Defining the Niche of Dormant Disseminated Breast Tumor Cells with High-Resolution Spatial Profiling
Abstract
In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. There is mounting clinical and experimental evidence to support the hypothesis that these late-arising metastatic lesions originate from disseminated tumor cells (DTCs) that left the primary tumor early on and lay dormant for years before being triggered somehow to re-enter the cell cycle. Strategies to prevent dormant DTC re-emergence or kill dormant DTCs before they awaken would be game-changing. However, we have lacked an understanding of the biology underlying tumor dormancy ? e.g., what keeps dormant DTCs from growing, why they are chemoresistant, and whether they rely on unique pathways to survive ? necessary to develop such approaches. We and others have committed considerable effort over the last decade applying high-throughput approaches (e.g., RNAseq, proteomics) to appropriate models to identify molecules that induce and sustain DTC quiescence or others that protect DTCs from chemotherapy. However, despite these efforts, the field has identified only a handful of putative regulators of dormancy across cancers. Therefore, there is a need for transformative technology that can define all of the molecules that constitute the dormant niche ? in its entirety, and in context, and at once. In this application, we posit that multiplexed error robust fluorescence in situ hybridization (MERFISH) represents such a technology. Put simply, MERFISH allows the simultaneous measurement of up to 1,000 genes with cellular resolution in intact tissue. It has never been applied to tissues harboring DTCs before, and we believe that its application has the potential to enumerate all of the extracellular factors that comprise the niche harboring DTCs: (i) upon their arrival, (ii) during sustained periods of quiescence/dormancy, (iii) upon proliferation, and (iv) after the delivery of chemotherapeutics. Our goal is to advance this proof-of-concept study beyond our innovative culture models (Aim 1) and murine models of dormancy (Aim 2) to patient specimens within the next 3 years. Doing so would form the backbone of future Breakthrough applications, where we would also functionally assess the relevance of identified molecules as targets for metastasis prevention, and partner with clinical collaborators to bring our findings to the forefront of metastasis prevention strategies designed to prolong the lives of people with breast cancer. Given our goals, this project addresses two of the Breast Cancer Research Program?s overarching challenges. Namely, successful addressing our stated aims will allow us to make great strides in uncovering mechanisms of dormancy and re-emergence by enumerating the molecular constituents of the dormant niche. As discussed, we will ultimately leverage these findings to develop DTC-targeted therapies that help eliminate mortality associated with metastatic breast cancer by preventing late-arising metastases.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 05, 2019
- Source ID
- W81XWH1910070XX0
Entities
People
- Simon Knott
Organizations
- Cedars-Sinai Medical Center
- United States Army