A recent study led by researchers at NYU Langone Health has identified a new mechanism by which pancreatic cancer cells regulate autophagy, the process where cells break down their own components to survive. The findings indicate that the environment surrounding these cancer cells plays a significant role in determining whether they grow rapidly or develop resistance to chemotherapy.
The research, published in Cell on February 16, describes how pancreatic cancer cells adjust their autophagy levels based not only on nutrient availability but also on their ability to sense the extracellular matrix (ECM), which is made up of fibers that surround tumor cells. According to the authors, both normal and cancerous cells thrive when anchored to a specific ECM. However, when cancer cells cannot detect this matrix, they increase autophagy.
The team discovered that certain ECM proteins like laminin are detected by a surface protein called integrin subunit α3 (integrinα3). In laboratory experiments using three-dimensional cultures of pancreatic cancer cells embedded in gel-like substances, researchers observed that proximity to the ECM influenced whether the cells had high or low levels of autophagy. Cells closer to the ECM grew faster with lower autophagy, while those farther away exhibited higher autophagy and greater resistance to chemotherapy.
This division within tumors means it is unlikely that a single drug could effectively target all pancreatic cancer cells. For example, hydroxychloroquine—the only FDA-approved drug for blocking autophagy—has shown limited effectiveness because it does not reach all tumor areas and not all cancer cells are in a high-autophagy state.
To explore potential treatment improvements, researchers genetically suppressed integrinα3 in cell cultures. This forced most of the cancer cells into high-autophagy mode and made them more susceptible to hydroxychloroquine. Removing integrinα3 resulted in a 50% reduction in cell survival compared with hydroxychloroquine alone.
Further experiments involved removing NF2, a protein that transmits signals from integrinα3 inside the cell. Knocking out NF2 reduced both autophagy and lysosomal function—a critical part of cellular survival mechanisms—leading to significantly less tumor growth and increased cell death.
The authors suggest that current strategies targeting autophagy provide only temporary results as cancer cells adapt over time. Their findings point toward combining approaches that disrupt both ECM-mediated regulation of autophagy and lysosomal function for potentially longer-lasting effects against pancreatic tumors.
Contributors included Drs. Emily Kawale, Zahidunnabi Dewan, Alec C. Kimmelman (NYU Langone), Robert Banh (NYU Langone Department of Biochemistry and Molecular Pharmacology), Andrew Aguirre and Joao Paulo (Dana-Farber Cancer Institute/Harvard Medical School), and Diane Simeone (Moores Cancer Center at UC San Diego).
Funding was provided by several National Cancer Institute grants as well as support from organizations such as the Damon Runyon Cancer Research Foundation, Lustgarten Foundation, and Stand Up to Cancer. Disclosures include Dr. Kimmelman's involvement with related patents and advisory roles with pharmaceutical companies.
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