Kras Mutation and Acinar Cell Sox9 Expression Drive the Development of Pancreatic Cancer

Cancer researchers have discovered the site where genetic and metabolic factors trigger the initiation of pancreatic cancer (pancreatic ductal adenocarcinoma or PDA).

To determine the origin of pancreatic ductal adenocarcinoma, investigators at the University of California, San Diego (USA) and the University of California, San Francisco (USA) labeled and traced pancreatic cell populations in mice after induction of a PDA-initiating Kras mutation.

The protein product of the normal Kras (Kirsten rat sarcoma viral oncogene) gene performs an essential function in normal tissue signaling, and the mutation of a Kras gene is an essential step in the development of many cancers. A single amino acid substitution is responsible for the activating mutation. The transforming protein that results is implicated in various malignancies, including lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas, and colorectal carcinoma.

Results published in the November 29, 2012, online edition of the journal Cancer Cell revealed that ductal and stem-like centroacinar cells were surprisingly resistant to oncogenic transformation, whereas acinar cells readily formed PDA precursor lesions with ductal features. Formation of acinar-derived premalignant lesions depended on ectopic induction of the ductal gene Sox9, which encodes for a protein that recognizes the nucleotide sequence CCTTGAG along with other members of the HMG-box class DNA-binding proteins.

The combination of Kras mutation and Sox9 expression accelerated the formation of premalignant PDA lesions.

“Previously, it was believed that this cancer arises from the epithelial cells in pancreatic ducts,” said senior author Dr. Maike Sander, professor of pediatrics and cellular and molecular medicine at the University of California, San Diego. “But in this study, we show that ducts have almost no response to oncogenic mutations – mutations that give rise to cancerous tumors.”

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University of California, San Diego
University of California, San Francisco