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Nat Biotechnol. 2016 Aug;34(8):845-51. doi: 10.1038/nbt.3586. Epub 2016 Jul 11.

A recellularized human colon model identifies cancer driver genes.

Author information

1
Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA.
2
Cancer Research Program, Houston Methodist Research Institute, Houston, Texas, USA.
3
Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
4
Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, USA.
5
Genetics, Genomics and Development, Cornell University, Ithaca, New York, USA.
6
University of Texas Medical School at Houston, Houston, Texas, USA.
7
Department of Chemistry, Rice University, Houston, Texas, USA.
8
Department of Surgery, Baylor College of Medicine, Houston, Texas, USA.
9
Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York, USA.
10
Chemical Biology in Surgery, Weill Cornell Medical College, New York, New York, USA.
11
Department of Biochemistry, Weill Cornell Medical College, New York, New York, USA.
12
Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
13
Department of Colorectal Surgery, Cleveland Clinic, Cleveland, Ohio, USA.

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.

Comment in

PMID:
27398792
PMCID:
PMC4980997
DOI:
10.1038/nbt.3586
[Indexed for MEDLINE]
Free PMC Article

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