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

Abstract:

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.

journal_name

Mol Cancer

journal_title

Molecular cancer

authors

Kong B,Cheng T,Qian C,Wu W,Steiger K,Cao J,Schlitter AM,Regel I,Raulefs S,Friess H,Erkan M,Esposito I,Kleeff J,Michalski CW

doi

10.1186/s12943-015-0483-1

subject

Has Abstract

pub_date

2015-12-18 00:00:00

pages

212

issn

1476-4598

pii

10.1186/s12943-015-0483-1

journal_volume

14

pub_type

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