The first mouse model of pancreatic cancer that recreates two subtypes of the human disease, has been created by scientists at Cold Spring Harbor Laboratory (CSHL). Their model will help researchers investigate why some pancreatic cancers are more aggressive, and what causes them to progress. Their model may lead the way to targeted therapies.
Their study, “Intraductal transplantation models of human pancreatic ductal adenocarcinoma reveal progressive transition of molecular subtypes,” is published in Cancer Discovery.
The most common type of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), has a poor prognosis and little improvement in patient outcomes. Recently, molecular analyses of patient tumors have identified two subtypes of the disease that behave very differently. The first subtype known as PDAC, is slow to progress and can be responsive to chemotherapy. The second subtype is known as basal PDAC, spreads quickly but does not respond to chemotherapy.
The researchers have been studying both subtypes using three-dimensional cultures of human cancer cells called organoids, and wanted to understand how cancer cells behave inside the pancreas, where surrounding tissues influence a tumor’s growth and progression.
“To address these limitations, we sought to establish an in vivo xenograft model that could recapitulate the basal-like and classical subtypes of PDAC. As the pancreatic ducts are the sites where preinvasive pancreatic neoplasms progress in humans, we reasoned that seeding the murine pancreatic ducts system with human neoplastic cells would offer new cellular and molecular insights into the mechanisms promoting progression of this malignancy,” noted the researchers.
The researchers transplanted a panel of human patient-derived PDAC organoids into the pancreatic ductal system of immunodeficient mice.
“We can now study these two subtypes of tumors within the same microenvironment where they develop in patients,” stated David Tuveson, MD, PhD, CSHL cancer director and the Roy J. Zuckerberg professor of cancer research. “This model is now our racehorse in pancreatic cancer research, allowing us to understand what drives these cancers and investigate therapeutic strategies that target each subtype’s particular vulnerabilities.”
The team has found that PDAC subtype is not a fixed identity. Some of the classical tumors in the mice progressed, acquiring the invasive nature as well as the molecular features of the basal subtype. The researchers discovered that activity of the K-Ras gene, a notorious driver of many cancers, was key to determining each tumor’s nature. They were also able to identify 13 other genes whose activity surged as the classical subtype tumors became invasive.
“A patient with classical subtype has a good prognosis. Maybe if we can induce classical subtype from basal subtype, the patient will have a better chance of survival,” stated Koji Miyabayashi, a postdoctoral researcher at CSHL.