Study provides insight into pancreatic cancer development
Cellular glitches, often seen in dementia, may interact with gene mutations
Glitches in a cellular process that are often seen in neurodegenerative diseases and dementia may also play a role in pancreatic cancer development, a study found.
Disturbances in a type of autophagy — a cellular process where unneeded molecules are broken down and recycled — may interact with KRAS gene mutations in pancreas cells to drive the disease, researchers said. They found that mice with KRAS mutations in their pancreatic cells showed impaired autophagy and protein accumulation that spurred a cancer-primed state.
Autophagy failure and protein aggregation are commonly associated with neurodegenerative diseases and dementia, where cognitive declines interfere with daily life activities. Studying these could provide scientists with insight into pancreatic cancer, potentially yielding new treatments.
“While this work is at an early stage, we can potentially learn from research into other diseases where we see protein clumping, such as dementia, to better understand this aggressive type of cancer and how to prevent it,” senior author Simon Wilkinson, PhD, a University of Edinburgh professor and Cancer Research UK (CRUK) senior fellow, said in a CRUK news story.
The study, “ER-phagy and proteostasis defects prime pancreatic epithelial state changes in KRAS-mediated oncogenesis,” was published in Developmental Cell.
Learning from dementia
Pancreatic cancer symptoms often don’t appear until late in the disease, when there aren’t many treatment options, CRUK said. The researchers set out to study how pancreatic cancer develops, looking at genetic causes and cell processes for clues.
In about 90% of cases, tumor cells have mutations in the KRAS gene that are thought to help them grow uncontrolled. Pancreatic cells carrying KRAS mutations may sometimes be considered precancerous, given their propensity to turn into full-blown cancer cells. But animal research suggests that cellular events beyond the mutation likely also occur to prompt overt pancreatic cancer to start growing.
Autophagy is a normal cellular process through which molecules that are not needed are broken down and recycled. Energy stored in those molecules can then be used for other purposes.
In some types of cancer, tumor cells take advantage of autophagy, sending the process into overdrive to generate energy that helps them divide and grow faster.
Wilkinson’s team wanted to understand whether alterations in autophagy may be an early driver of KRAS-associated pancreatic cancer. They were particularly interested in ER-phagy, a form of autophagy that occurs in a cell compartment called the endoplasmic reticulum (ER).
Through a series of experiments in mice, the scientists found that mutant KRAS in pancreatic cells seemed to sporadically suppress ER-phagy, rather than excessively activating it in pancreatic cells called acinar cells.
This process happened in areas where pancreatic cells were undergoing a state change called acinar-to-ductal metaplasia (ADM), which is known to be an early event in pancreatic cancer development.
Ultimately, ER-phagy failure increased the chances that ER proteins — including an injury marker called REG3B — would improperly accumulate instead of being cleared away.
Analyses of human pancreatic tissue similarly showed REG3B clumping nearby to ADM, suggesting these protein abnormalities are also relevant in humans.
These protein clumps caused pancreatic cells to take on an injury-like state, cooperating with mutant KRAS to drive ADM and inflammation that primes cells to turn into cancer.
“Pancreatic cancer can thus arise from … protein aggregates that are influenced by, and cooperate with, an oncogene [a gene that has potential to cause cancer],” the researchers wrote.
They noted that the data adds cancer to the group of diseases that may be driven by dysregulated proteostasis, or the normal function of a cell’s protein network.
“Interventions that ameliorate proteostatic failure — as proposed for conditions such as neurodegeneration — should be evaluated for preventing cancer development,” they wrote.
The team plans to further study autophagy in pancreatic cells to identify whether there are ways to predict, and potentially reverse, the initiation of pancreatic cancer. They’ll also look at whether factors such as age, sex, and diet play a role in this process and could help identify people at higher risk.
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