Abstract A10: In search of Kras resistance genes: Whole transcriptome analysis identifies critical pathways mediating resistance and sensitivity to oncogenic Kras
Authors: Bailey Jennifer M. , Alsina Janivette , McAllister Florencia , Hendley Audrey , Lafaro Kelly , Habibulla Anzer , Marchionni Luigi , Maitra Anirban , Leach Steven 
Published: October 2015

In human tumorigenesis, mutational oncogene activation is postulated to occur in either single cells or small numbers of cells, followed by clonal expansion and tumor initiation. In the field of pancreatic cancer research, transgenic animal models mimicking the human disease have contributed to major advancements in our understanding of pancreatic cancer biology. These models have allowed the effects of oncogenic Kras (KrasG12D) activation to be evaluated in different pancreatic compartments using Cre/Lox technology. When oncogenic Kras is expressed under the control of endogenous Kras regulatory elements and selectively activated in embryonic pancreatic epithelium using either Pdx-1:Cre, Ptf1a:Cre or Nestin:Cre driver lines, the KrasG12D allele induces murine pancreatic intraepithelial neoplastic lesions (mPanIN) at as early as two weeks of age. In adult pancreas, selective activation of oncogenic Kras in the acinar cell compartment using either tamoxifen-regulated Elastase (Ela):CreERT2, Mist1:CreERT2 or Ptf1:CreER driver lines also leads to effective mPanIN formation, supporting the possibility that adult acinar cells may serve as the cell type of origin for “ductal” neoplasia. In comparison, activation of oncogenic Kras in Sox9-expressing ductal epithelium leads to only low frequency mPanIN formation (Kopp et al, 2012), indicating that Sox9-expressing duct cells may be more resistant to transformation by oncogenic Kras. We have thoroughly interrogated the ability of the pancreatic ductal epithelium to respond to oncogenic Kras using the HNF1β:CreERT2 transgenic mouse. Our unpublished data support the findings of Kopp et al., as activation of Kras fails to induce mPanIN up to six months after the induction of recombination. Furthermore, combined KrasG12D activation and loss of the potent tumor suppressor p53 also fails to induce mPanIN formation from the HNF1β ductal compartment. In order to better understand the differential responsiveness of adult acinar and ductal cells to oncogenic Kras, we have FACS sorted acinar cells from PanIN-forming Mist1:CreERT2;LsL-Kras;mTmG mice and duct cells from non-PanIN forming HNF1β:CreERT2;LsL-Kras;mTmG mice at 0, 1 and 3 weeks following tamoxifen administration, and prior to the onset of any morphologic change. Following FACS-based cell isolation, we have performed whole genome transcriptional profiling to identify candidate genes mediating differential responsiveness to oncogenic Kras. This approach has identified a panel of candidate genes mediating Kras resistance in ductal cells, and a corresponding panel of candidate genes mediating Kras sensitivity in acinar cells. Genes potentially mediating Kras resistance in the ductal compartment include Plkha1, Slc9a9 and Pdcd10, while the loss of Gmnn and Med6 in the acinar cells appears to be associated with cell type-specific sensitivity to oncogenic Kras. Functional interrogation of identified genes is currently underway.

Citation Format: Jennifer M. Bailey, Janivette Alsina, Florencia McAllister, Audrey Hendley, Kelly Lafaro, Anzer Habibulla, Luigi Marchionni, Anirban Maitra, Steven Leach. In search of Kras resistance genes: Whole transcriptome analysis identifies critical pathways mediating resistance and sensitivity to oncogenic Kras. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A10.