Uncovering the mechanism of drug resistance in pancreatic cancer

University of Virginia researchers have discovered a new mechanism that drives drug resistance in pancreatic ductal adenocarcinoma, one of the deadliest cancers. Their groundbreaking findings could lead to more effective treatments and offer hope to patients facing this aggressive disease.

Uncovering the role of hypoxia in pancreatic cancer progression

Pancreatic tumors are known for their resistance to chemotherapy, due in part to their dense, poorly vascularized tissue structure, resulting in areas of low oxygen or hypoxia within the tumor. Professor Matthew J. Lazzara, of the Department of Chemical Engineering and the Department of Biomedical Engineering, and his team at UVA Engineering wanted to investigate how this hypoxic environment contributes to making cancer cells more aggressive and difficult to treat.

“Our question was simple: Does the low-oxygen environment in pancreatic tumors cause cancer cells to become more resistant to chemotherapy? And if so, does this occur through the same pathways as those triggered by growth factors?” said Lazzara. Growth factors are proteins naturally occurring in the body that stimulate cell growth and survival. In cancer, they can also help tumors grow and evade treatments like chemotherapy by triggering changes that make it harder for cancer cells to be destroyed.

The team's findings were astonishing. They showed that hypoxia actually shifts pancreatic cancer cells into a more aggressive, chemoresistant state. However, the change caused by oxygen deprivation is far more lasting than the similar effect caused by growth factors, making it a significant challenge to treat.

A new resistance mechanism

The study, published in Cancer Research, found that a specific process in cells is activated when pancreatic cancer cells are deprived of oxygen. This process involves changes in the way the cells' genetic material is altered and how signals are sent within the cell, making the cancer cells stronger and more resistant to chemotherapy. Unlike other changes caused by growth factors, this change caused by oxygen deprivation is particularly long-lasting – it can last for weeks after the cells have been exposed to low oxygen levels, making it difficult to treat the cancer effectively.

“We found that once the cancer cells go through this transition under hypoxic conditions, they are much more likely to resist chemotherapy. More importantly, we have identified several ways to interrupt and even reverse this process,” said Brooke Brown, a collaborator on the study.

Using innovative techniques to track cancer cells

To track the effects of hypoxia on pancreatic cancer cells, the researchers used an innovative hypoxia lineage tracing system developed by researchers at Johns Hopkins University. This allowed them to track cells exposed to low oxygen levels over time. Their findings were supported by data from multiple sources, including cell culture models, several mouse models, and computational analyzes of human patient data.

“This approach was novel because we combined cell-based models, animal studies and computational analyzes to comprehensively understand how hypoxia causes this chemoresistant state,” Lazzara said.

Implications for future treatment

The team's next steps are to study how these signaling pathways function in response to chemotherapy drugs known to trigger similar resistance processes.

“We are also studying how hypoxia affects other cells in the tumor environment, such as fibroblasts,” said Lazzara.

This research represents a significant potential advance for the treatment of pancreatic ductal adenocarcinoma. The ability to disrupt the persistent hypoxia-induced changes in pancreatic cancer cells offers a potential breakthrough in improving patient outcomes. With new strategies that specifically target these resistant cancer cells, future therapies could more effectively reduce tumor growth and combat chemoresistance, leading to better survival rates for pancreatic cancer patients.

“Our results highlight the importance of understanding the tumor microenvironment for the development of new therapies,” said Lazzara. “By targeting the signaling pathways that enable cancer cells to resist chemotherapy, we hope to provide pancreatic cancer patients with new, more effective treatment options.”

The study was supported by the National Institutes of Health and other major funding agencies and included collaboration with researchers at the University of Pennsylvania and the University of Oulu, Finland.