Disrupted Glucose Metabolism Led to High Levels of DNA Damage in Pancreatic Tissue: Study

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, contributing to approximately 95% of all cases,^1,2 and is the most aggressive and lethal cancer out of the 60 most common types or organ cancers worldwide.³ More than 90% of PDACs contain mutations in KRAS, so it is thought to be an initiating event in malignant transformation in these cancers. The mutated KRAS pathway leads to the deregulation of glucose, glutamine, and nucleic acid metabolism, allowing for the quick and uncontrolled proliferation of PDAC cells.

It has been suggested that imbalanced glucose metabolism may have a role to play in triggering the high frequency of KRAS mutations in PDAC, but evidence to date has been circumstantial. A new study published in Cell Metabolism⁴ used a well-established method of looking at DNA damage called γH2AX staining, which detects double-strand breaks in DNA, comparing nonmalignant pancreatic samples from people with and without a history of diabetes mellitus. Patients with diabetes had significantly more DNA damage than those without, and this effect appeared to be pancreas-specific, as control intestine samples showed no difference in DNA damage between individuals with and without diabetes.

Next, the researchers confirmed this result by feeding mice a high sugar and fat diet for 20 weeks before testing the level of DNA damage in their pancreata. Compared with mice fed a normal diet, these mice had substantially more DNA damage. A selection of other tissues from these mice showed no increase in DNA damage on the high-glucose diet, adding to the indication from the human samples that this effect was specific to the pancreas.

“The authors demonstrate that nontumor areas of the pancreata of PDAC patients exhibit elevated gH2AX (evidence of DNA damage) and elevated O-GlcNAcylation, results that could be recapitulated in mice by feeding a high-fat, high-sugar diet. The data in humans are consistent with the model that diabetic pancreata have increased O-GlcNAcylation and increased DNA damage,” said Kathryn Wellen, PhD, associate professor in the department of cancer biology at the University of Pennsylvania Perelman School of Medicine, Philadelphia.

Further human pancreatic cancer cell-line studies using exposures of high levels of glucose, glutamine, and palmitic acid confirmed the effect was glucose-specific, and not due to other dietary metabolites.

“The next steps to understand relevance [of this study] to humans are not trivial or obvious to me. It seems that it would be necessary to determine whether humans with type 2 diabetes mellitus or who consume excessive amounts of sugar, but without PDAC, harbor more pancreatic KRAS mutations,” said Dr Wellen.

However, if disrupted glucose metabolism is indeed responsible for a higher incidence of KRAS mutations and ultimately pancreatic cancer, this might be hard to prove further in animal models.

“The authors do not present in vivo evidence that interfering with the pathway that they describe can block diet-induced increased PDAC incidence,” said Dr Wellen, noting that evidence has been presented showing a high-fat diet can accelerate tumor formation and growth in mouse models already with mutant KRAS.^5,6

“The paradigm here is a bit different — the authors propose that high sugar exposure leads to more KRAS mutations. On its own, the sugar-induced mutations will likely not be sufficient to observe development of PDAC in mice,” said Dr Wellen.

Other than requiring more studies to confirm the link indicated in this promising early work, does the study have any immediate clinical implications?

“The paper supports the notion that controlling blood sugar in diabetic patients and limiting excess sugar consumption may help to prevent some cases of PDAC,” concluded Dr Wellen.

References

1. Campbell PJ, Yachida S, Mudie LJ, et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature. 2010:467(7319):1109-1113.
2. Notta F, Chan-Seng-Yue M, Lemire M, et al. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature. 2016;538(7625):378-382.
3. Carpelan-Holmström M, Nordling S, Pukkala E, et al. Does anyone survive pancreatic ductal adenocarcinoma? A nationwide study re-evaluating the data of the Finnish Cancer Registry. Gut. 2005;54(3):385-387.
4. Hu C-M, Tien S-C, Hsieh P-K, et al. High glucose triggers nucleotide imbalance through O-GlcNAcylation of key enzymes and induces KRAS mutation in pancreatic cells. Cell Metab. 2019;29(6):1334-1349. and
5. Philip B, Roland CL, Daniluk J, et al. A high-fat diet activates oncogenic Kras and COX2 to induce development of pancreatic ductal adenocarcinoma in mice. Gastroenterology. 2013;145(6):1449-1458.
6. Chang H-H, Moro A, Takakura K, et al. Incidence of pancreatic cancer is dramatically increased by a high fat, high calorie diet in KrasG12D mice. PLoS One. 2017;12(9):e0184455.