Loss of STAT3 Inhibits Acinar-to-Ductal Metaplasia and formation of Pancreatic Intraepithelial Neoplasia Induced by Oncogenic KRAS
Claudius Conrad MD, PhD, Andrew Warshaw, MD, Nabeel Bardeesy, PhD
Massachusetts General Hospital, Boston, MA
PURPOSE OF STUDY
Pancreatic ductal adenocarcinoma (PDAC) is believed to arise from precursor lesions called pancreatic intraepithelial neoplasia (PanIN) and frequently harbors oncogenic mutations in KRAS. In some transgenic models of pancreatic tumorigenesis driven by oncogenic KRAS, PanIN formation is associated with regions of acinar-to-ductal metaplasia (ADM).
We examined the role of STAT3 in KRAS-induced ADM and PanIN formation. We crossed a conditional STAT3 knockout allele into an established mouse model of pancreatic tumorigenesis (Pdx1-Cre; LSL-KRASG12D mice). Malignant transformation via the pancreatic intraepithelial neoplasia sequence (PanIN) was evaluated with H&E staining. We localized STAT-3 and its phosphorylation in PanIN lesions versus pancreatic ductal adenocarcinoma (PDAC) via immunohistochemical and immunofluorescent staining. Pancreatic cancer cell lines were treated with the JAK inhibitor AG490 and evaluated for growth kinetics and STAT3 phosphorylation status using western blotting
SUMMARY OF RESULTS
In mice which retained a wild-type STAT3 allele, prolific PanIN formation and large areas of ADM were observed by 12 weeks of age. These areas stained positively for activated STAT3 phosphorylated at Tyr705. However, in mice homozygous for the conditional STAT3 knockout allele, a dramatic reduction in both ADM and PanIN formation was observed.
Loss of STAT3 did not prevent ADM and pancreatic regeneration in response to pancreatic injury induced by the cytotoxic agent cerulein, suggesting that the importance of STAT3 in ductal metaplasia may be specific to KRAS-induced ADM. Finally, inhibition of STAT3 phosphorylation and activation prevented growth of some PDAC cell lines. These results suggest that STAT3 may play a role both in the initiation of pancreatic tumorigenesis and in the maintenance of a subset of fully-developed PDAC.