Targeting cancer cell metabolism in pancreatic adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of cancer death by 2030. Current therapeutic options are limited, warranting an urgent need to explore innovative treatment strategies. Due to specific microenvironment constraints including an extensive desmoplastic stroma reaction, PDAC faces major metabolic challenges, principally hypoxia and nutrient deprivation. Their connection with oncogenic alterations such as KRAS mutations has brought metabolic reprogramming to the forefront of PDAC therapeutic research. The Warburg effect, glutamine addiction, and autophagy stand as the most important adaptive metabolic mechanisms of cancer cells themselves, however metabolic reprogramming is also an important feature of the tumor microenvironment, having a major impact on epigenetic reprogramming and tumor cell interactions with its complex stroma. We present a comprehensive overview of the main metabolic adaptations contributing to PDAC development and progression. A review of current and future therapies targeting this range of metabolic pathways is provided.

Cancer-associated fibroblast-derived annexin A6+ extracellular vesicles support pancreatic cancer aggressiveness

“…Indeed, in PDA, a well-reported heterogeneous tumor (38), hypoxia (39), inflammatory response (40), and extracellular matrix (8) are predominant factors that could modulate such dialogue. At present, most PDA patients are following one of the baseline therapies made of gemcitabine, FOLFIRINOX, or gemcitabine plus nab-paclitaxel (except for patients enrolled in phase 2/3 protocols).…”

State of the art and future directions of pancreatic ductal adenocarcinoma therapy

“…NEUZILLET et al, PDAC state of the art 13 for tumor initiation and progression (Hanahan & Weinberg, 2011). Both oncogenes, with a driver role for oncogenic KRAS, and the tumor microenvironment are involved in this process (Cairns, Harris, & Mak, 2011;Cohen et al, 2015). The extensive and poorly vascularized desmoplastic stromal reactions in PDAC leads to tumor hypoxia and nutrient deprivation, yet without evidence of major cell death (Bergers & Hanahan, 2008).…”

“…This suggests that pancreatic cancer cells adapt to metabolically challenging survival conditions in their microenvironment early in tumor development. Several changes occur in response to oxygen and nutrient deprivation: increased glycolysis even in aerobic conditions, as well as increased amino acid (AA) uptake derived from protein degradation, protein glycosylation, and fatty acid synthesis (Cohen et al, 2015;Ryan, Hong, & Bardeesy, 2014b). In addition, recycling and scavenging of cellular and extra-cellular components through autophagy and macropinocytosis have been shown to be applicable in PDAC (Cohen et al, 2015;Ryan et al, 2014b).…”

“…The metabolic fate of glutamine is multifaceted: it can be used for lipid biosynthesis, as a nitrogen donor for AA and nucleotide biosynthesis, as a carbonic substrate for the re-feeding of the mitochondrial TCA cycle through a phenomenon called "anaplerosis", and as fuel for cell energy production through glutaminolysis (Cohen et al, 2015;DeBerardinis & Cheng, 2010). PDAC cells metabolize glutamine through a non-canonical pathway in which transaminases play a crucial role.…”

Pancreatic cancer from bench to bedside: molecular pathways and treatment options

“…Moreover; it is known that cancer cells compared to normal cells have specific metabolic dependencies, they have increased need of the amino acid glutamine (41). Kras is responsible for reprogramming glutamine metabolism in PDAC (42). Targeting the Warburg effect has shown that the p53 status of PDAC determined the response to inhibitors of the enzyme lactate dehydrogenase-A (43).…”