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Project

AMPK: a master switch integrating metamoblism and immune effector functions in tumor-associated macrophages

Tumor-associated macrophages (TAMs) are the orchestrators of the inflammatory response in tumors. TAMs exist as a phenotypic spectrum ranging from tumoricidal M1-like macrophages (MOs) to pro-tumoral M2-like MOs. It is becoming clear that MOs alter their metabolism to meet the energetic requirements imposed by their functional polarization, but these processes are ill defined. MO heterogeneity reflects the plasticity and versatility of these cells in response to microenvironmental signals. The tumor microenvironment (TME) is a harsh environment characterized by hypoxia and poor nutrient supply. We have shown that DNA-damage inducible transcript 4, a suppressor of mTORC1, is strongly induced by hypoxic TAMs and alters their metabolism. This metabolic reprogramming is critical to their proangiogenic functions. Less is known how TAMs are influenced by nutrient restriction in the TME. AMP-activated protein kinase (AMPK), a master regulator of cellular metabolism and autophagy, is activated by poor nutrient supply. There is increasing evidence that AMPK activation and inhibition of autophagy abrogate inflammatory responses. The role of AMPK in TAMs is an uncharted topic, as is the link between autophagy and immune suppression. We will investigate how AMPK reprograms TAM metabolism, activates autophagy in TAMs and how autophagy is related to immune suppression. This project might result in ground-breaking novel concepts and new therapeutic targets in cancer immunotherapy.

Date:1 Oct 2016 →  30 Sep 2020
Keywords:macrophages, AMPK, metamoblism
Disciplines:Morphological sciences, Oncology
Project type:PhD project