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In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis.
Roper, Jatin; Tammela, Tuomas; Cetinbas, Naniye Malli; Akkad, Adam; Roghanian, Ali; Rickelt, Steffen; Almeqdadi, Mohammad; Wu, Katherine; Oberli, Matthias A; Sánchez-Rivera, Francisco J; Park, Yoona K; Liang, Xu; Eng, George; Taylor, Martin S; Azimi, Roxana; Kedrin, Dmitriy; Neupane, Rachit; Beyaz, Semir; Sicinska, Ewa T; Suarez, Yvelisse; Yoo, James; Chen, Lillian; Zukerberg, Lawrence; Katajisto, Pekka; Deshpande, Vikram; Bass, Adam J; Tsichlis, Philip N; Lees, Jacqueline; Langer, Robert; Hynes, Richard O; Chen, Jianzhu; Bhutkar, Arjun; Jacks, Tyler; Yilmaz, Ömer H.
Afiliação
  • Roper J; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.
  • Tammela T; Division of Gastroenterology, Tufts Medical Center, Boston, Massachusetts, USA.
  • Cetinbas NM; Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA.
  • Akkad A; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.
  • Roghanian A; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.
  • Rickelt S; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.
  • Almeqdadi M; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.
  • Wu K; Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.
  • Oberli MA; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.
  • Sánchez-Rivera FJ; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.
  • Park YK; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.
  • Liang X; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.
  • Eng G; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.
  • Taylor MS; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.
  • Azimi R; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.
  • Kedrin D; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.
  • Neupane R; Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • Beyaz S; Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • Sicinska ET; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.
  • Suarez Y; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.
  • Yoo J; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.
  • Chen L; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.
  • Zukerberg L; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA.
  • Katajisto P; Department of Pathology, Tufts Medical Center, Boston, Massachusetts, USA.
  • Deshpande V; Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA.
  • Bass AJ; Department of Surgery, Tufts Medical Center, Boston, Massachusetts, USA.
  • Tsichlis PN; Department of Surgery, Tufts Medical Center, Boston, Massachusetts, USA.
  • Lees J; Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • Langer R; Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
  • Hynes RO; Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
  • Chen J; Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • Bhutkar A; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA.
  • Jacks T; Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA.
  • Yilmaz ÖH; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.
Nat Biotechnol ; 35(6): 569-576, 2017 06.
Article em En | MEDLINE | ID: mdl-28459449
ABSTRACT
In vivo interrogation of the function of genes implicated in tumorigenesis is limited by the need to generate and cross germline mutant mice. Here we describe approaches to model colorectal cancer (CRC) and metastasis, which rely on in situ gene editing and orthotopic organoid transplantation in mice without cancer-predisposing mutations. Autochthonous tumor formation is induced by CRISPR-Cas9-based editing of the Apc and Trp53 tumor suppressor genes in colon epithelial cells and by orthotopic transplantation of Apc-edited colon organoids. ApcΔ/Δ;KrasG12D/+;Trp53Δ/Δ (AKP) mouse colon organoids and human CRC organoids engraft in the distal colon and metastasize to the liver. Finally, we apply the orthotopic transplantation model to characterize the clonal dynamics of Lgr5+ stem cells and demonstrate sequential activation of an oncogene in established colon adenomas. These experimental systems enable rapid in vivo characterization of cancer-associated genes and reproduce the entire spectrum of tumor progression and metastasis.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Colorretais / Transplante de Órgãos / Modelos Animais de Doenças / Genes Neoplásicos / Edição de Genes / Neoplasias Hepáticas Limite: Animals Idioma: En Ano de publicação: 2017 Tipo de documento: Article
Texto completo
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XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Colorretais / Transplante de Órgãos / Modelos Animais de Doenças / Genes Neoplásicos / Edição de Genes / Neoplasias Hepáticas Limite: Animals Idioma: En Ano de publicação: 2017 Tipo de documento: Article