Functional screening of amplification outlier oncogenes in organoid models of early tumorigenesis

Ameen A. Salahudeen; Jose A. Seoane; Kanako Yuki; Amanda T. Mah; Amber R. Smith; Kevin Kolahi; Sean M. De la O; Daniel J. Hart; Jie Ding; Zhicheng Ma; Sammy A. Barkal; Navika D. Shukla; Chuck H. Zhang; Michael A. Cantrell; Arpit Batish; Tatsuya Usui; David E. Root; William C. Hahn; Christina Curtis; Calvin J. Kuo

Cell Reports (Nov 2023)

Functional screening of amplification outlier oncogenes in organoid models of early tumorigenesis

Ameen A. Salahudeen,
Jose A. Seoane,
Kanako Yuki,
Amanda T. Mah,
Amber R. Smith,
Kevin Kolahi,
Sean M. De la O,
Daniel J. Hart,
Jie Ding,
Zhicheng Ma,
Sammy A. Barkal,
Navika D. Shukla,
Chuck H. Zhang,
Michael A. Cantrell,
Arpit Batish,
Tatsuya Usui,
David E. Root,
William C. Hahn,
Christina Curtis,
Calvin J. Kuo

Affiliations

Ameen A. Salahudeen: 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; Corresponding author
Jose A. Seoane: 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; Corresponding author
Kanako Yuki: Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA
Amanda T. Mah: Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA
Amber R. Smith: Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA
Kevin Kolahi: Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA
Sean M. De la O: Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA
Daniel J. Hart: Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA
Jie Ding: Stanford University School of Medicine, Department of Medicine, Divisions of Oncology, Stanford, CA 94305, USA
Zhicheng Ma: Stanford University School of Medicine, Department of Medicine, Divisions of Oncology, Stanford, CA 94305, USA
Sammy A. Barkal: Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA
Navika D. Shukla: Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA
Chuck H. Zhang: Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA
Michael A. Cantrell: Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA
Arpit Batish: Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA
Tatsuya Usui: Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA
David E. Root: Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA
William C. Hahn: 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
Christina Curtis: 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
Calvin J. Kuo: Stanford University School of Medicine, Department of Medicine, Divisions of Hematology, Stanford, CA 94305, USA; Corresponding author

Journal volume & issue: Vol. 42, no. 11
p. 113355

Abstract

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Summary: 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.

CP: Cancer

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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