even localized tumors have systemic effects and host factors (e.g., age, obesity) have a significant impact on tumor evolution. Thus, we will incorporate these into each of our focus areas and study tumors in the context of the patient. Our goal is that an improved understanding of how ITH drives disease progression will lead to changes in clinical practice, including the development of novel, more effective individualized combination treatment strategies.