Pancreatic Cancer: How Cells Use ‘Self-Feeding’ to Survive & Resist Treatment

Pancreatic cancer, a notoriously aggressive disease, presents a significant challenge to clinicians due to its ability to adapt and resist treatment. New research from NYU Langone Health sheds light on a key mechanism driving this resilience: the regulation of autophagy, a cellular “self-feeding” process, influenced by the cancer cells’ interaction with the surrounding tissue environment. The findings, published in the journal Cell, suggest potential new avenues for therapeutic intervention.

Autophagy allows cells to survive under stressful conditions by breaking down and recycling their own components. In the context of cancer, this process can provide a crucial lifeline, enabling cells to withstand nutrient deprivation and the cytotoxic effects of chemotherapy. Researchers have long known that autophagy is often elevated in pancreatic cancer, but the factors controlling its activation have remained incompletely understood.

The NYU Langone team discovered that a critical regulator of autophagy in pancreatic cancer cells is their ability to sense the extracellular matrix (ECM) – a network of fibers and molecules that surrounds cells in tissues. Specifically, cancer cells detect structural proteins within the ECM, such as laminin, through a protein on their surface called integrin α3 subunit (integrin3). This interaction dictates whether the cells prioritize growth or survival.

“Our findings show that detection of the ECM by pancreatic cancer cells allows them switch between states of active growth and autophagic survival,” explains Mohamad Assi, a postdoctoral researcher in the Department of Radiation Oncology at NYU Langone and the study’s first author.

To investigate this phenomenon, the researchers grew pancreatic cancer cells in three-dimensional spheres embedded in a gelatinous substance, mimicking the tumor microenvironment. They observed that cells actively sensing the ECM exhibited low levels of autophagy and a high growth rate. Conversely, cells further away from the ECM, and therefore less able to detect it, ramped up autophagy to enhance their survival capabilities.

This spatial heterogeneity within pancreatic tumors has significant implications for treatment. The study suggests that a population of cancer cells, shielded by high autophagy levels, are better equipped to withstand chemotherapy. This explains, in part, why current treatments often achieve only limited and temporary success.

The challenges of targeting autophagy are further underscored by the limited efficacy of hydroxychloroquine, the only FDA-approved drug specifically designed to block the process. Researchers believe this is because only a subset of cancer cells within a tumor are actively engaged in high levels of autophagy at any given time, limiting the drug’s overall impact.

However, the NYU Langone team demonstrated a potential strategy to overcome this limitation. By genetically suppressing integrin α3 in their 3D cell cultures, they forced nearly all cancer cells into a high-autophagy state. This rendered hydroxychloroquine significantly more effective at eliminating the cells, resulting in a 50% reduction in cancer cell survival compared to hydroxychloroquine alone.

Further experiments revealed another promising target: the NF2 protein. NF2 normally inhibits the signal triggered by integrin α3 activity. By inhibiting NF2, researchers were able to significantly reduce cellular autophagy by slowing down the function of lysosomes – essential cellular structures involved in the autophagic process and other survival pathways. This inhibition led to dramatic reductions in pancreatic tumor growth and triggered cancer cell death.

The researchers caution that current strategies to block autophagy are often short-lived, as cancer cells eventually adapt and find alternative survival mechanisms. Their findings suggest that a more durable approach may involve simultaneously targeting both the regulation of ECM-mediated autophagy levels and lysosomal function. This dual strategy could potentially disrupt the cancer cells’ ability to switch between growth and survival modes, ultimately leading to more effective and long-lasting antitumor responses.

Research published in March 2021 by the University of California San Diego School of Medicine and Moores Cancer Center, also highlighted the importance of autophagy in pancreatic cancer. That study, published in Cancer Cell, described how pancreatic cancer cells utilize autophagy to digest intracellular proteins and use the resulting amino acids as an energy source, effectively circumventing nutrient deficiencies and surviving in the challenging tumor microenvironment. This earlier work further supports the idea that targeting autophagy could be a viable therapeutic strategy.

Metabolic reprogramming, the ability of cancer cells to alter their metabolic pathways to adapt to nutrient stress, is a hallmark of pancreatic cancer. As noted in a February 2024 article in Nature, pancreatic cancer cells can utilize glucose, amino acids, and lipids as energy sources, and also interact metabolically with surrounding cells to promote tumor progression. Understanding these complex metabolic interactions is crucial for developing effective therapies.