Concomitant Pancreatic Activation of Kras super(G) super(1) super(2) super(D) and Tgfa Results in Cystic Papillary Neoplasms Reminiscent of Human IPMN

Growth factors have been implicated in pancreatic carcinogenesis. In this study we analyzed the effect of Tgfa overexpression in addition to mutant Kras super(G) super(1) super(2) super(D) by crossing Elastase-Tgfa mice with p48 super(+) super(/) super(C) super(r) super(e); Kras super(+) super(/) super(L) super(S) super(L) super(-) super(G) super(1) super(2) super(D) mice. We show that concomitant expression of TGF alpha and Kras super(G) super(1) super(2) super(D) accelerates the progression of mPanIN lesions to metastatic pancreatic cancer and leads to the development of cystic papillary lesions resembling human intraductal papillary mucinous neoplasms (IPMN). Microarray data in mice revealed an IPMN signature and IPMNs expressed MUC1 and MUC5AC but not MUC2, similar to human pancreatobiliary IPMNs. Invasive ductal adenocarcinoma developed from PanINs and IPMNs, suggesting precursor lines for both lesion types in this model. In conclusion, Egfr signaling in synergy with oncogenic Kras may be a prerequisite for IPMN development and progression to pancreatic cancer.