Functional role of PGAM5 in epithelial homeostasis and colorectal cancer

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Colorectal cancer (CRC) is the second leading cause of death from cancer worldwide. Aside from CRC developing spontaneously, especially in elderly patients, there is an increased risk for colorectal cancer in patients with inflammatory bowel disease (IBD). Both CRC and IBD occur in genetically susceptible individuals through poorly understood mechanisms and involve dysregulation of intestinal epithelial homeostasis. We have identified the molecule PGAM5 as a novel key factor of gut homeostasis and cell survival. PGAM5 is a mitochondrial phosphatase which might serve as a platform connecting several cell death pathways to mitochondrial stress and dynamics.PGAM5-deficient animals were more susceptible to epithelial cell death and loss of gut tissue homeostasis. Of note, our preliminary findings and initial proteomics data suggest a role of PGAM5 in the development of CRC. Our data demonstrate that PGAM5 is strongly up-regulated in both human and mouse CRC. PGAM5-deficient cancer cells showed a significant reduction in the Wnt/ beta-catenin signaling. On the basis of our preliminary data, we therefore hypothesize that PGAM5 plays an important role in CRC and gut homeostasis. However, the molecular mechanism by which PGAM5 exerts these function and the signaling pathway involved in these processes are yet to be defined. In order to better understand the functional role of PGAM5 in gut tissues homeostasis and colorectal cancer development, we seek to study PGAM5 using experimental mouse models for CRC and to identify relevant pathways and interaction partners of PGAM5 in intestinal epithelial cells. In four work packages we will first identify the functional role of PGAM5 in intestinal epithelial cell homeostasis and in experimental models of spontaneous and inflammation-dependent colorectal cancer. We will further determine PGAM5 regulated genes and pathways in intestinal epithelial cells and cancer cells. Finally, in a translational approach we will evaluate our findings for the relevance to human colorectal cancer using patient tissues and a sophisticate xenograft model. Our ultimate goal is an improved understanding of the function of PGAM5 in tissue homeostasis and colorectal cancer. We are confident to uncover whether influencing PGAM5 expression or function in CRC might be therapeutically effective.