How does pancreatic cancer defy treatment?

Pancreatic cancer is the third deadliest cancer in the United States, after lung and colorectal cancer, although it is less common. It is also among the most difficult to treat effectively, as pancreatic cancer stem cells are rapidly developing resistance to conventional and targeted therapies, such as chemotherapy and emerging immunotherapies. As a result, the 5-year survival rate for people diagnosed with pancreatic cancer is only 10%.

In a new research paper published January 18, 2023 in Nature CommunicationsAn international team of scientists, led by researchers at the University of California San Diego School of Medicine and the Sanford Consortium for Regenerative Medicine, is revealing another way in which more resistant pancreatic cancer cells challenge treatment by tapping into a member of the protein family. These normally suppress tumors to help cancer cells avoid treatment and grow more quickly.

Previous research has shown that resistance to pancreatic cancer treatment results from differing responses to conventional agents, which is fueled by the heterogeneity (diversity) of cancer cells – and in particular, the properties of stem cells that promote treatment resistance.

In the new study, senior author Tanishtha Rhea, PhD, formerly professor of pharmacology and medicine and director of the division of cancer biology at the University of California San Diego School of Medicine, and colleagues investigated how epigenesis (the large number of proteins that tell the genome) changes. What to do) rather than genetic changes (specific to the genes themselves) may be driving resistance.

“Pancreatic cancer stem cells, which are aggressive cancer cells that can resist conventional therapies and cause tumor relapse, depend on epigenetic regulation to protect themselves and promote survival and growth,” said Ria, a professor of physiology and cellular biophysics at Columbia University. Associate director of translational research at the Herbert Irving Comprehensive Cancer Center.

“We wanted to identify the basic tools and mechanisms that cancer stem cells use to better understand treatment resistance – and possibly how to circumvent it.”

Rea and colleagues focused on SMARCD3, a member of the SWI/SNF family of proteins that regulate chromatin, a mixture of DNA and proteins that make up chromosomes and is required for stem cell function in development.

But while SWI-SNF subunits often act as tumor suppressors, the researchers found that SMARCD3 was upregulated in cancer, particularly abundant in pancreatic cancer stem cells and upregulated or increased in human disease.

And when the researchers deleted SMARCD3 from models of pancreatic cancer, the loss of the protein reduced tumor growth and improved survival, especially in the context of chemotherapy.

“Importantly, we found that SMARCD3 helps control lipid and fatty acid metabolism, which is associated with treatment resistance and poor prognosis in cancer,” Rea said.

“Our data indicate that treatment-resistant pancreatic cancer cells rely on SMARCD3 to help ensure a metabolic landscape in which they can evade anticancer therapies and grow robustly. This makes SMARCD3 an exciting new target for potential therapies.”

Co-authors are L. Paige Ferguson, Matthew L. McDermott, Mari Nakamura, Kendall Chambers, Nirakar Rajbhandari, and Michael Hamilton, all at UC San Diego and the Sanford Consortium for Regenerative Medicine. Jovylyn Gatchalian, Nikki K. Lytle and Diana C. Hargreaves, Salk Institute for Biological Studies; Sarah Brynn Rosenthal and Vera Favinskaya, University of California, San Diego; Sonia Albini, Université Paris-Saclay, Université Ivry, Inserme, Genethon, Integrier; Martin Wartenberg, Inti Zlobek, José A. Galvan, and Eva Karamitopoulou, all from the University of Bern, Switzerland; Alexis Washer and Andrew M. Lowe, UC San Diego Cancer Center and Morris; Christian M. Schurch, University Hospital and Comprehensive Cancer Center Tuebingen, Germany; Pierre Lorenzo Burri, Sanford Burnham Prebys Institute for Medical Discovery; and Benoit G. Bruno, University of California, San Francisco.

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