The most common form of pancreatic cancer, pancreatic ductal adenocarcinoma is highly difficult to treat, with a five-year survival rate of only 8%. There is one therapeutic target that has led to encouraging preclinical results: inhibition of oncogenic KRAS, a mutation that is present in over 90% of pancreatic ductal adenocarcinomas. However, in mouse models of this disease, genetic extinction of oncogenic Kras has resulted in recurrence that no longer relies on the Kras oncogene. For this reason, improved strategies are needed to fight this cancer.
"Multiple oncogenic processes are initiated at the cell surface, where KRAS physically and functionally interacts to direct signaling essential for malignant transformation and tumor maintenance," stated Giulio Draetta, MD, PhD, Chief Scientific Officer and Professor of Genomic Medicine at the University of Texas MD Anderson Cancer Center. "Insights into the complexity of the surfaceome [the repertoire of proteins present on the cell surface] have been technologically limited until recently, and in the case of pancreatic cancer, the genetic control of the function and composition of the pancreatic cancer surfaceome in the context of KRAS signaling remains largely unexplored."
Dr. Draetta designed a target-discovery platform able to investigate oncogenic KRAS-dependent changes of the surfaceome in pancreatic ductal adenocarcinoma. He and his team of researchers found that the protein syndecan 1 (SDC1, also known as CD138) is upregulated by oncogenic KRAS at the cell surface, where it controls macropinocytosis, a metabolic pathway essential to the growth of this cancer.
"To date, pharmacological inhibition of macropinocytosis has not been accomplished," remarked Dr. Draetta, the senior author of the study, which has now been published in Nature. "Our findings on the critical role for SDC1 in regulating macropinocytosis in KRAS-driven pancreatic cancer invites exploration of SDC1 targeting for therapeutic intervention."
He added, "We think the cell surface is an exciting place to look for more clues about how cancer cells are fundamentally different from normal cells. Already, monoclonal antibodies directed at SDC1 are being tested for multiple myeloma, a scientific step that may open up clinical study of similar therapies for pancreatic cancer."
For More Information
Yao W, Rose JL, Wang W, et al (2019). Syndecan 1 is a critical mediator of macropinocytosis in pancreatic cancer. Nature. [Epub ahead of print] DOI: 10.1038/s41586-019-1062-1
Image credit: MD Anderson Cancer Center