Wells Lab Shows How Oxygen Deprivation Rewires Pancreatic Tumors

Pancreatic cancer is one of the most deadly forms of cancer — and one of the most difficult to treat. But new research led by Department of Pharmaceutical Chemistry professor Jim Wells, PhD, sheds light on a lesser-understood process in tumor development: how a lack of oxygen alters proteins on the surface of cancer cells, potentially creating new targets for therapies. 

Recently publishing their findings in the Journal of Proteome Research, Wells and his team, which included grad student and PhD candidate Irene Lui as well as postdoc researcher and Helen Hay Whitney Fellow Kaitlyn Schaefer as the co-lead authors, revealed how the hypoxic, or low-oxygen, environment characteristic of pancreatic cancer reshapes the protein breakdown of the tumor. 

“Pancreatic cancer is one of the most hypoxic of all cancers,” Wells said. “My lab has developed a tool for tagging proteolytic events on the surface of cells that provide a diagnostic event.”  

Using mass spectrometry to track where proteins are being cleaved, Wells analyzed four pancreatic cancer cell lines grown under both normal oxygen and low-oxygen conditions. The results were striking. Under low-oxygen conditions, cancer cells showed significant remodeling of their surface proteins — particularly those involved in adhesion and motility, processes that are linked to metastasis. 

“The fact that we can identify these cleaved proteins means we can actually build antibodies that are selected for them,” Wells said. “It’s a safety margin — a way to target tumor-specific changes without affecting healthy cells.” 

Wells, who is also a Harry Wm. and Diana V. Hind Distinguished Professor in Pharmaceutical Sciences, said that, in addition to examining proteins on the cell surface, the team studied the surrounding environment known as the secretome. They identified cleaved proteins released into the surrounding space that are known to influence immune and inflammatory responses, as well as tissue development and metabolism. 

The long-term goal, Wells said, is to translate these discoveries into better diagnostic tools or treatments. Although this study focuses on pancreatic cancer, Wells believes the approach could have broader applications. For example, he said, prostate cells are the next most hypoxic. 

Wells credited UCSF’s translational research ecosystem with helping discoveries like his move closer to the clinic. “We’re at an all-time high when it comes to translating basic science into real therapeutic benefits,” he said, adding that collaboration plays a significant role in his lab’s research and discovery efforts. 

The implications of this work come into sharper focus during National Cancer Research Month, observed each May to honor researchers driving innovation in cancer care. 

“With these data that we generate, we can add to databases that can then be searched by AI to look for patterns,” he said. “We’re just scratching the surface here.”