USA researchers uncover novel mechanism that supports survival of pancreatic cancer cells

Shashi Anand, Ph.D., a postdoctoral researcher, is studying how pancreatic cancer cells adapt to live in low-oxygen environments.

Pancreatic tumors are notoriously aggressive and highly resistant to therapy, making pancreatic cancer the third leading cause of cancer-related death in the United States. With the goal of finding more successful treatment of the disease, researchers at the USA Health Mitchell Cancer Institute and the Frederick P. Whiddon College of Medicine at the University of South Alabama are examining how pancreatic cancer cells adapt to live under low-oxygen environments, a state known as hypoxia. 

Findings from their study, “MYB sustains hypoxic survival of pancreatic cancer cells by facilitating metabolic reprogramming,” were recently published in EMBO Reports, a high-impact journal that publishes scientific research in all areas of molecular biology. Shashi Anand, Ph.D., is the lead author of the article. Anand is a postdoctoral researcher in the lab of Ajay Singh, Ph.D., a professor of pathology at the Frederick P. Whiddon College of Medicine and leader of the Cancer Biology Program at the Mitchell Cancer Institute. 

The unique histopathology of pancreatic cancer, such as its highly fibrotic nature and poor vasculature, renders the cancer cells severely hypoxic – a major reason why these tumors are so aggressive and therapy resistant. Anand said their studies have found that MYB, a protein-coding gene, plays an essential role in the survival of pancreatic cancer cells under hypoxia. 

“We have found that MYB levels go up in hypoxic cancer cells and help cancer cells in reprogramming their metabolism to reduce dependency on oxygen,” Anand said. “Importantly, we also found that MYB affected the expression and function of hypoxia-inducible factor 1 alpha (HIF1α), a protein believed to be the master regulator of the hypoxia adaptive response in cells.” Research on HIF1α won the Nobel Prize in Medicine in 2019 due to its high significance in health and disease. 

“We noticed in our study that MYB was essential for full functionality of HIF1α,” Anand said. “When we silenced MYB expression in pancreatic cancer cells by genetic manipulation, they failed to form tumors in mice despite forced overexpression of the HIF1α protein.”

Their findings are significant since hypoxia is an inevitable environmental stress that tumor cells face as they evolve and progress. “Adaptive mechanisms that help cancer cells survive under hypoxia also make them more aggressive and resistant to chemotherapies,” Anand explained. “Thus, our findings expose novel therapeutic vulnerabilities that can be targeted for effective treatment of pancreatic cancer.” 

The work is supported by funding from the National Cancer Institute. Additional authors from the Mitchell Cancer Institute and the Whiddon College of Medicine are Mohammad Aslam Khan, Ph.D.; Haseeb Zubair, Ph.D.; Sarabjeet Kour Sudan, Ph.D.; Kunwar Somesh Vikramdeo, Ph.D.; Sachin Kumar Deshmukh, Ph.D.; Shafquat Azim, Ph.D.; Sanjeev Kumar Srivastava, Ph.D.; Seema Singh, Ph.D.; and Ajay Singh, Ph.D. 

Read the full article in EMBO Reports.