Hollings researchers reveal why some pancreatic tumors behave differently

(Press-News.org) A new study led by Aaron Hobbs, Ph.D., and Rachel Burge, Ph.D., at MUSC Hollings Cancer Center, reveals why a specific gene mutation behaves differently from other variants. The study, published in Cancer Research, a journal of the American Association for Cancer Research, shows that the mutation drives a less aggressive form of pancreatic cancer, challenging notions about how the gene functions and identifying new opportunities for personalized treatments.

Pancreatic cancer is among the toughest cancers to detect early, and it’s even harder to treat. Unlike many cancers fueled by a mix of genetic changes, most pancreatic tumors share a common driver – the gene KRAS. When mutated, KRAS pushes cells into constant overdrive and reshapes their surroundings. Together, these factors make KRAS-driven pancreatic tumors fast-moving, treatment-resistant and difficult to control.

But not all KRAS mutations act the same way in pancreatic cancer. One specific variant – known as G12R – stands out because it behaves differently from other KRAS mutations. Patients whose tumors carry the G12R mutation often live longer and respond better to treatment than those with more common mutations. Until now, the biological reasons behind these differences have been unclear.

This study sought to answer that question. The project brought together scientists across multiple disciplines, including molecular biologists, bioinformaticians, pathologists, imaging specialists, and clinicians at partner institutions across the country, each contributing specialized tools and perspectives.

“Pancreatic cancer is incredibly intricate,” Burge said. “No one lab could answer this question alone. This study is the product of many experts working together. That multidisciplinary approach allowed us to uncover mechanisms that had been missed for years.”

A closer look at an unusual mutation KRAS mutations are present in approximately 95% of pancreatic cancers. Most fuel aggressive tumor growth and resistance to therapy. But KRAS G12R, found in about 15% of cases, stands out. Patients whose tumors carry the mutation often have better outcomes, including earlier-stage diagnoses, better responses to treatment and longer survival time.

“It’s always been a peculiar mutation,” Hobbs noted. “Clinicians could see the difference in patient outcomes, but the molecular explanation just wasn’t there.”

To explore the biology behind G12R, the team developed several models to study the mutation from the earliest stages of tumor formation through advanced disease. These included engineered cell lines, patient-derived tumors and mouse-implanted human tumors.

The researchers first modeled G12R in mice. Typically, introducing a KRAS mutation leads mice to rapidly develop pancreatic tumors that resemble human disease. But with G12R, something unexpected happened: The mice did not develop cancer.

Across several genetically engineered mouse models – some activating the mutation only in the pancreas and others throughout the body – G12R failed to reliably initiate tumors. Even after a full year, most mice carrying the mutation showed no signs of cancer, while mice with a more common KRAS mutation developed aggressive metastatic disease.

This unexpected result prompted the team to investigate whether G12R functions differently in human pancreatic cancer, in ways that may not be fully captured by mouse models.

A surprising discovery inside the cell The difference came down to how KRAS sends signals inside the cell.

Most KRAS mutations activate two major pathways that fuel cell growth. One is controlled by a protein called PI3K, and the other involves a key regulator of gene activity called ERK.

Mouse models showed strong activation of both pathways. But in human pancreatic cancer cell lines, the KRAS mutation did not activate the PI3K pathway. This meant that a long-held assumption, that KRAS fuels pancreatic cancer by driving both PI3K and ERK signaling, applied to mice but not to humans.

The researchers also uncovered another key difference: Although G12R activated the ERK pathway, less of the activated ERK reached the cell nucleus, where it would normally turn on genes that accelerate tumor growth. Without that “nuclear push,” G12R tumors grew more slowly and behaved less aggressively.

These signaling differences have implications in terms of why KRAS-targeted therapies behave differently in mice than in humans.

“When you inhibit KRAS in the mouse, you get a double hit,” Hobbs explained. “But in humans, you only hit one pathway. That may be why some therapies work great in mice but underperform in human patients.”

A gentler tumor environment The team also examined how G12R shapes the tumor microenvironment – the network of cells, fibers and immune signals surrounding a tumor that help it to grow. Pancreatic tumors are known for their dense, collagen-rich stroma, which forms a tough, fibrous shell that can prevent chemotherapy from reaching cancer cells. 

“In pancreatic cancer, the tumor itself can be tiny. Most of what you see is the stromal shell surrounding it,” Burge said. “Being able to separate the tumor from its environment helped us see differences no one had identified before.”

G12R tumors produced significantly less collagen than other KRAS tumors. The collagen they did produce was also structurally different – looser and less rigid. Because collagen creates a protective barrier around many pancreatic tumors, a thinner collagen network may allow chemotherapy to penetrate deeper and reach cancer cells more effectively.

Moreover, G12R tumors showed reduced cell movement. Since cell movement enables cancer to spread, or metastasize, limited mobility may further slow disease progression.

These differences may help to explain why some pancreatic cancer patients with the G12R mutation experience slower disease spread and better treatment responses, particularly when chemotherapy is given before surgery.

Implications for patient care Together, the study’s findings offer several biological reasons why pancreatic cancer patients with the KRAS G12R mutation often have better outcomes. These include:

Weaker, slower-moving cancer cells. Reduced ability to remodel surrounding tissue. Less collagen, making tumors more penetrable. Lower migratory ability, which may limit metastasis. Understanding the unique weaknesses of G12R could allow future researchers to develop therapies that exploit these vulnerabilities to slow or stop pancreatic tumor growth, such as by blocking ERK from entering the nucleus, disrupting collagen formation or reducing cell movement.

“If we can identify patients whose tumors carry KRAS G12R, we may be able to approach their care differently,” Hobbs said. “These tumors may be more sensitive to certain treatment sequences, and the biology gives us clues as to why.”

Currently, pancreatic cancers caused by KRAS are treated largely the same way. Although more research is needed, these findings point to the potential value of tailoring treatments to specific KRAS mutations.

“This study doesn’t solve the problem today,” Hobbs added, “but it lays the groundwork for how we could potentially improve survival for pancreatic cancer patients in the future.”

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About MUSC Hollings Cancer Center  

MUSC Hollings Cancer Center is South Carolina’s only National Cancer Institute-designated cancer center with the largest academic-based cancer research program in the state. With more than 230 faculty cancer scientists from 20 academic departments, it has an annual research funding portfolio of more than $50 million and sponsors more than 200 clinical trials across the state. Hollings specialists include surgeons, medical oncologists, radiation oncologists, radiologists, pathologists, psychologists and other clinical providers equipped to provide the full range of cancer care from diagnosis to survivorship. Hollings offers state-of-the-art cancer screenings, diagnostics, therapies and surgical techniques within its multidisciplinary clinics. Dedicated to preventing and reducing the cancer burden statewide, the Hollings Office of Community Outreach and Engagement works with community organizations to bring cancer education and prevention information to affected populations throughout the state. For more information, visit  hollingscancercenter.musc.edu.

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