Why Pancreatic Cancer Is So Deadly: New Study Reveals Hidden Invasion Pathway

Brazilian researchers have found that stellate pancreatic cells produce periostin, which reshapes surrounding tissue and allows tumors to spread more easily, helping explain why the disease is so aggressive and deadly.

A new Brazilian study published in the scientific journal Molecular and Cellular Endocrinology has identified a critical role for the protein periostin and stellate pancreatic cells in enabling pancreatic cancer to invade nerves and spread at an early stage, raising the likelihood of metastasis.

The findings show that the tumor actively alters nearby healthy tissue to gain a strong invasive ability. This process helps explain why the disease is so aggressive and hard to treat, while also highlighting potential targets for more precise and personalized therapies.

Why pancreatic cancer is so lethal

The most common form of pancreatic cancer is adenocarcinoma, which develops in the glandular tissue responsible for producing pancreatic juice. It represents about 90% of all diagnosed cases. While pancreatic cancer is less common than many other cancers, it is among the deadliest, with a mortality rate that closely matches how often it occurs. Worldwide, there are an estimated 510,000 new cases each year and nearly the same number of deaths.

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.

How tumors reprogram surrounding tissue

The research was carried out at the Center for Research on Inflammatory Diseases (CRID), one of FAPESP’s Research, Innovation, and Dissemination Centers (RIDCs), and was led by first author Carlos Alberto de Carvalho Fraga. The team aimed to uncover the molecular and cellular processes behind nerve invasion. To do this, they used advanced methods that make it possible to analyze the activity of thousands of genes within individual cells and determine their precise location in the tissue.

“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.

After examining data from 24 pancreatic cancer samples, the researchers found that the stroma, meaning the supportive tissue surrounding the tumor, actively contributes to disease progression. A key discovery involved pancreatic stellate cells, which were shown to produce high levels of periostin, a protein that can reshape the extracellular matrix, the framework that supports and organizes 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.

A microenvironment that fuels invasion and blocks treatment

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.”

Targeting periostin for precision treatment

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.

Reference: “Periostin-positive stellate cells associated with perineural invasion in pancreatic adenocarcinoma” by Carlos Alberto de Carvalho Fraga, Catarina Rosa e Silva Santos, Kayo Felipe Barbosa Lima, Gustavo Henrique Brasil Rodrigues, Caio Cesar Fernandes Nobre Porto, Maria Nathália de Menezes, Gabriel Victor Lucena da Silva, Adriana Simizo, Ana Kelly da Silva Fernandes Duarte, Jussara Almeida de Oliveira Baggio, Amanda Karine Barros Ferreira Rodrigues, Karol Fireman de Farias, Elaine Virginia Martins de Souza Figueiredo, Carolinne de Sales Marques, Pedro Luiz Serrano Uson Junior, Paulo Vidal Campregher and Helder I. Nakaya, 15 October 2025, Molecular and Cellular Endocrinology.
DOI: 10.1016/j.mce.2025.112678

Funding: São Paulo Research Foundation

Never miss a breakthrough: Join the SciTechDaily newsletter.
Follow us on Google and Google News.