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.
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA.
authors.forename: Huanhuan Joyce
authors.initials: HJ
authors.lastname: Chen
authors.affiliation: Cancer Research Program, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Zhubo
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York, USA.|Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
authors.affiliation: Genetics, Genomics and Development, Cornell University, Ithaca, New York, USA.
authors.forename: Asmita
authors.initials: A
authors.lastname: Bhattacharya
authors.affiliation: University of Texas Medical School at Houston, Houston, Texas, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Savage
authors.affiliation: University of Texas Medical School at Houston, Houston, Texas, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Serda
authors.affiliation: Department of Chemistry, Rice University, Houston, Texas, USA.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Mackeyev
authors.affiliation: Department of Surgery, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Curley
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Bu
authors.affiliation: Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York, USA.
authors.forename: Lihua
authors.initials: L
authors.lastname: Wang
authors.affiliation: Chemical Biology in Surgery, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Shuibing
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Leona
authors.initials: L
authors.lastname: Cohen-Gould
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, Ohio, USA.|Department of Colorectal Surgery, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Emina
authors.initials: E
authors.lastname: Huang
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA.
authors.forename: Xiling
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York, USA.|Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Lipkin
authors.affiliation: Cancer Research Program, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
authors.affiliation: Cancer Research Program, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Shuler
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics; D002474:Cell-Free System / Q000378:metabolism; D002478:Cells, Cultured; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D020869:Gene Expression Profiling / Q000379:methods*; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism*; D038081:Organogenesis; D023822:Tissue Engineering / Q000379:methods
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D009363:Neoplasm Proteins