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Background  Pancreatic acinar cell carcinoma (ACC) is a rare tumor entity with an unfavorable prognosis. Recent whole-exome sequencing identified p53 mutations in a subset of human ACC. Activation of the mammalian target of rapamycin (mTOR) pathway is associated with various pancreatic neoplasms. We thus aimed at analyzing whether activation of mTOR with a concomitant loss of p53 may initiate ACC.    Methods  We generated transgenic mouse models in which mTOR was hyperactivated through pancreas-specific, homozygous  tuberous sclerosis 1  ( Tsc1 ) deficiency, with or without deletion of p53 ( Tsc1   -/-   and  Tsc1   -/-   ; p53   -/-  ). Activity of mTOR signaling was investigated using mouse tissues and isolated murine cell lines. Human ACC specimens were used to corroborate the findings from the transgenic mouse models.    Results  Hyperactive mTOR signaling in  Tsc1   -/-   mice was not oncogenic but rather induced a near-complete loss of the pancreatic acinar compartment. Acinar cells were lost as a result of apoptosis which was associated with p53 activation. Concomitantly, ductal cells were enriched. Ablation of p53 in  Tsc1 -deficient mice prevented acinar cell death but promoted formation of acinar cells with severe nuclear abnormalities. One out of seven  Tsc1   -/-   ; p53   -/-   animals developed pancreatic tumors showing a distinctive tumor morphology, reminiscent of human ACC. Hyperactive mTOR signaling was also detected in a subset of human ACC.    Conclusion  Hyperactive mTOR signaling combined with loss of p53 in mice induces tumors similar to human ACC.    Electronic supplementary material  The online version of this article (doi:10.1186/s12943-015-0483-1) contains supplementary material, which is available to authorized users.

Pancreas-specific activation of mTOR and loss of p53 induce tumors reminiscent of acinar cell carcinoma