title: Liver-Tumor Hybrid Organoids for Modeling Tumor Growth and Drug Response In Vitro.
abstract: Current in vitro models for tumor growth and metastasis are poor facsimiles of in vivo cancer physiology and thus, are not optimal for anti-cancer drug development. Three dimensional (3D) tissue organoid systems, which utilize human cells in a tailored microenvironment, have the potential to recapitulate in vivo conditions and address the drawbacks of current tissue culture dish 2D models. In this study, we created liver-based cell organoids in a rotating wall vessel bioreactor. The organoids were further inoculated with colon carcinoma cells in order to create liver-tumor organoids for in vitro modeling of liver metastasis. Immunofluorescent staining revealed notable phenotypic differences between tumor cells in 2D and inside the organoids. In 2D they displayed an epithelial phenotype, and only after transition to the organoids did the cells present with a mesenchymal phenotype. The cell surface marker expression results suggested that WNT pathway might be involved in the phenotypic changes observed between cells in 2D and organoid conditions, and may lead to changes in cell proliferation. Manipulating the WNT pathway with an agonist and antagonist showed significant changes in sensitivity to the anti-proliferative drug 5-fluoruracil. Collectively, the results show the potential of in vitro 3D liver-tumor organoids to serve as a model for metastasis growth and for testing the response of tumor cells to current and newly discovered drugs.
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Wake Forest University Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC, 27157-1094, USA.
authors.forename: Aleksander
authors.initials: A
authors.lastname: Skardal
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Wake Forest University Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC, 27157-1094, USA.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Devarasetty
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Wake Forest University Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC, 27157-1094, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Rodman
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Wake Forest University Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC, 27157-1094, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Atala
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Wake Forest University Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC, 27157-1094, USA. ssoker@wakehealth.edu.
authors.forename: Shay
authors.initials: S
authors.lastname: Soker
mesh_terms: D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005472:Fluorouracil / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009940:Organoids / Q000378:metabolism* / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: D005472:Fluorouracil
keywords: Drug screening; Metastasis; Organoids; Tissue engineering; Tumor models