Activation of KrasG12D and Tgfa leads to an accelerated carcinogenesis and the develoment of IPMN lesions in a novel endogenous mouse model of pancreatic cancer

Introduction: Besides activation of an oncogenic KrasG12D mutation, growth factors have been implicated in pancreatic carcinogenesis. In this study we analyzed the effect of pancreas-specific Tgfa overexpression in addition to conditional activation of mutant endogenous KrasG12D.

Methods: Elastase-Tgfa mice were crossed to p48+/Cre;Kras+/LSL-G12D mice. Pancreata were analyzed at different time points and after development of malignant tumors using IHC, IF, WB, quantitative RT-PCR and Affymetrix array.

Results: Concomitant expression of Tgfa and mutated KrasG12D leads to an accelerated progression of mPanIN lesions to metastatic pancreatic cancer. Malignant tumors developed after 5–8 months compared to 12–15 months in KrasG12D littermates. Furthermore, the development of cystic papillary lesions with striking resemblance to human IPMNs were notable. IPMN-like lesions express Muc1 and Muc5AC but not Muc2 or Cdx2 and microarray analysis reveals an IPMN signature in the early carcinogenic process. In addition, genes found to be highly expressed in human IPMNs and Ras activation were found to be increased in KrasG12D;Tgfa pancreata compared to KrasG12D and Tgfa littermates. Thus, these lesions resemble the pancreatobiliary type of human IPMN making this mouse model the first endogenous tumor model of this increasingly detected and clinical important entity. In older mice progression of cystic papillary lesions to invasive and metastatic PDAC was notable suggesting a second (IPMN) precursor lesion in addition to PanINs in this model.

Conclusion: Tgfa-induced Egfr signaling in addition to oncogenic Kras accelerates pancreatic carcinogenesis and may be a prerequisite for IPMN lesion development and progression to malignant tumors.