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A novel pancreatic cancer model originated from transformation of acinar cells in adult tree shrew, a primate-like animal.

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机构: [1]Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Central Laboratory of Yan'an Hospital, Affiliated to Kunming Medical University, Kunming, Yunnan 650051, China. [2]Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China. [3]Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China. [4]Kunming Primate Research Center, Chinese Academy of Sciences, Kunming, Yunnan 650223, China. [5]Department of Pathology, Institute of Basic Medical Sciences and Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China. [6]Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
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关键词: Pancreatic cancer Animal model Tree shrew Acinar cells Cdkn2b

摘要:
Pancreatic cancer is one of the most lethal common cancers. The cell of origin of pancreatic ductal adenocarcinoma (PDAC) has been controversial, and recent evidence suggested acinar cells as the most probable candidate. However, the genetic alterations driving the transformation of pancreatic acinar cells in fully mature animals remain to be deciphered. In this study, lentivirus was used as a tool to introduce genetic engineering in tree shrew pancreatic acinar cells to explore the driver mutation essential for malignant transformation, establishing a novel tree shrew PDAC model, because we found that lentivirus could selectively infect acinar cells in tree shrew pancreas. Combination of oncogenic KRASG12D expression and inactivation of tumor suppressor genes Tp53, Cdkn2a and Cdkn2b could induce pancreatic cancer with full penetrance. Silencing of Cdkn2b is indispensable for Rb1 phosphorylation and tumor induction. Tree shrew PDAC possesses the main histological and molecular features of human PDAC. The gene expression profile of tree shrew PDAC was more similar to human disease than a mouse model. In conclusion, we established a novel pancreatic cancer model in tree shrew and identified driver mutations indispensable for PDAC induction from acinar cells in mature adults, demonstrating the essential roles of Cdkn2b in the induction of PDAC originating from adult acinar cells. Tree shrew could thus provide a better choice than mouse for a PDAC model derived from acinar cells in fully mature animals. © 2019. Published by The Company of Biologists Ltd.

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出版当年[2019]版:
大类 | 2 区 医学
小类 | 2 区 细胞生物学 2 区 病理学
最新[2023]版:
大类 | 3 区 医学
小类 | 2 区 病理学 3 区 细胞生物学
第一作者:
第一作者机构: [1]Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Central Laboratory of Yan'an Hospital, Affiliated to Kunming Medical University, Kunming, Yunnan 650051, China. [2]Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China.
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通讯机构: [1]Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Central Laboratory of Yan'an Hospital, Affiliated to Kunming Medical University, Kunming, Yunnan 650051, China. [2]Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China. [4]Kunming Primate Research Center, Chinese Academy of Sciences, Kunming, Yunnan 650223, China. [6]Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan 650223, China. [*1]32 East Jiaochang Road, Kunming, Yunnan 650223, China [*2]245 East of Renmin Road, Kunming, Yunnan 650051, China [*3]32 East Jiaochang Road, Kunming, Yunnan 650223, China
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