Functional screening of amplification outlier oncogenes in organoid models of early tumorigenesis.
Autor: | Salahudeen AA; Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA; University of Illinois at Chicago College of Medicine, Department of Medicine, Division of Hematology and Oncology, Chicago, IL 60612, USA; Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago College of Medicine, Chicago, IL 60612, USA; University of Illinois Cancer Center, Chicago, IL 60612, USA. Electronic address: ameen@uic.edu., Seoane JA; Stanford University School of Medicine, Department of Medicine, Divisions of Oncology, Stanford, CA 94305, USA; Cancer Computational Biology Group, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain. Electronic address: joseaseoane@vhio.net., Yuki K; Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA., Mah AT; Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA., Smith AR; Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA., Kolahi K; Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA., De la O SM; Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA., Hart DJ; Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA., Ding J; Stanford University School of Medicine, Department of Medicine, Divisions of Oncology, Stanford, CA 94305, USA., Ma Z; Stanford University School of Medicine, Department of Medicine, Divisions of Oncology, Stanford, CA 94305, USA., Barkal SA; Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA., Shukla ND; Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA., Zhang CH; Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA., Cantrell MA; Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA., Batish A; Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA., Usui T; Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA., Root DE; Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA., Hahn WC; Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, 450 Brookline Avenue, Boston, MA 02215, USA., Curtis C; Stanford University School of Medicine, Department of Medicine, Divisions of Oncology, Stanford, CA 94305, USA; Stanford University School of Medicine, Department of Medicine, Divisions of Genetics, Stanford, CA 94305, USA., Kuo CJ; Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA. Electronic address: cjkuo@stanford.edu. |
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Jazyk: | angličtina |
Zdroj: | Cell reports [Cell Rep] 2023 Nov 28; Vol. 42 (11), pp. 113355. Date of Electronic Publication: 2023 Nov 01. |
DOI: | 10.1016/j.celrep.2023.113355 |
Abstrakt: | Somatic copy number gains are pervasive across cancer types, yet their roles in oncogenesis are insufficiently evaluated. This inadequacy is partly due to copy gains spanning large chromosomal regions, obscuring causal loci. Here, we employed organoid modeling to evaluate candidate oncogenic loci identified via integrative computational analysis of extreme copy gains overlapping with extreme expression dysregulation in The Cancer Genome Atlas. Subsets of "outlier" candidates were contextually screened as tissue-specific cDNA lentiviral libraries within cognate esophagus, oral cavity, colon, stomach, pancreas, and lung organoids bearing initial oncogenic mutations. Iterative analysis nominated the kinase DYRK2 at 12q15 as an amplified head and neck squamous carcinoma oncogene in p53 -/- oral mucosal organoids. Similarly, FGF3, amplified at 11q13 in 41% of esophageal squamous carcinomas, promoted p53 -/- esophageal organoid growth reversible by small molecule and soluble receptor antagonism of FGFRs. Our studies establish organoid-based contextual screening of candidate genomic drivers, enabling functional evaluation during early tumorigenesis. Competing Interests: Declaration of interests A.A.S. has served as a consultant for Boehringer Ingelheim and Pharmacosmos and is a former employee of Tempus Labs. C.J.K. is a scientific advisory board member for Surrozen, Inc., Mozart Therapeutics, and NextVivo. C.C. has served as a scientific advisory board member/consultant for Genentech, Grail, DeepCell, Nanostring, and Viosera. W.C.H. is a consultant for Thermo Fisher, Solasta Ventures, MPM Capital, KSQ Therapeutics, Tyra Biosciences, Frontier Medicine, Jubilant Therapeutics, RAPPTA Therapeutics, Hexagon Bio, Serinus Biosciences, Function Oncology, and Calyx. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.) |
Databáze: | MEDLINE |
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