Abstract A84: PDAC initiation and progression occurs more rapidly from KrasG12D-expressing ductal cells than KrasG12D-expressing acinar cells in the absence of Trp53
Authors: Lee Alex , Dubois Claire , Schaeffer David , Sander Maike , Kopp Janel 
Published: December 2016

PDAC development is associated with the formation of premalignant duct-like lesions called pancreatic intraepithelial neoplasias (PanIN). PanIN are thought to initially form as low-grade hypermucinous PanIN1 lesions then become less mucinous and contain nuclear nuclear atypia. Although these lesions are known to be associated with PDAC, with the exception of PanIN3 lesions, it is unknown whether PanINs directly contribute to PDAC. To model PanIN and PDAC initiation, animal models have been created to express one of the most common PDAC mutations, oncogenic KrasG12D, in pancreatic cells. Expression of KrasG12D specifically in acinar cells results in widespread formation of low-grade PanIN lesions, where as KrasG12D expression in ductal cells results in low numbers of low-grade PanIN. This suggests that both acinar and ductal cells can contribute to low-grade PanIN, but these lesions form more readily from acinar cells in the presence of KrasG12D. The contribution of acinar and ductal cells to PDAC, however, is less clear. Recent studies have shown that loss of Brg1 or biallelic expression of Trp53R172H are required for ductal cell transformation, however loss of Brg1 in acinar cells prevents PanIN formation in the presence of KrasG12D and only one copy of Trp53R172H is required for transformation of KrasG12D-expressing acinar cells. This suggests that the genetic or epigenetic changes needed for ductal and acinar cell transformation are different. However, the underlying impact of cellular origin to tumorigenesis remains unclear. To address this open question, we examined whether acinar or ductal cells expressing oncogenic Kras contribute to PDAC in the absence of Trp53. Using our novel Sox9CreER;KrasG12D or Ptf1aCreER;KrasG12D mouse models combined with a condition knockout allele for Trp53, we created Sox9CreER;KrasG12D;Trp53f/f (Duct:Kras-p53) or Ptf1aCreER;KrasG12D;Trp53f/f (Acinar:Kras-p53) mice. Our unpublished analysis of these mice show that KrasG12D induces lethal PDAC from ductal and acinar cells in the absence of Trp53. Remarkably, the survival of mice with ductal-cell-derived PDAC is significantly shorter than the survival of mice with acinar-cell-derived PDAC. Through analysis of these mice at earlier time points, we demonstrated that this difference in survival appears to be primarily due to the rapid induction of high-grade PanIN lesions and PDAC from ductal cells by as early as four weeks after the induction of recombination. In contrast, tumor development from acinar cells is initiated at a slower pace, requires loss of the mature acinar cell fate, and is associated with the formation of large numbers of low-grade PanIN, as well as a lower number of high-grade lesions. Altogether, these early events appear to delay tumor formation from acinar cells compared to ductal cells. Thus, cellular origin has important affects on tumor initiation and progression. Finally, cellular origin not only appears to impact initiation of tumorigenesis, but the tumors arising from ductal and acinar cells also appear to differ. Our studies revealed that gross distant metastases occurred from ductal-cell-derived PDAC, but was not observed in mice with acinar-cell-derived PDAC. This suggests that the inherent phenotype of the tumors resulting from acinar and ductal cells may also differ. In sum, work by our group and others have shown that both acinar and ductal cells can contribute to PDAC. Importantly, our work shows that cell of origin alone can impact the course of tumor development and affect the metastatic nature of PDAC.

Citation Format: Alex Lee, Claire Dubois, David Schaeffer, Maike Sander, Janel Kopp.{Authors}. PDAC initiation and progression occurs more rapidly from KrasG12D-expressing ductal cells than KrasG12D-expressing acinar cells in the absence of Trp53. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A84.