MedComm | The biological role of metabolic reprogramming in pancreatic cancer


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Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, characterized by early metastasis and resistance to all forms of treatment. The extremely high mortality rate of patients with PDAC can be attributed to the lack of both an early diagnosis and appropriate targeted therapy. Because the pancreas is located in a place difficult to observe, the early diagnosis of PDAC in routine examinations is nearly impossible. Furthermore, current biomarkers are inadequate to detect PDAC efficiently, especially in the early stages. 

Recently, metabolic reprogramming, an emerging hallmark of cancer, has generated renewed interest. Cancer cells rewire their metabolism to promote their growth and  proliferation. Based on recent evidence of metabolic adaptation in PDAC cells, the metabolic features of PDAC could constitute attractive therapeutic opportunities. 

In this review, the authors discuss how PDAC cells alter their metabolism to facilitate growth and how metabolismtargeted therapies could be used to improve the prognosis of patients with PDAC.

In PDAC cells, oncogenic KRAS upregulates glucose transporter 1 (GLUT1), which increases glucose uptake.Oncogenic KRAS also upregulates hexokinase 1/2 (HK1/2), phosphofructokinase 1, and lactate dehydrogenase A (LDHA) to promote glycolysis. Furthermore, the hypoxic microenvironment and other mechanisms cooperate with oncogenic KRAS to increase the expression of glycolytic enzymes and maintain cytosolic ATP. PDAC cells also reprogram amino acid metabolism. Various amino acid transporters are upregulated markedly in PDAC cells to meet the metabolic demand. The amino acid glutamine (Gln) is important for tumor cell as a major source of carbon and nitrogen, contributing to biosynthesis of macromolecules. PDAC cells are poorly vascularized and in a state of nutrient deprivation.Thus, PDAC cells have alternative mechanisms by which they acquire nutrients needed to survive and grow. To acquire sufficient fuel, PDAC cells activate mechanisms, such as autophagy, macropinocytosis, and metabolic interaction with surrounding noncancerous cells within the tumor microenvironment (Fig. 1).

Fig.1 Nutrient acquisition strategies utilized by PDAC cells

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