Abstract PO-038: Activation of Kras and loss of Pten induces pancreatic ductal adenocarcinoma from pancreatic acinar cells in mice

Cellular origin has an impact on tumorigenesis of pancreatic ductal adenocarcinoma (PDAC). We have previously demonstrated the effects of Pten loss and/or Kras activation in adult pancreatic ductal cells and their involvement in PDAC tumorigenesis. However, mature acinar cells have not been studied in this genetic context before. We used adult Ptf1aCreER;KrasG12D mice with homozygous (Ptenf/f (KPf/f)) or heterozygous (Ptenf/+ (KPf/+)) loss of Pten to specifically express KrasG12D and reduce Pten in the acinar cell lineage to examine this phenotype. We found that KPf/f mice reach humane endpoint much faster than KPf/+ or KP+/+ mice do, suggesting Pten limits tumor development and progression. Upon morphological examination, we found that most tumors develop as moderately or well differentiated or a mixture of both with cystic lesions and gastric-type glands dominating tumor architecture. Morphologically, no differences were found between KPf/f and KPf/+ mice. Tumors have large areas of Alcian Blue and PAS positivity that vary between tumors but not between genotypes. We characterized the tumors by immunohistochemistry (IHC) and found that they are Mucin 1 positive and Mucin 2 negative, regardless of their genotype. Additionally, we stained them for Mucin 5AC, Keratin 20, and Claudin 18 and found variable patterns of positivity amongst tumors regardless of genotype. In summary, our data shows that loss of Pten in acinar cells in context of Kras activation can promote PDAC. In contrast, our previous data demonstrates that loss of Pten alone can predispose ductal, but not acinar cells to tumorigenesis, and activation of Kras further synergizes with Pten reduction. These data suggest that ductal cells are more sensitive than acinar cells to Pten perturbation. Citation Format: Wesley J. Hunt, Claire L. Dubois, Atefeh Samani, Farnaz Taghizadeh, David F. Schaeffer, Maike Sander, Janel L. Kopp. Activation of Kras and loss of Pten induces pancreatic ductal adenocarcinoma from pancreatic acinar cells in mice [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-038.