Pancreatic stellate cells perform a wide range of vital tasks in the pancreas as long as they are in a healthy quiescent state. However, when activated, they play a key role in the development of pancreatitis, fibrosis, and ultimately pancreatic cancer. Prof. Minoti Apte, Director of the Pancreatic Research Group at the University of New South Wales (UNSW) in Sydney, has spent her entire scientific career studying these cells. She was recently awarded the Herbert Falk Award for her groundbreaking research results. The award ceremony took place during the Falk Foundation Symposium 242 “Advances in Hepatology – from Mechanistic Insights to Novel Therapeutic Concepts” in Berlin (Germany) on October 24, 2025.

Prof. Apte, what characterizes healthy pancreatic stellate cells?

Healthy pancreatic stellate cells are able to store large amounts of vitamin A in lipid droplets. This is one of their main signatures. When these cells become activated due to injury, the first change that occurs is the loss of the lipid droplets. In the pancreas, stellate cells also appear to have an immune function. Similar to macrophages, they can phagocytose damaged cells, and they produce cytokines and chemokines. In a healthy pancreas, they are responsible for the turnover, regulation, and repair of the extracellular matrix. They secrete extracellular matrix proteins as well as the enzymes that digest these proteins. In addition, they exhibit stem cell-like features, enabling them to convert into other cell types, such as beta-like cells.

You have also worked with hepatic stellate cells. What similarities are there between these two cell types?

Knowledge of hepatic stellate cells dates back many years; they were first described about 150 years ago. 
Our work was inspired by hepatic stellate cells, but the main focus is on pancreatic stellate cells. Scientific research on pancreatic stellate cells is relatively recent. Stellate cells in the liver share several similarities with those in the pancreas. Both store vitamin A in cytoplasmic lipid droplets. Both have quiescent and activated states, and both are activated by a variety of inflammatory mediators, oxidative stress, and other metabolic changes. Upon activation, they produce large amounts of extracellular matrix proteins, leading to fibrosis. Both types of stellate cells are also known to play a role in facilitating cancer progression. 

And the differences? 

We were able to show that pancreatic stellate cells are directly activated by alcohol and that they have the capacity to metabolize alcohol. This was not known before. It was previously believed that stellate cells were activated only by oxidative stress or by other processes occurring during alcohol metabolism. We demonstrated that exposure to alcohol can directly activate stellate cells, which represents one important difference.
Another difference is their location. In the exocrine pancreas, stellate cells are found around acinar cells, and there is crosstalk between these cell types. Acinar cells are exocrine pancreatic cells that synthesize and secrete digestive enzymes. These proteins in turn can activate stellate cells.
However, the most significant difference between the liver and the pancreas is the presence of endocrine tissue in the pancreas. Beta cells, located in the pancreatic islets of Langerhans, are responsible for synthesizing and secreting insulin to regulate blood glucose levels. Pancreatic stellate cells have also been found in and around these islets, where they can interfere with beta-cell function. Thus, pancreatic stellate cells operate in a distinct context—compared to their hepatic equivalent, they are part of a different organ.

What did you investigate?

We started this work at the end of my PhD in 1997. Chronic pancreatitis is characterized by extensive fibrosis, and at that time little attention was paid to fibrosis; it was generally considered merely an epiphenomenon of chronic inflammation. Given that hepatic stellate cells had been well recognized for their role in hepatic fibrosis, we wondered whether similar mechanisms may apply to the pancreas. The idea was that if we could identify the cells responsible for fibrosis, we might be able to target them at an early stage. That is why we focused on pancreatic stellate cells.

You talked about injuries in the pancreas. What kind of injuries? 

The most common injury is acute inflammation, often caused by gallstones or alcohol, but there are also other causes of pancreatitis, such as hypertriglyceridemia, bacterial or viral infections, and others. Acute pancreatitis can progress to chronic pancreatitis, which is characterized by fibrosis. Recurrent episodes of acute pancreatitis cause increasing damage to the pancreas, eventually resulting in chronic damage of the gland. As a result, patients may lose digestive enzyme production and become unable to properly digest their food. If the endocrine system is affected, diabetes may develop. Nerve damage can also occur, leading to chronic pain.

Which morphological changes occur when pancreatic stellate cells transform from a quiescent state into an activated state?

The first change that appears to occur is the loss of the vitamin A-containing lipid droplets. The cells then begin to express a protein called alpha-smooth muscle actin (α-SMA), which is commonly used as a marker of activation. Subsequently, they secrete large amounts of extracellular matrix proteins and produce their own cytokines, such as interleukins, which can act on the stellate cells themselves. During the acute pancreatitis stage, activation of stellate cells is important and necessary. In this setting, neutrophil infiltration occurs, whereas in the chronic stage, macrophage infiltration predominates. We have shown that stellate cells communicate closely with macrophages, leading to mutual activation, and this feed-forward loop can result in the extensive fibrosis seen in chronic pancreatitis. 

Can certain foods or other substances also act as triggers? 

Alcohol is a strong trigger. The cells can maintain this activation even when there is no more alcohol present. There is no particular diet that has been identified, but high fat intake is known to activate these cells as well. Smoking, especially in combination with alcohol consumption, is another important trigger of the pancreatic stellate cells. If we expose animals to alcohol and smoke, we observe much more fibrosis than with either alone. This combination results in a much quicker progression to chronic pancreatitis. And that is clinically relevant because epidemiologically, smoking has been shown to accelerate the progression of alcoholic pancreatitis. 

And the mechanisms you have described are the path to cancer? 

This is definitely related to cancer. Important mutations in the development of pancreatic cancer affect the KRAS oncogene, among others. When pancreatic acinar cells harbor those mutations, they become key precursors to pancreatic intraepithelial neoplasia, abbreviated as PanINs, which can develop into pancreatic ductal adenocarcinoma, abbreviated as PDAC. In animal models, we have observed that activated stellate cells are present around PanINs: thus very early in the carcinogenic process, you find activated stellate cells. Our hypothesis is that these cells are already helping the PanIN cells to proliferate so that they develop into cancer. 

Do you have tools to interrupt or reverse the activation of these cells? 

If you can find a way to target stellate cells—either keeping them quiet, reversing activated cells to quiescence, or killing them—then maybe you can stop the progression of fibrosis. There are a couple of pathways responsible for the reversal of activated stellate cells, and we are trying to look at these pathways to see what happens. For example, using vitamin A: If we culture these activated stellate cells in culture medium supplemented with retinol, they can return to normal. There are already clinical trials looking at the effects of vitamin A on pancreatic cancer. We have peroxisome proliferator-activated receptor gamma agonists, or PPAR-γ agonists, such as troglitazone; they can be used to reverse activated stellate cells to their normal state. Activation of vitamin D receptors in the cells could also eventually reverse the cells. We have shown that this cholesterol-lowering drug inhibits the activation of stellate cells. Currently, one simvastatin trial is being registered as a clinical study including patients suffering from chronic pancreatitis with pain. There are definitely ways to target stellate cells in terms of trying to make them quiet. Another pathway is the urokinase-type plasminogen activator (uPA). It plays an important role in tumorigenesis, tumor progression, and metastasis. In pancreatic cancer, uPA is upregulated and associated with poor survival. The idea is to identify those patients who might benefit from uPA inhibition. We have demonstrated in many different models that a compound that specifically inhibits uPA can not only prevent cancer growth but, above all, almost completely eliminates metastasis. And that is crucial in pancreatic cancer.

Is it possible to detect very early stages in order to take appropriate preventive measures? 

The symptoms of pancreatic cancer appear very late in most patients. Therefore, the challenge is to diagnose the disease at an early stage. Maybe we could select a population that is “high risk.” One of these populations consists of certain people with new-onset diabetes. They are diagnosed with diabetes two to three years before their cancer diagnosis. Something is happening within their pancreas at the time they receive the diagnosis of diabetes, but no one knows what. Something in the pancreas is progressing. We investigated the role of stellate cells in glucose intolerant mice bearing a KRAS mutation which makes the mice susceptible to developing pancreatic cancer. We found that PanIN cells (the earliest lesions of pancreatic cancer) in these mice are already surrounded by activated stellate cells. Our hypothesis is that interactions between the stellate cells and PanIN cells lead to the secretion of exosomes, which affect the beta cells in the endocrine system. Exosomes are vesicles which carry protein, lipids, or DNA signals to other cells. We have already shown that the function of beta cells, specifically insulin secretion, is inhibited by exosomes. The resulting hyperglycemia can activate stellate cells, which in turn can further facilitate PanIN progression. This loop continues, which then maybe leads to cancer. We are trying to find out what is the cargo in these exosomes that causes insulin deficiency and whether any detected mediator may be differentially expressed in exosomes of patients with new-onset diabetes with pancreatic cancer compared to new-onset diabetes without pancreatic cancer. 

Are there biomarkers that indicate early cancer development? 

Our PhD student found one particular marker which is very interesting. When we conducted a study and tested a limited number of patients, we found that this particular marker was significantly reduced in a group of patients with newly diagnosed diabetes and pancreatic cancer compared to those without pancreatic cancer. If this marker is measured at the time of new-onset diabetes and you follow up with the patient, and if that marker keeps decreasing, then maybe you have to look more closely for signs of early cancer. That’s the kind of work that is ongoing, but there is a lot more to do.

Why are you focusing your scientific research specifically on the stellate cells?

At the beginning, nobody worked on pancreatic stellate cells; nobody had expertise. Nobody was looking at the connection between cancer, stellate cells, and endocrine cells until we started. We found that niche, which is why this project was funded all these years. So, we were lucky. That’s one practical reason why we have focused on this topic. But the main reason for me is that these pancreatic stellate cells are like my baby (laughs). I wanted to figure out how they work, what makes them “tick” this way. It was a completely unknown field. Furthermore, there had been no progress for decades in the field of pancreatic cancer. Although there were many chemotherapy treatments, the survival rate of patients was very poor. Many researchers realized that it was necessary to target the microenvironment of the cancer and stop the crosstalk. And this work keeps on going. 

When you solve one problem, the next one immediately arises.

Yes, whenever you discover something new, many new questions arise. If you know more about stellate cells, what is the relationship to the endocrine cells? What about vascular cells and endothelial cells? How do all these cells work together? How does a particular target affect this or that cell? You have to consider the entire organ and the entire patient. This is a very complicated story. 

Don’t you sometimes think it’s too complicated for me, that it’s too much for me? 

I don’t think it’s too much. I think, at most, that a lifetime is too short to get an answer to all these questions. But we were pioneers in that area. Today, the biology of stellate cells is much better understood. Our work has shifted a little from the biology of these cells to their role in disease and how we might treat patients. I have a medical background, and I’m interested in pathology and the clinical situation. My main focus is the patients. Maybe we haven’t explained all the mechanisms, but it may not matter in the end if you achieve results, stopping patients from getting cancer or preventing metastasis. That is the philosophy we work by. All we can do is keep trying and not give up. 

What does the Herbert Falk Research Prize mean to you?

That was such an honor, and it was so unexpected. I think the prize was awarded for the first time with the pancreas in mind, and the first time a woman was considered (laughs). This prize will support the work we want to do now. At least I can give my postdocs some salary for half a year. At the moment, funding is a major challenge. This money is very, very helpful.