Researchers have halted pancreatic tumor formation in a mouse model that faithfully mimics the human disease by deleting a single gene and have identified three potential therapeutic targets for treating the disease in humans.
Pancreatic ductal adenocarcinoma is the most common form of pancreatic cancer and accounts for around 85% of cases. It is particularly aggressive and is typically only diagnosed in the latter stages of the disease. The disease is characterized by therapeutic resistance and is essentially considered incurable. Pancreatic ductal adenocarcinoma (PDA) has the worst prognosis of any major malignancy. At all stages of the disease, the one-year relative survival rate is only 20% and the five-year survival rate just 7%.
Researchers at NYU School of Medicine and the University of Michigan used a well-known mouse model to test whether the deletion of the ataxia-telangiectasia group D-complementing (Atdc) gene slowed the progression of PDA. The human homolog of Atdc is upregulated in most PDA cases.
The research focused on acinar cells in the pancreas. Acinar cells secrete digestive enzymes into the small intestine which can lead to low level damage. Acinar cells can readily revert to stem cell types, as can pancreatic duct cells. These cells commonly become cancerous due to DNA changes, including KRAS gene changes which drive the growth of tumors in 90% of pancreatic cancers.
Under stress, the cells undergo acinar-to-ductal metaplasia (ADM) and revert to a primitive cell type to resupply cells, which progresses to pancreatic intraepithelial neoplasia (PanIN), where normal controls over cell multiplication cease to work. PanIN is a precursor to PDA.
The researchers hypothesized that the Atdc gene plays an important role in the development of tumors and the deletion of that gene may slow down cancer growth. They discovered the deletion of the gene totally blocked the formation of tumors.
In the study, mutant KRAS and other genetic abnormalities were responsible for the development of aggressive pancreatic cancer in 100% of the mice used in the study when the Atdc was present and in none of the mice that lacked the gene. Deleting the gene protected the mice from developing PDA.
The researchers determined Atdc is necessary for KRAS-driven ADM and PanIN. Further research showed the Atdc gene triggers the cell signaling protein beta-catenin, which activates several genes, including SOX9. SOX9 has previously been associated with the development of ductal stem cells and their aggressive growth in PDA. Without the Atdc gene, the cells could not induce SOX9 expression, thus preventing cancer growth,
The research suggests Atdc, beta catenin, and SOX9 could all be potential targets for treating pancreatic cancer in humans.
The research is detailed in the paper – ATDC is required for the initiation of KRAS-induced pancreatic tumorigenesis – which was recently published in the journal Genes & Development. DOI: 10.1101/gad.323303.118