Seed Grant Recipients

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with very few treatment options and essentially no cure. Inflammatory conditions of the pancreas (e.g. chronic pancreatitis) as well as environmental factors (smoking, diet) are known to increase the risk of pancreatic cancer, providing opportunity for preventive or interceptive strategies.

It is well established that activating Kras mutations play a necessary role in pancreatic cancer initiation and tumor growth. Further mutations of suppressor genes contribute to accelerating disease development. In sharp contrast, environmental factors that promote tumor development, including the role of chronic pancreatitis, are much less explored and understood.

Hereditary pancreatitis is an early-onset form of chronic pancreatitis caused by mutations in the digestive proteases (enzymes that break down proteins). Carboxypeptidase A1 (CPA1) variants that lead to impaired protein secretion and endoplasmic reticulum (ER) stress are highly overrepresented in pediatric cases of chronic pancreatitis. These mutations of the human CPA1 cause autosomal dominant hereditary chronic pancreatitis, and as risk factors, can contribute to pancreatic cancer susceptibility.

In this proposal we will investigate whether hereditary pancreatitis accelerates pancreatic cancer development. We will use a model with pancreas-specific oncogenic Kras and a loss-of-function mutation in CPA1, which results in protein misfolding and causes chronic pancreatitis via an ER stress related mechanism. Through creating early-onset pancreatitis, we will be able to gain a deeper understanding of how inflammation promotes tumor growth. The study will offer critical insight into how hereditary-pancreatitis associated pancreatic cancer develops and how chronic inflammation promotes tumor growth in the pancreas.