Title |
Pancreas-specific activation of mTOR and loss of p53 induce tumors reminiscent of acinar cell carcinoma
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Published in |
Molecular Cancer, December 2015
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DOI | 10.1186/s12943-015-0483-1 |
Pubmed ID | |
Authors |
Bo Kong, Tao Cheng, Chengjia Qian, Weiwei Wu, Katja Steiger, Jing Cao, Anna Melissa Schlitter, Ivonne Regel, Susanne Raulefs, Helmut Friess, Mert Erkan, Irene Esposito, Jörg Kleeff, Christoph W. Michalski |
Abstract |
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. 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. 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. Hyperactive mTOR signaling combined with loss of p53 in mice induces tumors similar to human ACC. |
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Demographic breakdown
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Members of the public | 1 | 50% |
Scientists | 1 | 50% |
Mendeley readers
Geographical breakdown
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Unknown | 19 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Master | 5 | 26% |
Student > Bachelor | 3 | 16% |
Researcher | 3 | 16% |
Professor | 2 | 11% |
Student > Ph. D. Student | 1 | 5% |
Other | 1 | 5% |
Unknown | 4 | 21% |
Readers by discipline | Count | As % |
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Medicine and Dentistry | 6 | 32% |
Biochemistry, Genetics and Molecular Biology | 5 | 26% |
Agricultural and Biological Sciences | 1 | 5% |
Nursing and Health Professions | 1 | 5% |
Neuroscience | 1 | 5% |
Other | 1 | 5% |
Unknown | 4 | 21% |