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 journalArticlepeer-review

55 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 languageEnglish (US)
Pages (from-to)845-851
Number of pages7
JournalNature Biotechnology
Volume34
Issue number8
DOIs
StatePublished - Jul 11 2016

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Medicine(all)
  • Molecular Medicine
  • Biomedical Engineering
  • Applied Microbiology and Biotechnology

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