Abstract 1960: Diffusion MR imaging detects differential progression of pathology in two mutant KRas mouse models of pancreatic neoplasia
Authors: Venkatasubramanian Palamadai N. , Smith Matthew , Mascrinas Emman , Diaz Andrew , Castellanos Karla , DeCant Brian , McKinney Ron , Grippo Paul J. , Wyrwicz Alice M. 
Published: August 2019

Abstract
A significant clinical need exists for understanding the early changes in pancreatic cancer (PC) progression and employing imaging of cellular and tissue phenotypes to detect neoplasia. We have investigated the development of early pathology in EL-Kras and p48-Cre/LSL-Kras (EK and KC, respectively) mice using diffusion MR imaging. These models express mutant Kras via different mechanisms yet recapitulate pancreatic precursor lesions seen in human PC. Our ex vivo investigation shows that diffusion MR imaging based only on endogenous contrast not only detects pre-neoplastic pathology in EK and KC mice, but also differentiates the progression of pathology in these mouse models. Fixed pancreata from EK and KC mice at 4M, 8M and 12M (n=4/group) were examined by diffusion imaging on a 14.1T MR microimager. Mean diffusivity was calculated for acinar lobules and lesions. Pancreata evaluated by MRI were processed for histology (H&E and trichrome) to determine percent area of tissue containing normal, acinar-ductal metaplasia (ADM), fibrosis and neoplasia. Diffusivity was lower in the acinar compartment of EK mice at 4M (0.83x10-3mm2/s) relative to KC mice (1.21x10-3mm2/s) and normal controls (1.17x10-3mm2/s), suggesting that Kras-related pathology targets the acinar cells of EK mice at a younger age than KC mice. Acinar diffusivity, however, did not change further in EK mice at 8 and 12 months, indicating little or no progression of pathology. In contrast, acinar diffusivity progressively decreased with age in KC mice (8M: 0.68x10-3mm2/s; 12M: 0.59x10-3mm2/s) indicating a later onset, but more advancing pathology. Changes in tissue diffusivity arise from a complex combination of cytological changes induced by pathology. Lower diffusivity in EK mice at 4M probably arises from higher levels of ADM (31.7%) compared to 4M KC mice (ADM 11.7%). Reduced diffusivity in KC mice at 8 and 12M most likely is related to elevated fibrosis in those mice (60.0-62.5%) which is relatively low in EK mice (13.3-18.3%). While diffusion MR images revealed the presence of fluid-filled cysts in both models, only KC mice showed lesions with much lower diffusivity (0.55-0.39x10-3mm2/s). Lower diffusivity indicates high cellularity in these neoplastic lesions which are likely mPanINs. Histology revealed that mPanINs which occupied 11.7-18.8% of the tissue in the KC mouse pancreas, are mostly absent in EK mice. Based on our imaging and histology results, MR-measured diffusivity might be a useful marker to assess the onset and progression of PanIN and cystic disease in PC.
Citation Format: Palamadai N. Venkatasubramanian, Matthew Smith, Emman Mascrinas, Andrew Diaz, Karla Castellanos, Brian DeCant, Ron McKinney, Paul J. Grippo, Alice M. Wyrwicz. Diffusion MR imaging detects differential progression of pathology in two mutant KRas mouse models of pancreatic neoplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1960.