Abstract LB-507: A color coded fluorescent transgenic mouse model of spontaneous pancreatic cancer for imaging spectrally distinct cancer cells and stroma

Abstract

Abstract Conditional fluorescent (mTmG) indicator mice constitutively express a conditional tdTomato transgene (mTmG) that converts to the expression of EGFP following exposure to Cre recombinase. PdxCre+, mTmG+ mice express bright, membrane-targeted, green fluorescent protein (mG) specifically in the pancreatic epithelial parenchyma. Non-epithelial pancreatic tissues and non-pancreatic tissues ubiquitously express membrane-targeted tdTomato (mT), providing a red fluorescent backlight in imaging studies. In the present report, we have applied the strengths of the PdxCre+, mTmG+ dual color system to the study of spontaneous tumor development in a triple transgenic PdxCre, LSL-KrasG12D/+, LSL-Trp53R172H/+ mouse model of human pancreatic ductal adenocarcinoma (PDAC). We generated mice that follow the well-described progression of pre-neoplastic changes in the pancreas, and ultimately develop fluorescent pancreatic tumors, recapitulating the sequence of events that occur in human PDAC in an imagable mouse model system. To establish this model, we intercrossed four lines of transgenic mice [PdxCre (C), LSL-KrasG12D/+(K), LSLTrp53R172H/+(P), and mTmG (mTmG)] and generated small cohorts of quadruple transgenics (CKPmTmG) and littermate controls. Like PdxCre+, mTmG+ dual transgenic mice, CKPmTmG mice demonstrated green fluorescent pancreata and red fluorescent non-pancreatic tissues. As in the non-fluorescent PdxCre, LSL-KrasG12D/+, LSL-Trp53R172H/+ (CKP) parental line, CKPmTmG mice developed pancreatic dysmorphia and dysplasia within the first several weeks of life. These changes were accompanied by development of pancreatic tumors and were associated with early mortality not seen in littermate controls. Ex vivo imaging of CKPmTmG mice at necropsy demonstrated a spectrum of pathologic findings, including cystic and solid pancreatic tumor masses surfaced by distorted and distended green fluorescent pancreatic ducts and duct-like structures. The non-epithelial pancreatic tissues provided a red fluorescent background. Histologic findings included ductal dilatation, ductal atypia with features of pancreatic intraepithelial neoplasia (PanIN) as previously described in CKP mice, atrophy of pancreatic acini, and duct-centered desmoplasia entrapping the occasional isolated pancreatic islet. This dual color, quadruple transgenic mouse model enables us to apply fluorescence imaging technology to the study of tumor microenvironment in mice genetically engineered to develop pancreatic cancer spontaneously. Based on preliminary studies, this mouse model promises to be a valuable tool with which to address many intriguing questions and timely controversies regarding the pathogenesis of human pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-507. doi:1538-7445.AM2012-LB-507