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An in vivo functional genomics screen of nuclear receptors and their co-regulators identifies FOXA1 as an essential gene in lung tumorigenesis.
Hight, Suzie K; Mootz, Allison; Kollipara, Rahul K; McMillan, Elizabeth; Yenerall, Paul; Otaki, Yoichi; Li, Long-Shan; Avila, Kimberley; Peyton, Michael; Rodriguez-Canales, Jaime; Mino, Barbara; Villalobos, Pamela; Girard, Luc; Dospoy, Patrick; Larsen, Jill; White, Michael A; Heymach, John V; Wistuba, Ignacio I; Kittler, Ralf; Minna, John D.
Afiliación
  • Hight SK; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas
  • Mootz A; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Kollipara RK; Eugene McDermott Center for Human Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • McMillan E; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Yenerall P; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Eugene McDermott Center for Human Genetics, University of Texas Southwestern Medica
  • Otaki Y; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of General Surgical Science, Gunma University Graduate School of Medicin
  • Li LS; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Avila K; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Peyton M; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Rodriguez-Canales J; Department of Translational and Molecular Pathology, MD Anderson Cancer Center, Houston, TX, USA.
  • Mino B; Department of Translational and Molecular Pathology, MD Anderson Cancer Center, Houston, TX, USA.
  • Villalobos P; Department of Translational and Molecular Pathology, MD Anderson Cancer Center, Houston, TX, USA.
  • Girard L; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Dospoy P; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Cente
  • Larsen J; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
  • White MA; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Heymach JV; Department Thoracic and Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
  • Wistuba II; Department of Translational and Molecular Pathology, MD Anderson Cancer Center, Houston, TX, USA.
  • Kittler R; Eugene McDermott Center for Human Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Minna JD; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, D
Neoplasia ; 22(8): 294-310, 2020 08.
Article en En | MEDLINE | ID: mdl-32512502
Using a mini-library of 1062 lentiviral shRNAs targeting 40 nuclear hormone receptors and 70 of their co-regulators, we searched for potential therapeutic targets that would be important during in vivo tumor growth using a parallel in vitro and in vivo shRNA screening strategy in the non-small cell lung cancer (NSCLC) line NCI-H1819. We identified 21 genes essential for in vitro growth, and nine genes specifically required for tumor survival in vivo, but not in vitro: NCOR2, FOXA1, HDAC1, RXRA, RORB, RARB, MTA2, ETV4, and NR1H2. We focused on FOXA1, since it lies within the most frequently amplified genomic region in lung adenocarcinomas. We found that 14q-amplification in NSCLC cell lines was a biomarker for FOXA1 dependency for both in vivo xenograft growth and colony formation, but not mass culture growth in vitro. FOXA1 knockdown identified genes involved in electron transport among the most differentially regulated, indicating FOXA1 loss may lead to a decrease in cellular respiration. In support of this, FOXA1 amplification was correlated with increased sensitivity to the complex I inhibitor phenformin. Integrative ChipSeq analyses reveal that FOXA1 functions in this genetic context may be at least partially independent of NKX2-1. Our findings are consistent with a neomorphic function for amplified FOXA1, driving an oncogenic transcriptional program. These data provide new insight into the functional consequences of FOXA1 amplification in lung adenocarcinomas, and identify new transcriptional networks for exploration of therapeutic vulnerabilities in this patient population.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Biomarcadores de Tumor / Carcinoma de Pulmón de Células no Pequeñas / Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina / Trombospondina 1 / Genómica / Factor Nuclear 3-alfa del Hepatocito / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Neoplasia Asunto de la revista: NEOPLASIAS Año: 2020 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Biomarcadores de Tumor / Carcinoma de Pulmón de Células no Pequeñas / Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina / Trombospondina 1 / Genómica / Factor Nuclear 3-alfa del Hepatocito / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Neoplasia Asunto de la revista: NEOPLASIAS Año: 2020 Tipo del documento: Article Pais de publicación: Estados Unidos