"PROJECT SUMMARY One of the hallmarks of cancer is the reprogramming of metabolism from oxidative phosphorylation that takes place in mitochondria to glycolysis, regardless of oxygen availability. This so-called ?Warburg effect? is an important disease driver and hallmark of poor outcome. However, it is now clear that there is greater complexity in tumor metabolism, as mitochondria continue to play an important role in the bioenergetics of transformed cells, and fuel key cancer traits of proliferation, drug resistance, stemness and invasion. Work supported by CA78801 demonstrated that a pool of the cancer gene, survivin present in mitochondria of tumor cells maintained oxidative phosphorylation metabolism. In turn, energy produced via this pathway enabled the subcellular movement of mitochondria to the cortical cytoskeleton of tumor cells, fueling membrane lamellipodia dynamics, turnover of focal adhesion complexes, and sustained phosphorylation of cell motility kinases. Together, this led to heightened tumor chemotaxis, invasion and metastasis, in vivo. Published in the peer-reviewed literature (Sci Signal 8:389, 2015;? PNAS 112:8638, 2015), and discussed in three invited review articles (Pharmacol Rev 102:42, 2015;? Cell Cycle 14:20, 2015;? Clin Cancer Res 22:540, 2016), these results supported a model of spatiotemporal mitochondrial bioenergetics as a requirement of tumor cell motility, invasion and metastasis. In follow-up studies, we have now found that changes in mitochondrial size and shape, known as dynamics, as well as mechanisms of organelle quality control, such as mitophagy, are essential regulators of this pathway. Specifically, conditions that impair mitochondrial fusion, promote exaggerated mitochondrial fragmentation (fission), or activate mitophagy suppress mitochondrial trafficking and block tumor cell motility. Therefore, the hypothesis that organelle dynamics and quality control regulate spatiotemporal mitochondrial bioenergetics and metastatic competence can be formulated, and will constitute the focus of the present revision application. In continuity with the objectives of CA78810, the first specific aim will elucidate how mitochondrial fusion and fission regulate organelle movements, membrane-actin dynamics and the machinery of tumor cell motility. The second specific aim will focus on Parkin-dependent and - independent mitophagy, and a novel role of the FUNDC2 molecule as novel ?metastasis suppressors?, regulating mitochondrial recruitment to the cortical cytoskeleton and the bioenergetics of tumor cell invasion. As dynamics and quality control are the primary effectors of mitochondrial heterogeneity, these studies are an ideal match to the objective of the PQ5 Program, will conclusively answer its overarching question of how does mitochondrial heterogeneity influence tumorigenesis or progression, and uncover actionable therapeutic targets to limit disease dissemination in the clinic. " |