Abstract LB-382: MR microscopy detects architectural changes in the pancreas of mutant Kras mouse models of pancreatic cancer

Abstract

Abstract Pancreatic cancer (PC) is a devastating disease due to the lack of early detection resulting in late diagnosis and poor prognosis. Thus, there is a need for a technology that can visualize morphological and cellular changes in the pancreas when the cancer cells are at a pre-invasive stage. Nearly 90% of human PC have a mutation in Kras and several mouse models that express mutant Kras develop precancerous lesions resembling those in humans. Using MR microimaging, we examined pancreata from EL-Kras (ELK) and Pdx1-Cre/LSL-Kras (PCK) mice which target mutant Kras to the pancreas via unique approaches. EL targeting employs human mutant Kras where nearly all acinar cells express this oncogene, while Pdx1 targeting uses a mutation in an endogenous mouse Kras allele. The source (human vs. mouse), targeting (EL vs. Pdx1) and delivery (artificial vs. endogenous) of mutant Kras contribute to altered phenotypes including differences in normal appearing parenchyma, frequency of acinar-ductal metaplasia, precancerous lesion formation, and progression to advanced disease. We examined pancreas from both mutant Kras mouse models using MR microimaging and compared their MR signature to that of control mice. Fixed pancreata were imaged on a 14.1T microimager. T2-weighted, high spatial resolution images were acquired with fat suppression using a fast spin-echo 3D imaging protocol and isotropic pixel size of ∼70μm. MR data was reconstructed to provide volume images of the pancreatic components and their spatial relationship to each other. T2-weighted MR microimages had high spatial resolution and excellent endogenous contrast that enabled the visualization of acinar cells, islets and stroma in the normal pancreas. T2-weighted images of ELK pancreas showed poor contrast and delineation between acinar cells, islets and stroma indicating changes in their T2-relaxation times possibly as a result of changes at the cellular level. Contrast between pancreatic components in the PCK pancreas was similar to control. Volume images of the pancreas from both mutant Kras mice showed unique differences from control in stromal architecture. While the normal mouse pancreas had a dense, concentrated network of stroma, the ELK mouse pancreas showed only a sparse network with reduced signal intensity, and the PCK mouse pancreas had a more extensive network of stroma. These differences in stromal architecture of mutant Kras pancreas detected by MR microscopy most likely represent transgene-induced alterations in the composition of extracellular matrix (ECM) and might have implications for the development of pancreatic pre-cancerous lesions and cancer. Ours is the first report of MR microimaging of ECM in the intact mouse pancreas of relevant mouse models of PC. Deciphering the differences in ECM among these two models is the focus of ongoing work. Our results suggest that MR volume imaging at high spatial resolution may have potential in detecting morphological and cellular changes associated with pre-invasive and invasive stages of PC. (Supported by Jay Wertheimer Pancreatic Cancer Research Fund and NIH S10 RR13880) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-382.