Metabolic profiling of pancreatitis and KRAS-induced pancreatic cancer in a mouse model


Pancreatic cancer (PC) is the fourth leading cause of cancer death. The prognosis for individuals with PC has evolved slowly in the past decades due to limited progress in methods for early diagnosis and therapy. PC is genetically heterogeneous and mutated KRAS is known to be one of the drivers of the disease. Transgenic KRAS mouse models have, therefore, been used to investigate the disease development. In this context, metabolomics can contribute to the identification of metabolic deviations associated with this type of cancer. This work aimed at characterizing the metabolic changes in mouse pancreatic tissue due to the benign condition of pancreatitis and PC progression in KRAS-mice, from low-grade to high-grade PC, using 1H-Nuclear Magnetic Resonance (NMR)-based metabolomics. Pancreatic extracts were obtained from healthy wild-type (WT,C57BL/6) mice (controls, n=7), WT mice with pancreatitis, induced by caerulin injections (n=6), LSL-KrasG12D/+-p48Cre/+ mice with PanIN lesions (low-grade, n=5, and high-grade, n=7) and LSL-KrasG12/D+;LSL-Tpr53R172H/+;Pdx-1-Cre mice with spontaneous PC (adenocarcinoma, n=6, and sarcomatoid, n=9) [1]. Pancreatitis induced a pancreatic metabolite profile that was distinct from both normal tissue and low-grade PC, with changed levels in some amino acids, organic acids and nucleotides. In addition, progression of pancreatic carcinogenesis was characterized by decreased levels of glutamine, 2-phosphoglycerate, phosphocholine, phosphoethanolamine, glycerophosphocholine and UDP-glucose or -glucuronate, and increased levels of 3-HBA, ascorbate, lactate, niacinamide, glucose and sucrose. No significant metabolic differences were observed between the two adenocarcinoma and sarcomatoid tumors. Given the considerable heterogeneity of pancreatic tissue, normalization of metabolite levels by cell number enabled the determination of metabolic deviations from those simply due to differences in cell numbers/distribution in pancreatic tissue. In conclusion, metabolomics may be useful to help define metabolic biomarkers of pancreatitis and of PC onset and progression.


Carneiro T, Serrão E, Pinto J, Barros A, Brindle K, Gil, AM

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