Link between inflammation and pancreatic cancer development uncovered


Date:
September 16, 2021
Source:
University of Texas M. D. Anderson Cancer Center
Summary:
A new study finds that pancreatic cells display an adaptive
response to repeated inflammation that initially protects against
tissue damage but can promote tumor formation in the presence of
mutant KRAS.



FULL STORY ==========================================================================
A new discovery from researchers at The University of Texas MD Anderson
Cancer Center has clarified the long-established connection between inflammation and pancreatic cancer development. According to the study published today in Science, pancreatic cells display an adaptive response
to repeated inflammatory episodes that initially protects against tissue
damage but can promote tumor formation in the presence of mutant KRAS.


==========================================================================
The authors demonstrated that mutant KRAS -- which is found in roughly 95%
of all pancreatic cancers -- supports this adaptive response, leading
to selective pressure to maintain the cancer-causing mutation.

"We discovered that a single transient inflammatory event induced
long-term transcriptomic and epigenetic reprogramming of epithelial cells
that cooperated with oncogenic KRAS to promote pancreatic tumors long
after the inflammation was resolved," said corresponding author Andrea
Viale, M.D., assistant professor of Genomic Medicine. "In the setting
of repeated pancreatitis, KRASmutations can be acquired early on to
limit tissue damage, suggesting the existence of a strong evolutionary
pressure to select mutated cells and providing a possible explanation
for the nearly universal presence of mutant KRASin pancreatic cancers." Clarifying the connection between inflammation and cancer Inflammation
has long been linked to tumor development in several cancer types, but
the specific reasons behind this connection were previously unclear. The research team, led by co-first authors Edoardo Del Poggetto, Ph.D., postdoctoral fellow, and I-Lin Ho, graduate student in the Viale
Laboratory, sought to study the effect of pancreatitis -- a condition
of inflammation in the pancreas linked with a higher risk of pancreatic
cancer -- on pancreatic epithelial cells.

The researchers stimulated transient inflammation in a model system of inducible KRAS-driven pancreatic cancer. Inflammation caused immediate pathological changes in pancreatic cells, but they resolved within
one week.

However, activation of KRASeven monthsfollowing the resolution of
inflammation resulted in accelerated tumor formation compared with
controls, suggesting that inflammation drives long-term changes in
epithelial cells that cooperate with mutant KRASto promote cancer
development.



==========================================================================
Deep molecular analysis of epithelial cells following a single
inflammatory event demonstrated substantial reprogramming of gene
expression and epigenetic regulation that persisted long after recovery
of the tissue damage, a process the researchers termed "epithelial
memory." This cellular reprogramming activated pathways related to cell survival, proliferation and embryonic development, which are similar to pathways active during cancer development.

Epithelial memory enables rapid response to limit tissue damage during recurrent pancreatitis The cellular reprogramming caused by inflammation
also facilitated the acquisition of acinar-to-ductal metaplasia (ADM),
a reversible process in which pancreatic acinar cells acquire features of ductal cells. Acinar cells are responsible for producing and secreting digestive enzymes, while ductal cells are responsible for delivering
those enzymes to the small intestine. ADM, a process that normally
occurs in response to pancreatic damage, is thought to be a pancreatic
cancer precursor.

In the context of epithelial memory, repeated inflammatory episodes
resulted in the rapid and extensive appearance of ADM with minimal signs
of cellular damage, suggesting that the cellular reprogramming protects
the pancreas against an accumulation of tissue damage. These findings
also clarify that ADM is not a cancer precursor state, but rather an
adaptive response to inflammation.

Previous research has shown that KRAS mutations can induce and stabilize
ADM.

Here, the authors demonstrated that induction of mutant KRAS during
repeated inflammations resulted in more pronounced ADM and virtually no
tissue damage.

Thus, the authors predict thatcells undergoing inflammation would have
a strong positive selection for KRASmutations or other alterations that stimulate ADM and limit damage accumulations.

"We are working to better understand how cells maintain the epithelial
memory we observed, but our data suggest that KRASinitially has a
beneficial role during pancreatitis," Ho said. "There may be similar
phenomenon in other cancers with universal driver mutations, where
there is a strong pressure to select those mutations based on some
purpose unrelated to cancer development." The research team now is
working to develop strategies to stimulate ADM in the pancreas while
countering the selection pressure for mutated KRAS. If effective, the
work may offer new treatments for pancreatitis that could also prevent pancreatic cancer development.

========================================================================== Story Source: Materials provided by University_of_Texas_M._D._Anderson_Cancer_Center. Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. Edoardo Del Poggetto, I-Lin Ho, Chiara Balestrieri, Er-Yen Yen,
Shaojun
Zhang, Francesca Citron, Rutvi Shah, Denise Corti, Giuseppe
R. Diaferia, Chieh-Yuan Li, Sara Loponte, Federica Carbone, Yoku
Hayakawa, Giovanni Valenti, Shan Jiang, Luigi Sapio, Hong Jiang,
Prasenjit Dey, Sisi Gao, Angela K. Deem, Stefan Rose-John, Wantong
Yao, Haoqiang Ying, Andrew D.

Rhim, Giannicola Genovese, Timothy P. Heffernan, Anirban
Maitra, Timothy C. Wang, Linghua Wang, Giulio F. Draetta,
Alessandro Carugo, Gioacchino Natoli, Andrea Viale. Epithelial
memory of inflammation limits tissue damage while promoting
pancreatic tumorigenesis. Science, 2021; 373 (6561) DOI:
10.1126/science.abj0486 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210916142902.htm

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