Pancreatic cancer, compared to other types of leading cancer killers, is detected later and does not respond well to either new or established drugs.
Now a new UC San Francisco study has shed light on the origins of one type of deadly pancreatic cancer
Pancreatic cancer, compared to other types of leading cancer killers, is detected later and does not respond well to either new or established drugs.
Now a new UC San Francisco study has shed light on the origins of one type of deadly pancreatic cancer.
In a study published online on Feb. 23 in the journal Nature Cell Biology, researchers led by Matthias Hebrok, PhD, head of the UCSF Diabetes Center, reported the identification of a key gene that normally holds tumor development at bay but, when damaged by mutation, allows pancreatic tumors to develop.
Absent advances that could lead to earlier diagnosis and better treatment, only about 6 percent of those in the United States who are diagnosed with pancreatic cancer will be alive five years from now, according to a National Cancer Institute prediction. In the United States, pancreatic cancer receives little press but now kills nearly as many as breast cancer. The American Cancer Society estimates that 40,430 will die of breast cancer in 2014, while 39,590 will die of pancreatic cancer.
In their latest study, the UCSF researchers used a new mouse model they bred especially to explore a mutated gene, called Brg1, or SMARCA4 in humans. They found that loss of the protein encoded by the gene – a result of genetic mutation – helps to trigger development of a type of pancreatic cancer thought to arise from cells lining the digestive-enzyme-secreting ducts of the pancreas.
Brg1 Mutations in Pancreatic Cancer
Rapid advances in scientists’ ability to unravel genomes of both tumors and normal tissues have led to the discovery of many genes that are abnormal in certain cancers. However, not all of these abnormal mutations in cancer drive tumor growth, and the biological importance of many of these mutated genes awaits study in cells grown in the lab or in animal models.
Matthias Hebrok, PhD
Previous studies of pancreatic cancer often have focused on the role of a mutated protein called K-ras. K-ras is implicated in almost all cases of pancreatic cancer and is common in many other cancers. K-Ras has so far been notoriously difficult to target with new drugs, although UCSF researchers led by Kevan Shokat, PhD, recently identified a promising K-ras targeting strategy.
Hebrok’s team is exploring how other mutations – including Brg1 mutations – influence the development of pancreatic cancer in cells with mutated K-ras.
According to Hebrok, who studies both the normal and abnormal development of the pancreas, improved mouse models can help researchers sort out the different ways cancers can form within a single organ type. For instance, he and others have found evidence that pancreatic tumors that form from duct cells arise differently from those that arise from another type of pancreatic cell, called the acinar cell. The cancer type that arises from pancreatic duct cells has been less deadly when detected early.
“We are investigating preliminary evidence that pancreatic duct cells must lose their specialized characteristics, a process called de-differentiation, before they can become cancerous,” Hebrok said. “A K-ras mutation in a pancreatic duct cell cannot drive this process in a vacuum, but elimination of normally functioning Brg1 following K-ras mutation may drive tumor development.”
Targeting Brg1