Dementia-like protein found to accumulate in pancreatic cells before cancer develops

Scientists from the CRUK Scotland Centre have shown that precancerous pancreatic cells behave… as if they were suffering from neurodegeneration. The endoplasmic reticulum “cleaning” system (ER phagy, a specialized type of autophagy) breaks down, poorly folded proteins accumulate, and aggregates appear – a picture familiar from Alzheimer’s disease and dementia. It is these defects in maintaining proteostasis, together with the KRAS mutation, that push epithelial cells to change their state and activate an early oncogenesis program. The work was published on August 15, 2025 in Developmental Cell.

Pancreatic cancer remains one of the most difficult to treat: it is often detected late, and there are few effective early interventions. A new study adds to the “genetic” picture with early cellular protein quality failures. The authors saw “dementia-like” behavior specifically in precancerous populations, first in mice, and then noted similar protein accumulations in human pancreatic samples. This hints at a common mechanism: when ER phagy sags, the cell drowns in protein debris and more easily “switches” to a metaplastic state, from which precancerous lesions are just a stone’s throw away.

Background

Pancreatic cancer remains one of the most “silent” and deadly tumors: it is often detected late, and there are virtually no early, reliable biomarkers. At the same time, the vast majority of pancreatic adenocarcinomas begin with an oncogenic KRAS mutation in the exocrine epithelium. The first step on this path is acinar-ductal metaplasia (ADM): highly secreting acinar cells lose their “profession”, acquire ductal features and become more plastic and vulnerable to further genetic and environmental shocks. What exactly “pushes” the cell to this change in state is an open question, important for finding windows of early intervention.

The exocrine pancreas is an enzyme factory. Its cells operate at the limit of their synthetic capacity, so their survival depends on the quality of protein assembly and utilization. Two interconnected units are responsible for this: endoplasmic reticulum stress control (UPR) and autophagy, which utilizes defective structures and recycles components. In recent years, attention has shifted to selective autophagy of the ER - ER phagy: special "channels" for the removal of damaged areas of the ER. If ER phagy fails, the cells drown in proteotoxic stress: incorrectly folded proteins and their aggregates accumulate, inflammatory signals are triggered, and gene expression programs change. We know a similar picture from neurodegenerative diseases, where a lack of "cellular cleaning" makes neurons vulnerable.

In the pancreas, such “protein waste” can theoretically play a dual role. On the one hand, chronic stress increases inflammation and tissue damage (associated with pancreatitis, a known cancer risk factor). On the other hand, the proteotoxic background can facilitate the transition to metaplasia (ADM) and consolidate new, precancerous conditions, especially if the oncogenic KRAS is switched on in parallel. In an already formed tumor, autophagy often becomes a “crutch” for survival - and its inhibition can slow growth. But at the earliest stages, a deficit in quality control, on the contrary, can be the very “trigger” that transfers the epithelium to a vulnerable, plastic state.

Hence the logic of the new work: to catch the earliest phase of KRAS-dependent oncogenesis in the pancreas and check whether it begins with a local (spotted) failure of ER-phagy, accumulation of aggregates and a “breakdown” of proteostasis - the very scenario that has long been discussed in neurobiology. If so, three practical consequences immediately appear: (1) early risk biomarkers (markers of ER-phagy and protein aggregates in tissue and, possibly, in “liquid biopsy”); (2) window and stage-dependent intervention in the pathways controlling proteostasis and autophagy; (3) transfer of tools from neurodegenerative research (targets, dyes, sensors, modulators) to pancreatic oncoprevention.

What exactly did the researchers do?

• We observed how healthy acinar cells of the pancreas in mice eventually develop into precancerous states in the presence of oncogenic Kras.
• We measured markers of ER phagy and proteostasis stress, and monitored the formation of protein aggregates and “dumps” in the cell.
• They checked whether this phenomenon is repeated in humans: they analyzed tissue samples of the pancreas at different stages of cancer development.
• We combined morphology, molecular profiles and dynamics of cell “state change” (acinar-to-ductal metaplasia, ADM).

Key finding: An early and “patchy” (stochastic) failure of ER phagy is one of the earliest effects of oncogenic Kras in acinar cells. In genetic models where ER phagy is further impaired, Kras and the proteostasis defect work together to accelerate ADM and subsequent precancerous changes. This shifts the focus from “mutation → tumor immediately” to “mutation + protein quality defect → precancerous plasticity.”

Why This Matters (and How the Dementia Analogy Helps)

• Common link of diseases. Protein aggregates and proteotoxic stress are not only about the brain. In the pancreas, the same "clutter" can be an early trigger for cancer.
• New application points. If ER-phagy "sags" before the appearance of obvious lesions, its markers can be searched for in tissue (and later - in liquid biopsy) as early risk biomarkers.
• Therapy ideas: Autophagy modulators and proteostasis restoration pathways could become context-dependent targets - not for everyone, but at the earliest stage and in combination with a genetic profile.

What exactly was found (facts from the article)

• Precancerous cells showed accumulation of "problematic" proteins and their aggregation - a similarity to neurodegeneration, confirmed in human pancreatic samples.
• ER phagy - the part of autophagy that "takes out" defective areas of the endoplasmic reticulum - breaks down early and unevenly between cells.
• The combination of KRAS + ER-phagy failure enhances ADM (acinar-to-ductal metaplasia) - a transition to an "intermediate" state preceding precancerous changes.
• There is nothing here in terms of time of day and doses of caffeine - but there is a clear logic of events: first, dysfunction of cellular "cleaning", then protein "dumps", then - plasticity of the epithelium.

Terms you can't do without

• Autophagy - "utilization" of unnecessary things inside the cell; supplier of building blocks and cleaner.
• ER phagy is the targeted disposal of damaged endoplasmic reticulum, a protein factory.
• Proteostasis is the maintenance of protein quality and quantity; its breakdown leads to proteotoxic stress and aggregates.
• ADM - acinar-to-ductal metaplasia, a change in the identity of pancreatic cells; an early step toward precancer.
• KRAS is a driver mutation, almost a “calling card” of pancreatic cancer, but, as the work shows, genetics alone are not enough - cellular “environmental” failures are also important.

What this might mean for practice

• Early intervention window: If markers of ER phagy and protein aggregates are confirmed to be available in tissue/blood, this is an option for early risk stratification in surveillance groups.
• Cross-experience with neurology. Methods and molecular targets studied in dementia and diseases with protein aggregates can be transferred to pancreatic oncoprevention.
• Don't "switch on" autophagy blindly. Autophagy in cancer has two faces: later tumors sometimes "addict" to it as a fuel source. So the therapeutic logic here is stage and context.

Limitations and what's next

• Based on mouse models with validation in human samples; prospective clinical studies and markers for screening/monitoring are needed.
• It will be important to test how age, gender and nutrition influence ER phagy and proteostasis: the authors have already stated these directions as next steps.
• It is useful to clarify whether it is possible to “highlight” the vulnerability of precancerous cells to proteotoxic stress without feeding an already formed tumor.

Summary

Pancreatic precancer is not only mutations, but also an early "cleaning failure" in the cell: when ER-phagy breaks down, protein waste accumulates, and the epithelium becomes plastic and ready for an oncogenic revolution. Understanding this sequence gives new chances to catch the disease before it becomes deadly silent.

Source: Salomó Coll C. et al. ER-phagy and proteostasis defects prime pancreatic epithelial state changes in KRAS-mediated oncogenesis. Developmental Cell, 15 August 2025; DOI: 10.1016/j.devcel.2025.07.016.