Study reveals protein linked to spread of pancreatic cancer through nerves

Brazilian research shows that stellate pancreatic cells produce periostin, remodeling tissue and facilitating tumor infiltration, a key mechanism of the aggressiveness and high mortality of the disease.

By Fernanda Bassette  |  Agência FAPESP – A new Brazilian study published in the scientific journal Molecular and Cellular Endocrinology has revealed the key role of the protein periostin and stellate pancreatic cells in allowing pancreatic cancer to infiltrate nerves and spread early, increasing the risk of metastasis. The research demonstrates how the tumor reprograms part of the surrounding healthy tissue to acquire a high capacity for invasion. This mechanism is associated with the aggressiveness of the disease and the difficulty of treatment. It also points to possible targets for more precise therapies and personalized treatments. 

The most common type of pancreatic cancer is adenocarcinoma, which originates in the glandular tissue that produces pancreatic juice. It accounts for 90% of diagnosed cases. Although it is not among the most frequent types of cancer, it is considered an aggressive and highly lethal tumor, with a mortality rate almost equivalent to its incidence rate. Globally, there are approximately 510,000 new cases and nearly the same number of deaths each year. 

In Brazil, the National Cancer Institute (INCA) estimates there are about 11,000 cases and 13,000 deaths every 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 authors of the study 

The aggressiveness of this tumor is linked to perineural invasion, a process in which cancer cells infiltrate and spread along nerves. This can cause intense pain and facilitate the spread of the tumor to other regions. “Perineural invasion is a marker of cancer aggressiveness,” says Uson.

The study was conducted at the Center for Research on Inflammatory Diseases (CRID), one of FAPESP’s Research, Innovation, and Dissemination Centers (RIDCs), and its first author was researcher Carlos Alberto de Carvalho Fraga. The group sought to understand the molecular and cellular mechanisms underlying this invasion. To this end, they used technologies that allow the activity of thousands of genes in each cell to be analyzed and their exact position in the tissue to be mapped. “We were able to integrate data from dozens of samples with extremely powerful resolution,” says Helder Nakaya, principal investigator at CRID who led the study. Nakaya is also a senior researcher at Einstein Israelite Hospital and a professor at the University of São Paulo’s School of Pharmaceutical Sciences. 

When analyzing this set of information in 24 pancreatic cancer samples, the researchers observed that the stroma, or the tissue that supports the tumor, plays an active role in its progression. One of the most significant findings was the behavior of pancreatic and stellate cells, which express high levels of periostin, a protein capable of remodeling the extracellular matrix – the structure that organizes and maintains healthy tissue. 

The study points out that tumor cells depend on intense extracellular matrix remodeling processes to advance through tissue and reach nerves, a complex process involving specific enzymes and tissue disorganization. “Periostin participates in this remodeling, paving the way for tumor cells to invade,” Nakaya explains. The nerve, in turn, functions as a kind of “road” for this expansion. 

This altered environment generates a desmoplastic reaction: intense fibrosis around the tumor formed by cells and proteins that harden and inflame the tissue. This hinders the arrival of chemotherapy and immunotherapy drugs because they have more difficulty penetrating the hardened tissue. This creates a “microenvironment” that favors the survival and spread of the tumor. “That’s why pancreatic cancer is still so difficult to treat,” says Uson.

The oncologist emphasizes that this ability to infiltrate is decisive for the poor prognosis of patients with pancreatic cancer. “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.”

He says that more than half of pancreatic cancer cases show perineural invasion in the early stages, which is only discovered during 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.”

Promising target

Given this complex scenario, the researchers say that periostin emerges as a promising therapeutic target. Blocking its action or eliminating the stellate cells that produce it may reduce perineural invasion and limit the tumor’s metastatic capacity. “This work points to paths that may guide future approaches to treating pancreatic cancer,” says Nakaya. Clinical trials on other tumors are already testing antibodies against periostin. According to Nakaya, this helps explore whether this pathway may also be relevant in the pancreas.

Uson points out that this strategy is part of the advance 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 notes that there is currently no therapy that specifically targets perineural invasion and stresses that such a drug could be useful in treating several other cancers that share the same mechanism, including intestinal and breast cancers.

In addition to revealing new therapeutic targets, the work demonstrates the power of complex analyses performed using public databases. “We were able to ask and answer new questions that the original authors hadn’t considered,” says Nakaya. The researchers say the next step is to transform this knowledge into strategies and drugs that act predictively, before invasion occurs. “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.

The article “Periostin-positive stellate cells associated with perineural invasion in pancreatic adenocarcinoma” can be read at www.sciencedirect.com/science/article/abs/pii/S0303720725002291.