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Published on: December 23, 2022
Functional screening of amplification outlier oncogenes in organoid models of early tumorigenesis
Ameen A Salahudeen1, Jose A Seoane2, Kanako Yuki3
1Stanford 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.
Abstract:
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.
Insights
Organoid models identified DYRK2 and FGF3 as oncogenes driving head and neck and esophageal cancers, respectively. This approach enables functional evaluation of cancer-driving genomic alterations during early tumorigenesis.
Area of Science:
- Oncology
- Genomics
- Cancer Biology
Background:
- Somatic copy number gains are common in cancer but their oncogenic roles are often unclear due to large amplified regions.
- Evaluating the functional impact of these genomic alterations is crucial for understanding cancer development.
Purpose of the Study:
- To develop and apply an organoid-based screening method for identifying and functionally evaluating candidate oncogenic loci associated with copy number gains.
- To nominate specific oncogenes driving early tumorigenesis in head and neck and esophageal squamous cell carcinomas.
Main Methods:
- Integrative computational analysis of The Cancer Genome Atlas (TCGA) data to identify candidate oncogenic loci with extreme copy gains and expression dysregulation.
- Contextual screening of candidate oncogenes using tissue-specific organoid models (esophagus, oral cavity, colon, stomach, pancreas, lung) with lentiviral cDNA libraries.
- Functional validation of nominated oncogenes in organoid models with p53 mutations.
Main Results:
- The kinase DYRK2 was identified as an amplified oncogene in head and neck squamous cell carcinoma using p53-deficient oral mucosal organoids.
- FGF3 amplification at 11q13 was found in 41% of esophageal squamous cell carcinomas and promoted p53-deficient esophageal organoid growth.
- FGF3-driven growth was reversible through antagonism of Fibroblast Growth Factor Receptors (FGFRs).
Conclusions:
- Organoid-based contextual screening is an effective platform for the functional evaluation of candidate genomic drivers in early tumorigenesis.
- DYRK2 and FGF3 are validated oncogenes in specific squamous cell carcinoma contexts.
- Targeting FGFRs offers a potential therapeutic strategy for FGF3-driven esophageal cancers.
