A new discovery from researchers at the University of Texas MD Anderson Cancer Center has clarified the long-established link between inflammation and the development of pancreatic cancer.
The results of the study were published in the journal ‘Science’.
According to the study, pancreatic cells exhibit an adaptive response to repeated inflammatory episodes that initially protects against tissue damage, but may promote tumor formation in the presence of mutant KRAS.
The authors demonstrated that the KRAS mutant – which is found in about 95 percent of all pancreatic cancers – supports this adaptive response, leading to selective pressure to maintain the carcinogenic mutation.
“We found that a single transient inflammatory event induces long-term transcriptomic and epigenetic reprogramming of epithelial cells that cooperate with oncogenic KRAS to promote pancreatic tumors long after the inflammation resolves,” said the corresponding author. Andrea Viale, MD, assistant professor of genomic medicine. .
“In repeated pancreatitis, KRAS mutations can be acquired early to limit tissue damage, suggesting the existence of strong evolutionary pressure to select for mutated cells and providing a possible explanation for the almost universal presence of KRAS mutant in pancreatic cancers. Viale added.
Inflammation has long been linked to the development of tumors in several types of cancer, but the specific reasons behind this connection were previously unclear.
The research team, led by co-first authors Edoardo Del Poggetto, PhD, postdoctoral fellow, and I-Lin Ho, graduate student of the Viale lab, sought to study the effect of pancreatitis – an inflammatory condition in the pancreas linked with a higher risk of pancreatic cancer – on the pancreatic epithelial cells.
The researchers stimulated transient inflammation in a model system of inducible pancreatic cancer induced by KRAS.
The inflammation caused immediate pathological changes in the pancreatic cells, but they were gone within a week.
However, activation of KRAS even months after the inflammation resolved resulted in accelerated tumor formation compared to controls, suggesting that the inflammation leads to long-term changes in epithelial cells that cooperate with KRAS. mutant to promote cancer development.
Extensive molecular analysis of epithelial cells following a single inflammatory event demonstrated substantial reprogramming of gene expression and epigenetic regulation that persisted long after recovery from tissue damage, a process the researchers called “Epithelial memory”.
This cellular reprogramming activated pathways related to cell survival, proliferation and embryonic development, which are similar to pathways active during cancer development.
Cell reprogramming caused by inflammation also facilitated the acquisition of acinar-ductal metaplasia (ADM), a reversible process in which pancreatic acinar cells acquire the characteristics of ductal cells.
Acinar cells are responsible for the production and secretion of digestive enzymes, while duct cells are responsible for the delivery of these enzymes through the small intestine. ADM, a process that normally occurs in response to pancreatic damage, is believed to be a precursor to pancreatic cancer.
Against the background of epithelial memory, repeated inflammatory episodes resulted in the rapid and widespread onset of ADM with minimal signs of cellular damage, suggesting that cell reprogramming protects the pancreas against a buildup of tissue damage.
These results also clarify that ADM is not a precursor condition for cancer, but rather an adaptive response to inflammation.
Previous research has shown that mutations in KRAS can induce and stabilize ADM.
Here, the authors demonstrated that induction of mutant KRAS during repeated inflammation resulted in more pronounced ADM and virtually no tissue damage.
Thus, the authors predict that cells undergoing inflammation would have a strong positive selection for KRAS mutations or other alterations that stimulate ADM and limit damage accumulations.
“We are working to better understand how cells maintain the epithelial memory that we have observed, but our data suggests that KRAS initially has a beneficial role during pancreatitis,” Ho said.
“There may be a similar phenomenon in other cancers with universal conductor mutations, where there is a strong pressure to select these mutations based on a goal unrelated to cancer development,” Ho added.
The research team is now working to develop strategies to stimulate ADM in the pancreas while countering selection pressure for mutated KRAS.
If effective, the work could offer new treatments for pancreatitis that could also prevent the development of pancreatic cancer.
(With entries from ANI)
Disclaimer: This article was posted automatically from an agency feed without any text changes and has not been reviewed by an editor
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