In 2022 alone, half a million new cases of pancreatic cancer were diagnosed worldwide. This is an aggressive tumor whose incidence is on the rise in Western countries, though the reasons remain unknown. It affects both men and women equally and carries a grim survival rate of less than 9% at five years. Part of this is due to its asymptomatic nature, often leading to diagnosis in advanced or metastatic stages, complicating treatment. Hence the importance of finding biomarkers that enable early disease detection.
Dr. Núria Malats, an epidemiologist at the Spanish National Cancer Research Center (CNIO), has been dedicated to investigating biomarkers that allow for the identification of individuals at risk of developing pancreatic cancer. In 2022, she published a study that successfully linked a combination of intestinal bacteria to pancreatic tumors. A set composed of 17 microorganisms from the gut microbiota, when present in a specific combination, is associated with pancreatic cancer, both in its early and advanced stages. This work was chosen by the BMJ Gut journal as the study of the year, marking a significant advancement towards early detection of this type of cancer.
The GMFH editing team had the opportunity to interview Dr. Malats to discuss her findings.
Could this combination of intestinal microorganisms be used as a biomarker for identifying patients at risk of developing pancreatic cancer?
It’s still early, but our results certainly pave the way in that direction and also for potential population screenings to detect the disease in its early stages. Unlike other types of cancer, such as breast or lung cancer, there have been few advances in recent years in both the knowledge and control of pancreatic cancer. In this regard, over the last five years, a network of centers and experts has been established at the European and American levels to combine ideas and projects with the aim of better understanding its origin and finding ways to control it.
What led to the suspicion that the gut microbiota could be involved in pancreatic cancer?
I have been studying pancreatic cancer for over 30 years, and recently we began to see some inconclusive results associating oral periodontitis, a severe gum infection caused by bacterial plaque, with an increased risk of pancreatic tumors. Another subsequent study conducted with a European patient cohort found antibodies against an oral bacterium, Porphyromonas gingivalis, in patients with this tumor. So, I decided to undertake, alongside Peer Bork, director of the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, a large European study involving 4000 individuals, where we sought risk factors for pancreatic cancer. We noticed that periodontitis was one, and we started a small pilot study associating the oral microbiota profile with pancreatic cancer and chronic pancreatitis. In a second phase, we increased the sample of patients and collected samples of saliva, feces, urine, blood, and tissues from 60 pancreatic cancer patients, 60 controls, and 27 pancreatitis patients, an inflammation of the pancreas. An equal number of men and women participated, over 18 years old, although the average age was 70 years. The results of the sample sequencing are what we have presented in this article.
What were the main discoveries or insights gained from your research?
We have identified a signature of 17 microorganisms, mostly bacteria and one archaea, that distinguish pancreatic cancer from control individuals very effectively. This signature could potentially be present before cancer is diagnosed, allowing us to predict individuals at risk of developing it. Now we want to use a European patient cohorts to verify this. Within this signature, there are some ‘bad’ bacteria already known, like Fusobacterium nucleatum, also associated with colon cancer. We have also observed protective species, such as bifidobacteria, which, in a preliminary study, we have seen associated with the consumption of fish and vegetables.
What are the upcoming stages or plans in your research following these significant findings?
To translate this signature into a possible easy-to-implement test that could be used in screening programs. We are also studying whether it is possible to identify these bacteria in blood. At the moment, we are conducting studies in animal models to clarify what is happening. We see that when this combination of microorganisms appears, there is an increased risk of pancreatic cancer, but we do not know the mechanism behind it; or whether this combination of bacteria is a cause or consequence of the tumor, nor how it is participating in tumorigenesis.
In your comprehensive study involving 4000 individuals in Europe, were specific risk factors for pancreatic cancer identified?
We analyzed diet and drug consumption, such as metformin, commonly used in diabetes; this disease, along with obesity, are risk factors for this cancer. And we have seen that diabetic patients who take metformin have an imbalanced microbiota and an increased risk of developing pancreatic cancer. We also looked at the diet in a very preliminary study where we asked the same patients what they ate and how often, so we cannot draw firm conclusions yet. Although it is true that we have started to identify some protective profiles of microbiota associated with the consumption of certain plant-based foods.
I would very much like to contribute to the early diagnosis of this cancer through screening when the disease is still asymptomatic and the tumor is very small and susceptible to surgery and potential cure. For that, we need to know very well which population is at risk, find screening markers, and define the window of opportunity. My research focuses on defining which population is at high risk of developing pancreatic cancer.
Do you believe that considering gut microbiota will become a crucial aspect in both the diagnosis and treatment of pancreatic cancer moving forward?
It is clear that it is a multifactorial and very complex disease, and we are seeing that everything from microbiota metabolites to their composition influences it. It is possible that the metabolites and all the substances secreted by bacteria are infiltrating the pancreas and chronically inflaming it, and that in some cases, tobacco or alcohol is added to that, and the sum of everything ultimately leads to the development of a tumor. Therefore, the personalized medicine of the future must take into account all these factors and integrate them, and it will be in this way that we can end up defining people at risk. These individuals can benefit from early interventions targeted at the microbiota to reduce that risk, such as with probiotics, symbiotics, or postbiotics. Additionally, having biomarkers for the disease would allow the population to benefit from routine screening programs to monitor whether cancer appears in early stages.
