A recellularized human colon model identifies cancer driver genes

Huanhuan Joyce Chen; Zhubo Wei; Jian Sun; Asmita Bhattacharya; David J. Savage; Rita Serda; Yuri Mackeyev; Steven A. Curley; Pengcheng Bu; Lihua Wang; Shuibing Chen; Leona Cohen-Gould; Emina Huang; Xiling Shen; Steven M. Lipkin; Neal G. Copeland; Nancy A. Jenkins; Michael L. Shuler

doi:10.1038/nbt.3586

A recellularized human colon model identifies cancer driver genes

Huanhuan Joyce Chen, Zhubo Wei, Jian Sun, Asmita Bhattacharya, David J. Savage, Rita Serda, Yuri Mackeyev, Steven A. Curley, Pengcheng Bu, Lihua Wang, Shuibing Chen, Leona Cohen-Gould, Emina Huang, Xiling Shen, Steven M. Lipkin, Neal G. Copeland, Nancy A. Jenkins, Michael L. Shuler

Research output: Contribution to journal › Article › peer-review

78 Scopus citations

Abstract

Refined cancer models are needed to bridge the gaps between cell line, animal and clinical research. Here we describe the engineering of an organotypic colon cancer model by recellularization of a native human matrix that contains cell-populated mucosa and an intact muscularis mucosa layer. This ex vivo system recapitulates the pathophysiological progression from APC-mutant neoplasia to submucosal invasive tumor. We used it to perform a Sleeping Beauty transposon mutagenesis screen to identify genes that cooperate with mutant APC in driving invasive neoplasia. We identified 38 candidate invasion-driver genes, 17 of which, including TCF7L2, TWIST2, MSH2, DCC, EPHB1 and EPHB2 have been previously implicated in colorectal cancer progression. Six invasion-driver genes that have not, to our knowledge, been previously described were validated in vitro using cell proliferation, migration and invasion assays and ex vivo using recellularized human colon. These results demonstrate the utility of our organoid model for studying cancer biology.

Original language	English (US)
Pages (from-to)	845-851
Number of pages	7
Journal	Nature biotechnology
Volume	34
Issue number	8
DOIs	https://doi.org/10.1038/nbt.3586
State	Published - Jan 8 2016
Externally published	Yes

ASJC Scopus subject areas

Applied Microbiology and Biotechnology
Bioengineering
Molecular Medicine
Biotechnology
Biomedical Engineering

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Chen, H. J., Wei, Z., Sun, J., Bhattacharya, A., Savage, D. J., Serda, R., Mackeyev, Y., Curley, S. A., Bu, P., Wang, L., Chen, S., Cohen-Gould, L., Huang, E., Shen, X., Lipkin, S. M., Copeland, N. G., Jenkins, N. A., & Shuler, M. L. (2016). A recellularized human colon model identifies cancer driver genes. Nature biotechnology, 34(8), 845-851. https://doi.org/10.1038/nbt.3586

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title = "A recellularized human colon model identifies cancer driver genes",

abstract = "Refined cancer models are needed to bridge the gaps between cell line, animal and clinical research. Here we describe the engineering of an organotypic colon cancer model by recellularization of a native human matrix that contains cell-populated mucosa and an intact muscularis mucosa layer. This ex vivo system recapitulates the pathophysiological progression from APC-mutant neoplasia to submucosal invasive tumor. We used it to perform a Sleeping Beauty transposon mutagenesis screen to identify genes that cooperate with mutant APC in driving invasive neoplasia. We identified 38 candidate invasion-driver genes, 17 of which, including TCF7L2, TWIST2, MSH2, DCC, EPHB1 and EPHB2 have been previously implicated in colorectal cancer progression. Six invasion-driver genes that have not, to our knowledge, been previously described were validated in vitro using cell proliferation, migration and invasion assays and ex vivo using recellularized human colon. These results demonstrate the utility of our organoid model for studying cancer biology.",

author = "Chen, {Huanhuan Joyce} and Zhubo Wei and Jian Sun and Asmita Bhattacharya and Savage, {David J.} and Rita Serda and Yuri Mackeyev and Curley, {Steven A.} and Pengcheng Bu and Lihua Wang and Shuibing Chen and Leona Cohen-Gould and Emina Huang and Xiling Shen and Lipkin, {Steven M.} and Copeland, {Neal G.} and Jenkins, {Nancy A.} and Shuler, {Michael L.}",

note = "Funding Information: We thank the members of M.L.S.'s laboratory and N.A.J. and N.G.C.'s laboratory. We also thank H.E. Varmus for providing laboratory resources and helpful discussions. This work was supported by a US National Cancer Institute Physical Sciences-Oncology Center (NCI-PSOC) Young Investigator trans-network grant to H.J.C. and Z.W., US National Institutes of Health (NIH) grant UH2TR000516 to M.L.S., US National Science Foundation (NSF) grants NSF-1106153 to M.L.S. and NSF GRFP-2011131053 to H.J.C., NIH grant R01GM095990 to X.S., an Arnold O. Beckman Postdoctoral fellowship to H.J.C., a Welch Foundation grant C-0627 at Rice University to Y.M. and the Cancer Prevention Research Institute of Texas (CPRIT) (N.G.C. and N.A.J.). Publisher Copyright: {\textcopyright} 2016 Nature America, Inc. All rights reserved.",

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AU - Wei, Zhubo

AU - Sun, Jian

AU - Bhattacharya, Asmita

AU - Savage, David J.

AU - Serda, Rita

AU - Mackeyev, Yuri

AU - Curley, Steven A.

AU - Bu, Pengcheng

AU - Wang, Lihua

AU - Chen, Shuibing

AU - Cohen-Gould, Leona

AU - Huang, Emina

AU - Shen, Xiling

AU - Lipkin, Steven M.

AU - Copeland, Neal G.

AU - Jenkins, Nancy A.

AU - Shuler, Michael L.

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N2 - Refined cancer models are needed to bridge the gaps between cell line, animal and clinical research. Here we describe the engineering of an organotypic colon cancer model by recellularization of a native human matrix that contains cell-populated mucosa and an intact muscularis mucosa layer. This ex vivo system recapitulates the pathophysiological progression from APC-mutant neoplasia to submucosal invasive tumor. We used it to perform a Sleeping Beauty transposon mutagenesis screen to identify genes that cooperate with mutant APC in driving invasive neoplasia. We identified 38 candidate invasion-driver genes, 17 of which, including TCF7L2, TWIST2, MSH2, DCC, EPHB1 and EPHB2 have been previously implicated in colorectal cancer progression. Six invasion-driver genes that have not, to our knowledge, been previously described were validated in vitro using cell proliferation, migration and invasion assays and ex vivo using recellularized human colon. These results demonstrate the utility of our organoid model for studying cancer biology.

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A recellularized human colon model identifies cancer driver genes

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