Objective
The main objective of this exploratory and innovative project is to understand how inflammatory signals reshape the pancreas in Type 1 Diabetes—specifically how digestive cells transform through acinar-to-ductal metaplasia (ADM). From these pathological signs we find and test efficacy of molecular targets that could preserve and restore the acinar as well as the insulin-producing β-cells.
Our three specific aims are:
1 — Discover when and how pancreatic cells start to change in Type 1 Diabetes (T1D).
We want to find out if and when a process called acinar-to-ductal metaplasia (ADM)—a change where digestive cells in the pancreas begin to look and act like ductal cells—happens in people with T1D. By a large screen of pancreas samples from T1D, we will study how these changes relate to inflammation, the loss of insulin-producing cells, and signals of cellular stress or immune activity. This will tell us whether ADM is an early warning sign or a key step in the disease process, and which markers are specifically expressed in this process and can be used for therapeutic intervention.
2 — Translation into therapy: Understand what causes these changes and how to stop them
We will investigate which molecular “switches” drive ADM during inflammation. We’re focusing on three key pathways—called YAP, EGFR, and IFIH1—that connect inflammation, cell stress, and tissue remodeling. We will test whether turning these pathways up or down can prevent harmful changes or help the pancreas repair itself.
3 — Explore how a small RNA molecule called miR-155 links inflammation to pancreatic damage.
miR-155 is a molecule that becomes very active during inflammation. It can both trigger immune attacks and push pancreatic cells to change their identity. We will test whether blocking miR-155 can protect both the insulin-producing and digestive parts of the pancreas. This could open the door to new treatments that target one shared cause of inflammation and cell damage in T1D.
In summary, this project will uncover when and how pancreatic cells change during Type 1 Diabetes, identify the molecular signals that drive these changes, and test whether targeting key pathways—such as YAP, EGFR, and miR-155—can prevent tissue remodeling and protect insulin-producing cells.
Background Rationale
Our recent research has revealed surprising new insights into how the pancreas changes during the early stages of Type 1 Diabetes (T1D). We discovered that a key regulator called YAP, which normally helps cells recover from stress, behaves very differently in the diabetic pancreas. Instead of protecting the tissue, YAP becomes overactive in the digestive (exocrine) and ductal parts of the pancreas, where it actually worsens inflammation and makes cells more vulnerable to viral infection.
Indeed, a recent study from our group, in collaboration with a large consortium working on the link of virus, inflammation and T1D, found a significant increase in enteroviral RNA particles in the pancreas from organ donors with the T1D risk factor of T1D-associated autoimmunity as well as in manifest T1D. Also those enteroviral particles, remaining from infections, are found much more frequently in the whole pancreas, when compared to islets.
We also identified a small molecule called miR-155, which increases strongly in response to inflammation. While we expected it to act mainly in insulin-producing cells, we found that miR-155 was mostly present in ductal cells—especially in large, reorganized duct structures that appeared much more frequently in T1D. These same kinds of changes are known to occur during pancreatitis, where cells lose their normal identity and reorganize through a process called acinar-to-ductal metaplasia (ADM). Interestingly, similar ductal abnormalities were also seen in T2D, suggesting a shared mechanism linking ductal remodeling to islet inflammation.
Finally, when we grew human pancreatic tissue in the lab, we observed that the cells surrounding insulin-producing islets rapidly changed into duct-like cells marked by SOX9—and this transformation depended on YAP activity.
Together, these findings suggest that inflammatory and viral stress trigger the pancreas to remodel itself in ways that could accelerate the loss of insulin-producing cells. Understanding and controlling these early changes could open new paths to prevent or delay T1D.
Description of Project
An early therapeutic intervention for Type 1 diabetes is urgently needed. Therefore, it is of utmost significance to identify the driver of the disease. Beyond insulin therapy, major research in T1D has focused on blocking immune cell activation and their invasion into the pancreas to destroy the beta-cells. It is still unclear what triggers the immune cell to the pancreas. Recent data show not only a largely reduced mass of the insulin producing beta-cells, but also of the whole pancreas in patients with T1D; and the latter even before diagnosis. Furthermore, sustained pancreatic inflammation and infiltration of enteroviruses are signs of T1D even before diagnosis.
Therefore, we looked closer into the pancreases from several organ donors with T1D or with T1D associated autoimmunity before T1D diagnosis and observed a factor called YAP, which is physiologically absent in beta-cells, to be highly increased in the whole pancreas in autoimmunity and T1D. It is especially high in pancreatic ducts and areas where we also observed enteroviral RNA disposition, which remains present in the pancreas long after acute viral infection and drive inflammation in the pancreas, a state reminiscent of what we now call “long-Covid” in the case of infection with SARS-CoV2. To our surprise, YAP potentiates the deleterious effect of the enterovirus in pancreas cells as well as in islets; there is much more virus seen in the presence of YAP, more inflammation and more cell death. And this inflammation reservoir not only affects insulin producing beta-cells; it also leads to a disorganization in ductal cells.
Ducts form a network connecting acinar cells to the main pancreatic duct and duodenum. However, they are much more than conduits for secretions; they are dynamic, signaling-active epithelial cells with central function for homeostasis, injury response, inflammation, and pancreas regeneration; ductal cells maintain the pancreatic microenvironment. Physiologically, they may attempt to replace lost β-cells. However, in a T1D scenario, inflammation and antiviral signaling likely block endocrine redifferentiation and the compensation capacity to injury is lost.
This marks the beginning of this innovative grant project: we seek to find the ductal axes towards T1D progression. Large recent single cell analyses data from the pancreas are in line with the idea that ductal cells are a central hub where homeostasis converges-determining whether the pancreas regenerates or remodels pathologically. Our study reframes T1D not solely as an autoimmune disorder, but as multi-compartmental pancreatic disease involving epithelial plasticity, innate immunity, and immune-exocrine-endocrine crosstalk.
We will identify the changes in ductal characteristics in pancreas samples from organ donors before and after T1D diagnosis, and when signs of ductal dysregulation occurs and whether they are central to T1D progression. We will characterize these duct-like cells in culture; how they modify the pancreatic microenvironment to exacerbate inflammation and beta-cell failure. Using tractable already identified therapeutic targets, we will mechanistically dissect and pharmacologically modulate ductal changes- redefining how inflammation reshapes pancreatic tissue architecture in T1D and establishing novel interventions for early T1D.
Altogether, we have identified a novel loop how T1D could be initiated -by accelerated disposition of viral marks in the pancreas, which induces inflammation and drives ductal dysfunction and the specifically vulnerable beta-cell into death. Research of this project starts from the angle of the whole pancreas to identify the path from signs of ductal inflammation towards the destruction of beta-cells. By this strategy we hope to interfere very early in the disease, so that beta-cells are protected before the start of damage and T1D progression.
Anticipated Outcome
This project will identify the origin and the pathological mechanisms of YAP’s acinar and ductal expression in autoimmunity and T1D as a driver of pathological changes in the ductal structures of the pancreas leading to beta-cell destruction and T1D progression. This will bring a completely novel understanding of disease starting at an early point before disease onset, namely virus-/stress-induced inflammation of the whole pancreas. We will set up a pharmacological strategy to stop inflammation and beta-cell destruction potentiation by YAP through 3 parallel strategies which act on ductal dysfunction: (1) the inhibition of YAP itself, (2) inhibition of a specific growth signal in the pancreas which leads to ductal abnormalities and (3) the inhibition of a specific small RNA which is highly expressed in large ducts in T1D and fosters inflammation. With these targeted therapeutic strategies, alone or in concert, this project will establish novel biomarkers for early T1D progression at the level of pancreatic disorganization. By establishing exocrine/ductal plasticity and exocrine remodeling, we hope to preserve a healthier exocrine–endocrine microenvironment, reduce paracrine inflammatory/mitogenic signals to β-cells, and thus, preserve islet function.
Relevance to T1D
Therapies directed to the early cause of the disease are currently unavailable for patients with T1D. Understanding and targeting the mechanisms of damage in the pancreas and subsequent beta-cell demise in T1D is essential for therapy. This study looks at Type 1 Diabetes (T1D) in a new way. Instead of viewing it only as a disease caused by the immune system attacking insulin-producing beta-cells, we explore how other parts of the pancreas also play an important role. We focus on the “exocrine” cells—the cells that normally help with digestion—and how they change their identity and behavior during early diabetes.
Ancient data parallel enteroviral disposition in the pancreas with autoimmunity and T1D, and recent confirmation show marks of previous viral infection scattered throughout the whole pancreas organ and not specifically within islets. Now we see that this corresponds with the upregulation of the factor “YAP” in the exocrine pancreas; and thus, we have found the dangerous link: that YAP potentiates virus amplification and cell destruction, which leads to disorganisation of pancreatic ducts. This brings us to a completely novel paradigm for T1D therapy, namely to target the exocrine-duct conversion in pancreas. We believe that this process, called acinar-to-ductal metaplasia (ADM), happens early in the disease and may actually help drive the loss of insulin-producing cells. By studying how key molecular pathways control these changes, we aim to understand how inflammation reshapes the pancreas before diabetes is fully developed.
Our goal is to find ways to stop or even reverse these harmful changes using drugs that target these pathways. This could protect the pancreas, support insulin-producing cells, and offer new treatment options that go beyond traditional immune-suppressing therapies—helping to prevent or slow down T1D at its earliest stages.