A New Mouse Model Provides Insight Into the Ductal Cell Origin and Microenvironment of Human PDAC

Wednesday, April 8, 2020 - 9:15am - 10:00am
Lind 305
Daniel Billadeau (Mayo Clinic)
We have previously shown that the serine/threonine kinase GSK-3beta becomes progressively over-expressed during human PDAC development and is localized to the nucleus in the majority of moderately and poorly differentiated tumors. To understand the role of nuclear GSK-3beta in pancreas cancer development, we knocked in to the Rosa26 locus a GSK-3beta cDNA containing a nuclear localization signal sequence (referred to as NG), which was preceded by a lox-stop-lox cassette. These mice were crossed with pdx1-cre (C) and LSL-KRasG12D (K) mice to generate KNGC mice. Although NGC mice do not show any differences compared to C or KC animals at 4-weeks of age, KNGC mice present with loss of acinar cell tissue and expansion of ductal cell structures resembling those seen in human intrapapillary mucinous neoplasm (IPMN). RNA-seq analysis revealed the expression of Agr2 and AQP5, molecules found in human pancreatic ductal adenocarcinoma (PDAC) and whose expression are associated with terminal duct cells, a population with stem-like properties. Additionally, their was substantial desmoplasia surrounding the expanded ductal structures and the pancreas of KNGC mice were infiltrated with monocytes and macrophages expressing markers of the M2 phenotype. Interestingly, the Agr2+ ductal cells expressed high-levels of surface CX3CL1, a chemokine that attracts Ly6C+ monocytes. Significantly, we observed expression of many of the same markers and cell types in human IPMNs, suggesting that the KNGC model reflects IPMN development and could be used to study the early pre-tumor microenvironment and ultimately PDAC development.