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Open AccessArticle

PP2A Deficiency Enhances Carcinogenesis of Lgr5+ Intestinal Stem Cells Both in Organoids and In Vivo

1
Drug Development Center, Institute of New Drug Development, China Medical University, Taichung 40402, Taiwan
2
Integrative Stem Cell Center, China Medical University Hospital, Taichung 40402, Taiwan
3
Kim Forest Enterprise Co., Ltd., Taipei 22175, Taiwan
4
Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
5
Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 40402, Taiwan
6
Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
7
Department of Orthopaedics, China Medical University Hospital, Taichung 40402, Taiwan
*
Author to whom correspondence should be addressed.
Cells 2020, 9(1), 90; https://doi.org/10.3390/cells9010090
Received: 16 November 2019 / Revised: 27 December 2019 / Accepted: 28 December 2019 / Published: 30 December 2019
(This article belongs to the Special Issue 3D Stem Cell Culture)
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+ 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. View Full-Text
Keywords: carcinogen; protein phosphatase 2A (PP2A); intestinal tumor; intestinal organoid; Lgr5+ crypt stem cell carcinogen; protein phosphatase 2A (PP2A); intestinal tumor; intestinal organoid; Lgr5+ crypt stem cell
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MDPI and ACS Style

Yen, Y.-T.; Chien, M.; Lai, Y.-C.; Chen, D.-P.; Chuong, C.-M.; Hung, M.-C.; Hung, S.-C. PP2A Deficiency Enhances Carcinogenesis of Lgr5+ Intestinal Stem Cells Both in Organoids and In Vivo. Cells 2020, 9, 90. https://doi.org/10.3390/cells9010090

AMA Style

Yen Y-T, Chien M, Lai Y-C, Chen D-P, Chuong C-M, Hung M-C, Hung S-C. PP2A Deficiency Enhances Carcinogenesis of Lgr5+ Intestinal Stem Cells Both in Organoids and In Vivo. Cells. 2020; 9(1):90. https://doi.org/10.3390/cells9010090

Chicago/Turabian Style

Yen, Yu-Ting; Chien, May; Lai, Yung-Chih; Chen, Dao-Peng; Chuong, Cheng-Ming; Hung, Mien-Chie; Hung, Shih-Chieh. 2020. "PP2A Deficiency Enhances Carcinogenesis of Lgr5+ Intestinal Stem Cells Both in Organoids and In Vivo" Cells 9, no. 1: 90. https://doi.org/10.3390/cells9010090

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