mTORC2 and macrophage signaling in the colon during colitis and cancer

Macrophages are central cells for the maintenance of tissue integrity and for immune responses in the gastrointestinal (GI) tract. A dysregulation of macrophage function can promote inflammatory diseases such as inflammatory bowel disease that promote the development of colitis-associated cancer. The mechanistic target of rapamycin (mTOR) is a central regulator of many metabolic processes by integrating intracellular and environmental nutrient levels to control activation of immune cells by inflammatory stimuli. However, the role of mTOR complex 2 (mTORC2) in macrophages for regulating immune functions in the GI tract, a place of abundant nutrients and potential inflammatory triggers, remains unstudied. The central aim of our research proposal is to investigate the role of mTORC2 for colon homeostasis and inflammation during colitis and colitis- associated cancer. We will concentrate during the next 48 months on the role of mTORC2 in macrophages and its relevance for metabolic and immune cross-talk. By a combination of cutting- edge genetic, pharmacologic, and metabolomic approaches, the function of mTORC2 will be analyzed in vitro and in vivo in mice and men. The elucidation of how macrophages metabolically coordinate immune responses will have fundamental implications for our understanding of immunity. Assessing the role of mTORC2 for macrophage function and metabolism in the colon may provide novel therapeutic strategies to control chronic inflammatory disorders or cancer. Moreover, this proposal adds knowledge about potential anti-cancer effects of novel mTOR inhibitors that target mTORC1 as well as mTORC2.

Unexpected role of mTORC2 in colorectal cancer New results from researchers at the Center for Pathobiochemistry and Genetics at MedUniVienna show that a protein called mTORC2, against which novel anti-cancer drugs are currently being developed, is not active at all in colorectal cancer. mTORC2 activity was only found in certain immune cells that need mTORC2 to fight cancer cells. A tumor is not only composed of cancer cells but also contains a large number of different immune cells that normally fight against the cancer cells. However, many tumors have developed strategies to reprogram immune cells so that they then even support tumor growth. In the age of immunotherapy, which has been very successful in reactivating the immune system, research into how tumor and immune cells interact is of central importance. Here, the protein mTORC2 plays an important role, which is currently the target of a number of novel drugs that have been very successful in suppressing cancer cell growth in the test tube. There are therefore high expectations that mTORC2 inhibitors could be successful against a large number of cancers in the future. A MedUniVienna research team led by Thomas Weichhart's group has now discovered that mTORC2 is not active at all in colorectal cancer cells, but only in certain immune cells known as macrophages, which should normally fight cancer cells. These data have now been published in the Journal of Clinical Investigation Insight. The trio of first authors consisting of Karl Katholnig, Birgit Schütz and Stephanie Fritsch with their colleagues were able to show that a high activity of mTORC2 in macrophages is important to curb the growth of colorectal cancer in animal models. Karl Katholnig explains, "When we knocked down mTORC2 specifically in macrophages in the animal model, the growth of the colon tumor accelerated in these mice. Birgit Schütz adds, "Surprisingly, an mTORC2 inhibitor also had the same effect in this colon cancer model." However, a correlation could not only be shown in the animal model but also in humans. Stephanie Fritsch emphasizes, "We found that in colorectal cancer patients, high mTORC2 activity in macrophages is associated with a favorable outcome." These results suggest that maintaining, rather than inhibiting, mTORC2 may be therapeutically useful in colorectal cancer. Thomas Weichhart concludes, "Tumor cells even try to turn off mTORC2 in macrophages as soon as these cells enter the tumor clump to ensure their own survival." The researchers now want to find out how the tumor cells turn off mTORC2 in macrophages. After all, if this can be prevented, it could represent a new immunotherapy approach. In any case, it turns out that a full understanding of drug efficacy also involves the immune system.