PP2A Deficiency Enhances Carcinogenesis of Lgr5<sup>+</sup> Intestinal Stem Cells Both in Organoids and In Vivo
In most cancers, cellular origin and the contribution of intrinsic and extrinsic factors toward transformation remain elusive. Cell specific carcinogenesis models are currently unavailable. To investigate cellular origin in carcinogenesis, we developed a tumorigenesis model based on a combination of...
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doaj-0b9dab19cabd4b1cabf182451322a5272020-11-24T22:09:55ZengMDPI AGCells2073-44092019-12-01919010.3390/cells9010090cells9010090PP2A Deficiency Enhances Carcinogenesis of Lgr5<sup>+</sup> Intestinal Stem Cells Both in Organoids and In VivoYu-Ting Yen0May Chien1Yung-Chih Lai2Dao-Peng Chen3Cheng-Ming Chuong4Mien-Chie Hung5Shih-Chieh Hung6Drug Development Center, Institute of New Drug Development, China Medical University, Taichung 40402, TaiwanDrug Development Center, Institute of New Drug Development, China Medical University, Taichung 40402, TaiwanIntegrative Stem Cell Center, China Medical University Hospital, Taichung 40402, TaiwanKim Forest Enterprise Co., Ltd., Taipei 22175, TaiwanIntegrative Stem Cell Center, China Medical University Hospital, Taichung 40402, TaiwanCenter for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 40402, TaiwanDrug Development Center, Institute of New Drug Development, China Medical University, Taichung 40402, TaiwanIn most cancers, cellular origin and the contribution of intrinsic and extrinsic factors toward transformation remain elusive. Cell specific carcinogenesis models are currently unavailable. To investigate cellular origin in carcinogenesis, we developed a tumorigenesis model based on a combination of carcinogenesis and genetically engineered mouse models. We show in organoids that treatment of any of three carcinogens, DMBA, MNU, or PhIP, with protein phosphatase 2A (PP2A) knockout induced tumorigenesis in Lgr5<sup>+</sup> intestinal lineage, but not in differentiated cells. These transformed cells increased in stem cell signature, were upregulated in EMT markers, and acquired tumorigenecity. A mechanistic approach demonstrated that tumorigenesis was dependent on Wnt, PI3K, and RAS-MAPK activation. In vivo combination with carcinogen and PP2A depletion also led to tumor formation. Using whole-exome sequencing, we demonstrate that these intestinal tumors display mutation landscape and core driver pathways resembling human intestinal tumor in The Cancer Genome Atlas (TCGA). These data provide a basis for understanding the interplay between extrinsic carcinogen and intrinsic genetic modification and suggest that PP2A functions as a tumor suppressor in intestine carcinogenesis.https://www.mdpi.com/2073-4409/9/1/90carcinogenprotein phosphatase 2a (pp2a)intestinal tumorintestinal organoidlgr5<sup>+</sup> crypt stem cell |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yu-Ting Yen May Chien Yung-Chih Lai Dao-Peng Chen Cheng-Ming Chuong Mien-Chie Hung Shih-Chieh Hung |
spellingShingle |
Yu-Ting Yen May Chien Yung-Chih Lai Dao-Peng Chen Cheng-Ming Chuong Mien-Chie Hung Shih-Chieh Hung PP2A Deficiency Enhances Carcinogenesis of Lgr5<sup>+</sup> Intestinal Stem Cells Both in Organoids and In Vivo Cells carcinogen protein phosphatase 2a (pp2a) intestinal tumor intestinal organoid lgr5<sup>+</sup> crypt stem cell |
author_facet |
Yu-Ting Yen May Chien Yung-Chih Lai Dao-Peng Chen Cheng-Ming Chuong Mien-Chie Hung Shih-Chieh Hung |
author_sort |
Yu-Ting Yen |
title |
PP2A Deficiency Enhances Carcinogenesis of Lgr5<sup>+</sup> Intestinal Stem Cells Both in Organoids and In Vivo |
title_short |
PP2A Deficiency Enhances Carcinogenesis of Lgr5<sup>+</sup> Intestinal Stem Cells Both in Organoids and In Vivo |
title_full |
PP2A Deficiency Enhances Carcinogenesis of Lgr5<sup>+</sup> Intestinal Stem Cells Both in Organoids and In Vivo |
title_fullStr |
PP2A Deficiency Enhances Carcinogenesis of Lgr5<sup>+</sup> Intestinal Stem Cells Both in Organoids and In Vivo |
title_full_unstemmed |
PP2A Deficiency Enhances Carcinogenesis of Lgr5<sup>+</sup> Intestinal Stem Cells Both in Organoids and In Vivo |
title_sort |
pp2a deficiency enhances carcinogenesis of lgr5<sup>+</sup> intestinal stem cells both in organoids and in vivo |
publisher |
MDPI AG |
series |
Cells |
issn |
2073-4409 |
publishDate |
2019-12-01 |
description |
In most cancers, cellular origin and the contribution of intrinsic and extrinsic factors toward transformation remain elusive. Cell specific carcinogenesis models are currently unavailable. To investigate cellular origin in carcinogenesis, we developed a tumorigenesis model based on a combination of carcinogenesis and genetically engineered mouse models. We show in organoids that treatment of any of three carcinogens, DMBA, MNU, or PhIP, with protein phosphatase 2A (PP2A) knockout induced tumorigenesis in Lgr5<sup>+</sup> intestinal lineage, but not in differentiated cells. These transformed cells increased in stem cell signature, were upregulated in EMT markers, and acquired tumorigenecity. A mechanistic approach demonstrated that tumorigenesis was dependent on Wnt, PI3K, and RAS-MAPK activation. In vivo combination with carcinogen and PP2A depletion also led to tumor formation. Using whole-exome sequencing, we demonstrate that these intestinal tumors display mutation landscape and core driver pathways resembling human intestinal tumor in The Cancer Genome Atlas (TCGA). These data provide a basis for understanding the interplay between extrinsic carcinogen and intrinsic genetic modification and suggest that PP2A functions as a tumor suppressor in intestine carcinogenesis. |
topic |
carcinogen protein phosphatase 2a (pp2a) intestinal tumor intestinal organoid lgr5<sup>+</sup> crypt stem cell |
url |
https://www.mdpi.com/2073-4409/9/1/90 |
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