Pancreatic cancer, one of the deadliest forms of the disease, is notoriously resistant to treatment. Now, researchers at NYU Langone Health have uncovered a key reason why: cancer cells within a tumor aren’t all behaving the same way. A latest study, published February 16 in the journal Cell, reveals that pancreatic cancer cells adapt to their surroundings, toggling between rapid growth and a survival mode that shields them from chemotherapy. This adaptability, driven by how cells interact with the structural fibers around them, presents a significant challenge to developing effective therapies.
The research centers on a cellular process called autophagy, often described as a “self-eating” mechanism. When activated, autophagy allows cancer cells to break down their own components for sustenance, effectively pausing growth and becoming less vulnerable to drugs designed to kill rapidly dividing cells. Traditionally, autophagy was thought to be primarily regulated by nutrient availability. However, this new work demonstrates that the extracellular matrix (ECM)—the network of fibers surrounding cancer cells—plays a crucial role in dictating whether autophagy is switched on or off. Understanding this interplay could unlock new strategies for overcoming treatment resistance in pancreatic cancer.
How the Tumor Environment Dictates Cell Fate
The study’s first author, Mohamad Assi, PhD, a postdoctoral fellow in the Department of Radiation Oncology at NYU Langone, explained that the ability of pancreatic cancer cells to “sense” the ECM is critical. “Our findings present that the sensing of the ECM by pancreatic cancer cells enables them to switch between states of active growth and autophagic survival,” Assi said. Specifically, the researchers found that cancer cells detect proteins within the ECM, such as laminin, through a protein on their surface called integrin subunit α3 (integrinα3).
To mimic the complex environment of a tumor, the research team grew clusters of pancreatic cancer cells in three-dimensional spheres embedded in gel-like substances. By tracking autophagy levels using fluorescent proteins, they observed a clear pattern: cells firmly anchored to the ECM exhibited low autophagy and rapid growth, although those farther away, with limited contact, ramped up autophagy and entered a survival mode. This creates two distinct populations within the same tumor, each responding differently to treatment.
A Two-Faced Enemy: Implications for Immunotherapy
This discovery has significant implications for immunotherapy, a treatment approach that harnesses the body’s own immune system to fight cancer. Pancreatic cancer cells are known to evade immunotherapy by suppressing the display of certain proteins on their surface, effectively hiding from immune cells. The NYU Langone team found that autophagy is a key player in this process. By removing these “identification tags,” cancer cells become invisible to the immune system.
Previous research has shown that blocking autophagy can enhance the expression of these identification tags, making cancer cells more vulnerable to immune attack. However, the new study suggests that simply blocking autophagy isn’t enough. Because only a portion of cells within a tumor are actively using autophagy at any given time, a drug like hydroxychloroquine—which is approved by the Food and Drug Administration to block autophagy—has had limited success as a standalone treatment. The drug may not reach all tumor cells, and it won’t affect those that aren’t currently relying on autophagy for survival.
Targeting Both Autophagy and the ECM for Improved Outcomes
The researchers explored strategies to overcome this challenge. They found that genetically suppressing integrinα3—the protein that allows cancer cells to sense the ECM—forced nearly all cells into the high-autophagy survival mode. This made hydroxychloroquine significantly more effective, reducing cancer cell survival by 50% compared to using the drug alone.
Further experiments revealed another promising target: the protein NF2. NF2 acts as a brake on the integrinα3 signal, hindering autophagy. By removing NF2, the researchers were able to significantly reduce autophagy and trigger cancer cell death. Importantly, this was achieved by disrupting the function of lysosomes, cellular structures crucial for both autophagy and other survival pathways. These findings suggest that a combined approach—targeting both the ECM-mediated regulation of autophagy and lysosomal function—could provide more durable antitumor responses.
The Research Team and Funding
The study was led by researchers at the Perlmutter Cancer Center at NYU Langone, with contributions from colleagues at the Dana-Farber Cancer Institute, Harvard Medical School, and Moores Cancer Center at UC San Diego. The research was supported by grants from the National Cancer Institute, the Damon Runyon Cancer Research Foundation, the Lustgarten Foundation, and Stand Up to Cancer. Alec C. Kimmelman, MD, PhD, a senior study co-author, has a patent related to autophagy and has served as a consultant for several pharmaceutical companies, including Rafael/Cornerstone Pharmaceuticals, Deciphera, and AbbVie.
The findings underscore the remarkable adaptability of pancreatic cancer cells and highlight the need for more sophisticated treatment strategies. Researchers are now focused on developing therapies that can disrupt the interplay between cancer cells and their environment, potentially paving the way for more effective and lasting treatments for this devastating disease. The next step involves further preclinical studies to refine these combined therapeutic approaches and assess their potential for translation into clinical trials.
This article provides information for educational and informational purposes only and does not constitute medical advice. Please consult with a qualified healthcare professional for any health concerns or before making any decisions related to your health or treatment.
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