Comprehensive Molecular Characterization of the Hippo Signaling Pathway in Cancer
Copyright policy )Comprehensive Molecular Characterization of the Hippo Signaling Pathway in Cancer
Hippo signaling has been recognized as a key tumor suppressor pathway. Here, we perform a comprehensive molecular characterization of 19 Hippo core genes in 9,125 tumor samples across 33 cancer types using multidimensional "omic" data from The Cancer Genome Atlas. We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ. Hippo pathway activity is best characterized by a YAP/TAZ transcriptional target signature of 22 genes, which shows robust prognostic power across cancer types. Our elastic-net integrated modeling further reveals cancer-type-specific pathway regulators and associated cancer drivers. Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns. This study represents a systems-biology approach to characterizing key cancer signaling pathways in the post-genomic era.
- University of Florence Italy
- White Rose Consortium: University of Leeds; University of Sheffield; University of York United Kingdom
- Baylor College of Medicine United States
- University of Ferrara Italy
- Dan L Duncan Comprehensive Cancer Center United States
TAZ, Taz, pan-cancer analysis, PROMOTES, Medical Physiology, Cancer Genome Atlas Research Network, Growth, Gene, Models, Neoplasms, 2.1 Biological and endogenous factors, Aetiology, TUMOR PROGRESSION, pathway activity, Cancer, Tumor, Prognosis, PANCREATIC-CANCER, Gene Expression Regulation, Neoplastic, ORGAN SIZE CONTROL, Organ Size Control, GROWTH, Pathway activity, YAP, Yap, Life Sciences & Biomedicine, Biotechnology, Signal Transduction, 570, Cells, 610, Protein Serine-Threonine Kinases, Models, Biological, Article, Cell Line, 1300 Biochemistry, Genetics and Molecular Biology, Pan-cancer analysis, Cell Line, Tumor, Genetics, BREAST-CANCER, Humans, Hippo Signaling Pathway, Breast-Cancer, prognostic power, Neoplastic, Science & Technology, Base Sequence, Human Genome, driver mutation, driver mutation; miRNA regulation; pan-cancer analysis; pathway activity; prognostic power; TAZ; TCGA; tumor subtype; YAP; Base Sequence; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Models, Biological; Mutation; Neoplasms; Prognosis; Protein-Serine-Threonine Kinases; Signal Transduction, Driver mutation, Cell Biology, TCGA, Biological, GENE, Pancreatic-Cancer, Promotes, MicroRNAs, Gene Expression Regulation, Tumor subtype, tumor subtype, driver mutation; miRNA regulation; pan-cancer analysis; pathway activity; prognostic power; TAZ; TCGA; tumor subtype; YAP; Biochemistry, Genetics and Molecular Biology (all), CELLS, Mutation, driver mutation; miRNA regulation; pan-cancer analysis; pathway activity; prognostic power; TAZ; TCGA; tumor subtype; YAP, Tumor Progression, Biochemistry and Cell Biology, Prognostic power, miRNA regulation
TAZ, Taz, pan-cancer analysis, PROMOTES, Medical Physiology, Cancer Genome Atlas Research Network, Growth, Gene, Models, Neoplasms, 2.1 Biological and endogenous factors, Aetiology, TUMOR PROGRESSION, pathway activity, Cancer, Tumor, Prognosis, PANCREATIC-CANCER, Gene Expression Regulation, Neoplastic, ORGAN SIZE CONTROL, Organ Size Control, GROWTH, Pathway activity, YAP, Yap, Life Sciences & Biomedicine, Biotechnology, Signal Transduction, 570, Cells, 610, Protein Serine-Threonine Kinases, Models, Biological, Article, Cell Line, 1300 Biochemistry, Genetics and Molecular Biology, Pan-cancer analysis, Cell Line, Tumor, Genetics, BREAST-CANCER, Humans, Hippo Signaling Pathway, Breast-Cancer, prognostic power, Neoplastic, Science & Technology, Base Sequence, Human Genome, driver mutation, driver mutation; miRNA regulation; pan-cancer analysis; pathway activity; prognostic power; TAZ; TCGA; tumor subtype; YAP; Base Sequence; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Models, Biological; Mutation; Neoplasms; Prognosis; Protein-Serine-Threonine Kinases; Signal Transduction, Driver mutation, Cell Biology, TCGA, Biological, GENE, Pancreatic-Cancer, Promotes, MicroRNAs, Gene Expression Regulation, Tumor subtype, tumor subtype, driver mutation; miRNA regulation; pan-cancer analysis; pathway activity; prognostic power; TAZ; TCGA; tumor subtype; YAP; Biochemistry, Genetics and Molecular Biology (all), CELLS, Mutation, driver mutation; miRNA regulation; pan-cancer analysis; pathway activity; prognostic power; TAZ; TCGA; tumor subtype; YAP, Tumor Progression, Biochemistry and Cell Biology, Prognostic power, miRNA regulation
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