A new study from Brazil, published in the journal Molecular and Cellular Endocrinology, sheds light on how pancreatic cancer gains the ability to spread at an early stage. Researchers found that a protein called periostin, along with stellate cells in the pancreas, plays a crucial role in helping cancer cells invade nearby nerves. This early nerve invasion raises the risk of metastasis and is closely tied to how aggressive the disease becomes. The findings also highlight potential targets for more precise and personalized cancer treatments.
The research shows that pancreatic tumors do not act alone. Instead, they alter parts of the surrounding healthy tissue, effectively reprogramming it to support cancer invasion. This process helps explain why pancreatic cancer is so difficult to control once it begins to spread.
A Rare Cancer With a Deadly Impact
The most common form of pancreatic cancer is adenocarcinoma, which develops in the glandular cells that produce pancreatic juice. This type accounts for about 90% of all pancreatic cancer diagnoses. While pancreatic cancer is not among the most frequently diagnosed cancers, it is known for being especially aggressive. Its death rate nearly matches its diagnosis rate.
Worldwide, there are roughly 510,000 new pancreatic cancer cases each year, with nearly the same number of deaths reported annually.
In Brazil, estimates from the National Cancer Institute (INCA) point to about 11,000 new cases and 13,000 deaths each year. “It’s an aggressive cancer that’s difficult to treat. Around 10% of patients have a chance of long-term survival, such as five years after diagnosis,” says Pedro Luiz Serrano Uson Junior, an oncologist and one of the study’s authors.
Why Nerve Invasion Matters
One reason pancreatic cancer is so dangerous is a process known as perineural invasion. This occurs when cancer cells move into and spread along nerves. The process can cause severe pain and also helps the tumor reach other parts of the body more easily. “Perineural invasion is a marker of cancer aggressiveness,” Uson explains.
Because nerves connect different regions of the body, cancer cells that enter these pathways gain new routes for expansion.
Mapping the Tumor’s Hidden Support System
The research was carried out at the Center for Research on Inflammatory Diseases (CRID), one of FAPESP’s Research, Innovation, and Dissemination Centers (RIDCs). The study was led by researcher Carlos Alberto de Carvalho Fraga, with Helder Nakaya serving as principal investigator. Nakaya is also a senior researcher at Einstein Israelite Hospital and a professor at the University of São Paulo’s School of Pharmaceutical Sciences.
To uncover how nerve invasion occurs, the team used advanced tools that analyze the activity of thousands of genes in individual cells while mapping their exact locations within tumor tissue. “We were able to integrate data from dozens of samples with extremely powerful resolution,” Nakaya says.
The researchers examined 24 pancreatic cancer samples and found that the stroma, the connective tissue that supports the tumor, plays an active role in cancer progression rather than serving as a passive structure.
The Role of Periostin and Tissue Remodeling
One of the study’s most important findings involved pancreatic and stellate cells that produce large amounts of periostin. This protein is known for its ability to reshape the extracellular matrix – the structure that organizes and maintains healthy tissue.
Tumor cells rely on major changes to this matrix in order to push through tissue and reach nearby nerves. This remodeling process involves specialized enzymes and widespread tissue disruption. “Periostin participates in this remodeling, paving the way for tumor cells to invade,” Nakaya explains. Once cancer cells reach a nerve, it can act like a “road” that helps them spread further.
Why Treatments Struggle to Reach the Tumor
As the tumor environment changes, it triggers a desmoplastic reaction. This involves the buildup of dense, fibrous tissue around the tumor, made up of cells and proteins that stiffen and inflame the area. The hardened tissue makes it harder for chemotherapy and immunotherapy drugs to penetrate the tumor.
This protective microenvironment allows cancer cells to survive and continue spreading. “That’s why pancreatic cancer is still so difficult to treat,” says Uson.
Early Spread Leads to Poor Outcomes
According to Uson, the tumor’s ability to infiltrate surrounding tissue is a major reason for the poor outlook faced by many patients. “Perineural invasion is a sign that cancer cells have gained mobility. They escape the tumor mass, travel through healthy tissue, and reach nerve and lymphatic bundles, which carry them to other regions of the body, facilitating the development of metastases.”
More than half of pancreatic cancer cases already show signs of perineural invasion at an early stage. However, this spread is usually discovered only after surgery. “Unfortunately, we discover this perineural invasion after it’s already occurred. It’s only seen in the surgical specimen when it goes for biopsy,” Uson says.
Promising target
Given these challenges, the researchers believe periostin represents a promising target for future treatments. Reducing its activity or removing the stellate cells that produce it could help limit nerve invasion and slow the cancer’s ability to spread. “This work points to paths that may guide future approaches to treating pancreatic cancer,” Nakaya says.
Clinical trials in other types of cancer are already testing antibodies designed to block periostin. According to Nakaya, these efforts may help determine whether the same approach could work in pancreatic cancer.
Uson notes that this strategy aligns with the broader shift toward precision medicine. “If we can develop antibodies or drugs that block these stellate cells, we’ll have tools to prevent the tumor from acquiring this invasive capacity so early.” He adds that there is currently no treatment specifically aimed at perineural invasion and that such therapies could also benefit patients with other cancers, including intestinal and breast cancers.
Beyond identifying new treatment targets, the study also highlights the power of advanced data analysis using public databases. “We were able to ask and answer new questions that the original authors hadn’t considered,” Nakaya says.
The next step, according to the researchers, is turning these insights into treatments that act before invasion begins. “Precision medicine is advancing. In the future, we’ll treat patients based on genomic and molecular changes rather than tumor type specifically. This is a significant advance in oncology,” Uson concludes.
