The role of mitophagy in pancreatic cancer.

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Pancreatic cancer is currently ranked on fourth place of cancer related deaths. Although the prevalence of pancreatic cancer is still increasing and thus pancreatic cancer will reach rank two of cancer related deaths by the year 2030. Besides surgical resection of the tumor, which is essential for a curative treatment approach of pancreatic cancer, chemotherapy plays a central role. While chemotherapy was mainly used for treatment of locally irresectable and palliative cancer situations, today neoadjuvant treatment of locally advanced and also primary resectable pancreatic cancer gains more importance. Compared to conventional chemotherapy using gemcitabine, combination therapy with gemcitabine + nab-paclitaxel or the FOLFIRINOX regime showed promising results, with increased secondary resection rates and increased survival in locally advanced pancreatic cancer. Besides these achievements, in light of high sides effects and relative low rate of overall survival of established chemotherapy regimens, efforts have to be made to further improve therapy options for patients with pancreatic cancer. An important characteristic of cancer is its changed metabolism. Here, already Warburg and colleagues described a change in glucose metabolism away from oxidative phosphorylation and citric acid cycle to aerobe glycolysis. Furthermore, in pancreatic cancer, which nearly uniformly is associated with a mutation of the KRAS gene, changes in metabolism can be detected. In pancreatic cancer, there is a reduction of oxidative phosphorylation and citric acid cycle activity while glycolysis and activity the of the pentose phosphate pathway are increased. This results in reduced production of reactive oxygen species and an improved redox control of the cell, leading to increased cellular proliferation and progression of the tumor. For these changes in metabolism, mitophagy seems to play a pivotal role. Mitophagy is the targeted degradation of mitochondria by mechanisms of autophagy. By reduction of cellular mitochondrial content cancer cells adopt their metabolism leading to increased cellular proliferation and cancer progression. Recently a central regulator of mitophagy in KRAS mutated pancreatic cancer, namely the protein Nix, was identified. Nix is upregulated in pancreatic cancer and reduces cellular mitochondrial content by means of mitophagy. Inhibition of mitophagy in pancreatic cancer by targeting of Nix resulted in increased mitochondrial cellular content, reduced tumor proliferation and increased overall survival. The aim of the project is to further decipher the mechanisms of mitophagy and its impact on pancreatic cancer. This should built the basis for the development of new highly effective therapy options for patients with pancreatic cancer.