The previous cycle of CA78810 has continued to support important advances in our understanding of cancer biology. Mechanisms of deregulated cell death inhibition, cellular stress response, mitochondrial homeostasis, and metastatic competency were defined.
The specific aims of the original application were fulfilled, establishing new paradigms for NFkappaB-dependent gene expression and tumor cell invasion, in vivo. As part of these efforts, we have now identified a novel link between tumor metabolic reprogramming and enhanced cell motility. We found that survivin, a multifunctional pathway integrator exploited in virtually every human tumor, associates with the mitochondrial Complex II subunit, succinate dehydrogenase B (SDHB), and supports energy production through oxidative phosphorylation, potentially when nutrients are limiting. Accordingly, depletion of mitochondrial survivin, or pharmacologic or genetic silencing of SDHB, lowers ATP production, inhibits cellular respiration, induces biochemical markers of cellular starvation, and suppresses tumor cell migration and invasion. Therefore, the hypothesis that mitochondrial survivin contributes to tumor metabolic reprogramming via oxidative phosphorylation and enables the acquisition of metastatic traits can be formulated, and will constitute the theme of the present continuation application. Experiments in the first specific aim will elucidate the molecular requirements of survivin bioenergetics with respect to SDHB stability and function in cellular respiration, cooperation with mitochondrial chaperone-directed protein folding, and modulation of tumor metabolic reprogramming under normal and stress conditions. The second specific aim will dissect the impact of this pathway on cytoskeletal dynamics, characterize its signaling requirements with respect to epithelial-mesenchymal transition and mitochondrial retrograde gene expression, and elucidate the mechanistic interplay between nutrient-sensing tumor suppression, adaptive autophagy and enhanced cell motility. The third specific aim will map the role of survivin bioenergetics on tumor progression and metastatic dissemination in vivo, leveraging xenograft models of liver and bone metastasis reconstituted with genetically engineered tumor cell lines, and transgenic expression of mitochondrial survivin in the mouse prostatic epithelium, alone or in combination with tissue specific-deletion of the PTEN tumor suppressor gene. Overall, the experimental plan is designed to unravel a novel pathway of tumor progression, in which malignant cells chronically depleted of nutrients manage to produce sufficient energy through survivin-directed oxidative phosphorylation to bypass starvation-related tumor suppression, and sustain cell motility and invasive potential. The results may aid in the repurposing of survivin antagonists currently in the clinic as novel inhibitors of tumor metabolism and candidate anti-metastatic strategies in humans.
Tumors repurpose their energy sources to promote cellular proliferation and dissemination to distant organs. How this process is regulated is poorly understood, and may involve a complex interplay of signals that integrate the sensing of nutrients, the production of energy by subcellular organelles, like mitochondria, and the control of cellular movements. The studies proposed in this application are designed to elucidate this signaling network, and identify new targets of tumor cell metabolism suitable for anti-metastatic therapies in humans.
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