Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY Despite advances in cancer therapy, metastatic disease is overwhelmingly fatal and accounts for most cancer- related deaths. Systemic therapies fail to control disseminated disease due to a mix of innate and acquired resistance. The processes that drive drug resistance and metastasis are a combination of tumor cell-intrinsic mechanisms, such as genetic and epigenetic changes, and extrinsic factors, including the tumor immune microenvironment (TIME). I propose a comprehensive research and training plan to investigate both dimensions. F99 Phase: My doctoral work focuses on a cancer cell-intrinsic mechanism, the role of Claudin-1 (CLDN1) expression in promoting chemoresistance and metastasis in colorectal cancer (CRC). My work thus far (Aim 1A) details a novel mechanism in which CLDN1 interacts directly with the receptor tyrosine kinase Ephrin type-A receptor 2 (EPHA2) in CRC and inhibits its degradation. The increase in protein-level EPHA2 enhances AKT signaling and CD44 expression to promote cancer stemness and chemoresistance. Previous work has shown that CLDN1 expression promotes CRC metastasis in mouse models. My future work (Aim 1B) will investigate the molecular details of the CLDN1/EPHA2 interaction; compare patterns of CLDN1 and EPHA2 expression in patient-matched normal, primary tumor, and metastatic tumor tissues; and look specifically at the role of the CLDN1/EPHA2 interaction in promoting metastasis. Aim 1 will provide training in bioinformatics, organoid culture, and orthotopic metastasis models. K00 Phase: In my postdoctoral phase, I will study the extrinsic factors influencing breast cancer (BC) dormancy and metastasis in the liver. Cancer cells spread to distant organs early in tumor development. These disseminated tumor cells (DTCs) can enter a state of dormancy and survive initial therapy, only to reactivate years later, resulting in relapse. It is well-accepted that the factors regulating dormancy and reactivation depend on the microenvironment of the host organ. Even though hepatic BC metastases carry the worst prognosis, the factors regulating dormancy and reactivation in the liver are understudied, particularly in a fully intact TIME. In Aim 2.1, I will use immunocompetent mouse models to study the role of T-cells in regulating BC dormancy in the liver. Evidence suggests that hepatic stellate cell (HSC) activation may be a critical factor in DTC reactivation. Activated HSCs are a hallmark of non-alcoholic fatty liver disease (NAFLD). NAFLD is the most common liver disease in the world, but its impacts on BC metastasis are not well studied. Aim 2.2 will use mouse models of NAFLD to study its effect on BC dormancy and metastasis. Aim 2.3 will use innovative ex vivo whole tissue slice cultures to study the signaling networks regulating BC dormancy and immune evasion. Aim 2 will provide training in cancer immunology, advanced cancer models that accurately model the TIME, and analytical techniques capable of single-cell resolution. The proposed studies will offer insights into the causes and therapeutic vulnerabilities of metastatic disease and will provide a multidimensional training program that will prepare me for a career as an independent cancer researcher.
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