The research was published on August 15 in the journal Developmental Cell, and was funded by Cancer Research UK, with additional support from Wellcome, theMedical Research Council, and the Biotechnology and Biological Sciences Research Council.

Researchers from the Cancer Research UK Scotland Centre studied pancreas cells in mice over time, to see what was causing healthy cells to turn into cancer cells. They discovered that pancreatic cells at risk of becoming cancerous, known as pre-cancers, develop faults in the cell's recycling process (known as "autophagy").

In pre-cancer cells, the researchers noticed excess "problem protein" molecules forming clumps - behavior seen in neurological diseases such as dementia. The researchers also noticed similar clumping occurring in human pancreas samples, suggesting this happens during pancreatic cancer development.

Cancer Research UK Senior Fellow at the Institute of Genetics and Cancer at the University of Edinburgh, Professor Simon Wilkinson, said: "Our research shows the potential role autophagy disruption plays in the beginnings of pancreatic cancer. While 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."

Although survival for many types of cancer has improved over recent decades, this has not been the case for pancreatic cancer. This is partly because it is often diagnosed at a late stage, where treatment options are limited.** To address this, the researchers wanted to learn more about what may be causing pancreas cells to turn into cancer.

Multiple cancer types, including pancreatic cancer, are linked to a faulty mutation in a gene called KRAS, but scientists are increasingly learning that genetic changes are not the whole story.

One of the ways cells keep people healthy is by breaking down excess molecules they no longer need, through a recycling process called "autophagy." Autophagy is particularly important in the pancreas to control the level of digestive proteins and hormones the pancreas produces to help break down food.

Scientists have studied autophagy in detail over many years and are learning the key role it plays in diseases such as cancer. In some cases, cancer cells can become "addicted" to autophagy, hijacking the recycling process to help cancer cells divide and grow more quickly***.

This research, on the other hand, suggests the combined effect of the faulty KRAS gene and disrupted autophagy could be driving the development of pancreatic cancer. The researchers plan to study these processes in more detail, to see if they can help predict or possibly reverse the start of pancreatic cancer, and if factors like age, sex, or diet play a role.

Executive Director of Research and Innovation at Cancer Research UK, Dr Iain Foulkes, said:

"Around 10,500 people are diagnosed with pancreatic cancer in the UK each year and, sadly, too many of those cases are found at a stage where treatment options are limited. While further work is needed, these findings could provide vital clues into how we can better understand how pancreatic cancer develops."

Research into pancreatic cancer is one of Cancer Research UK's top priorities. We fund research into the causes of pancreatic cancer, tests to diagnose the disease, and clinical trials designed to look at improving treatment, reducing side effects, and controlling symptoms**.

The paper, titled "ER-phagy and proteostasis defects prime pancreatic epithelial state changes in KRAS-mediated oncogenesis" was published on August 15 in Developmental Cell.

Notes

*Pancreatic cancer statistics. Cancer Research UK. https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/pancreatic-cancer^[1]. Accessed July 2025.

**Research into pancreatic cancer. Cancer Research UK. https://www.cancerresearchuk.org/about-cancer/pancreatic-cancer/research-clinical-trials/pancreatic-cancer^[2]. Accessed July 2025.

***Pimentel et al. Autophagy and cancer therapy. Cancer Letter. 2024. doi: 10.1016/j.canlet.2024.217285.

"This is the first study to really examine how early this biomarker increases and where it begins rising in the brain," said Tomás R. Guilarte, lead researcher and dean of FIU's Robert Stempel College of Public Health & Social Work. "If we can use this information to help delay Alzheimer's progression by even five years, it can drastically improve patients' lives and reduce disease prevalence."

Guilarte, an internationally established expert on TSPO (or translocator protein 18 kDa) has studied the protein for more than three decades. His work helped establish it as a reliable imaging biomarker used in diagnosing neuroinflammation in various neurodegenerative, neurological and psychiatric disorders.

For this study, Guilarte and his team used advanced imaging software to track TSPO levels in genetically engineered mouse models of familial Alzheimer's and confirmed their findings using human brain tissue donated by members of the world's largest group of individuals with early-onset familial Alzheimer's, located in Antioquia, Colombia.

These families carry the "paisa" mutation, identified by the late Dr. Francisco Lopera, one of the authors of the study, who remained dedicated to finding ways to prevent Alzheimer's disease. For carriers of this mutation, symptoms typically begin in their 30s to 40s; they die in their 50s.

In the mouse model, researchers detected elevated TSPO levels in the subiculum - a critical part of the hippocampus - as early as six weeks of age, roughly equivalent to age 18-20 in humans. Microglia, the brain's main immune cells, specifically those clustered around amyloid plaques, had the highest levels of TSPO. Notably, female mice had higher TSPO levels, mirroring real-world statistics: two-thirds of Alzheimer's patients are women.

The brain tissue samples from the Colombian patients with the paisa mutation showed the same pattern. Even in late-stage Alzheimer's, TSPO remained high in microglia near plaques. These results raise new questions about TSPO's function - whether it contributes to damage or protects the brain - and whether blocking or enhancing it could halt disease progression.

The team is now working with a specially developed Alzheimer's mouse model lacking TSPO to explore these questions further. They're also expanding the study to include sporadic, late-onset Alzheimer's cases, the form that accounts for over 90% of all diagnoses.

"The more we understand these processes," said Daniel Martínez Pérez, first author and Ph.D. candidate in Guilarte's lab, "the closer we get to tailoring treatments that can truly help - before it's too late."