Friday, November 22, 2024
11/22/2024
Project Summary/Abstract Metastasis constitutes the primary cause of death for patients with cancer. Specific traits in advanced cancer, including an altered metabolism and reprogramming of the translation machinery to establish selective translation of specific mRNAs including regulators of cell metabolism, anti-apoptotic and pro-invasion factors, leads to metastasis. Tumor cells under different physiological stresses such as hypoxia, nutritional deprivation, and oxidative stress, inhibit global protein synthesis by downregulating canonical mRNA translation, but in response, cancer cells utilize specialized mechanisms of protein synthesis to sustain their survival1-6. There is little research to determine which metabolic mRNAs are translationally maintained or even upregulated following stress, which needs to be elucidated. We propose to study the role of a non-canonical, cap-dependent mRNA translation mechanism that functions during cell physiological stress when canonical mRNA translation is inhibited, in the regulation of Triple Negative Breast Cancer (TNBC), focused on cell metabolism critical for metastasis. TNBC is one the most aggressive and highly metastatic subtypes and is associated with poor prognosis7. A feature of TNBC models and patient tumors is dysregulated glycolysis, which is linked to chemotherapeutic resistance8. In this application, we propose to continue our studies on two hallmarks of invasive cancers, translational control, and metabolic reprogramming. The goal of this proposal is to delineate the molecular mechanisms by which the selective mRNA translation by DAP5 regulated TNBC metabolism and identify the pathways and metabolites that could ultimately be targeted to improved clinical outcomes in advanced breast cancer. The central hypothesis is that DAP5 is critical in regulating the metabolism of TNBC through selective translation of mRNA encoding metabolic regulators, particularly glucose metabolism and calcium homeostasis, which affect metastasis, and this is favored under stress conditions, where canonical cap- dependent translation is attenuated. The role of selective translation initiation in cancer metabolism is almost completely unexplored and we propose an exciting and novel concept for understanding a non-canonical mechanism mediated by DAP5 in the regulation of metastatic cancer cell metabolism. To this end, we will (1) Identify the metabolic mRNAs translated by DAP5 that are maintained following oxidative stress and characterize the metabolic functions of DAP5 in TNBC cells. (2) Determine the role of DAP5 in the metabolite identity of tumors and metastasis in vivo. (3) Validate that increased expression of DAP5 is associated with metabolic molecular biomarkers in available human primary tumor biopsies by comparing non-metastasized primary tumor to primary tumors that gave rise to metastases in TNBC.
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