GOT2 consider the tumor microenvironment

Abstract

To thrive in a hypoxic and nutrient-limited tumor microenvironment, pancreatic ductal adenocarcinoma (PDAC) cells rewire their metabolism. Understanding PDAC cell metabolism may uncover vulnerabilities that can be targeted for improved therapy. Three recent studies find that the PDAC tumor microenvironment modulates the functional consequences of depleting the mitochondrially localized aspartate transaminase GOT2, thus providing new insights into the metabolism of this lethal cancer.

Figure 1.. Interplay between pathways involving GOT2 and the tumor microenvironment.

Selected metabolic effects of hypoxia and GOT2 knockout are shown as red or purple arrows, respectively. Hypoxia decreases mitochondrial electron transport and re-oxidation of NADH to NAD+. This limits malate oxidation to oxaloacetate (OAA), which reduces aspartate synthesis by GOT2 and ultimately may slow nucleotide and/or protein synthesis. GOT2 knockout completely abrogates mitochondrial aspartate synthesis, such that reversal of the cytosolic (GOT1-mediated) arm of the malate-aspartate shuttle is the only means of aspartate synthesis for cells. Several mechanisms (highlighted in blue) can allow cells to buffer against these effects. Proteins or nutrients from stromal cells, such as cancer associated fibroblasts (CAFs), or necrotic cells, can be scavenged by specific transporters or by macropinocytosis, which is enabled by HIF1α signaling in cells with oncogenic KRAS. Access to extracellular pyruvate can promote a more oxidized NAD+/NADH ratio to indirectly support aspartate synthesis. GOT2 can also bind fatty acids (FA) and localize to the nucleus, where it associates with the transcription factor PPARδ to induce expression of immunomodulatory genes. Some, including Cox2, induce prostaglandin synthesis which inhibits cytotoxic T cells. Others, including Csf1 and Reg3g, encode soluble ligands that can recruit myeloid-derived suppressor cells (MDSCs) to the tumor microenvironment.