Abstract
Tumours frequently activate genes whose expression is otherwise biased to the testis, collectively known as cancer-testis antigens (CTAs). The extent to which CTA expression represents epiphenomena or confers tumorigenic traits is unknown. In this study, to address this, we implemented a multidimensional functional genomics approach that incorporates 7 different phenotypic assays in 11 distinct disease settings. We identify 26 CTAs that are essential for tumor cell viability and/or are pathological drivers of HIF, WNT or TGFβ signalling. In particular, we discover that Foetal and Adult Testis Expressed 1 (FATE1) is a key survival factor in multiple oncogenic backgrounds. FATE1 prevents the accumulation of the stress-sensing BH3-only protein, BCL-2-Interacting Killer (BIK), thereby permitting viability in the presence of toxic stimuli. Furthermore, ZNF165 promotes TGFβ signalling by directly suppressing the expression of negative feedback regulatory pathways. This action is essential for the survival of triple negative breast cancer cells in vitro and in vivo. Thus, CTAs make significant direct contributions to tumour biology.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / immunology
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Adenocarcinoma / mortality
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Adenocarcinoma of Lung
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Animals
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Antigens, Neoplasm / genetics*
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Apoptosis Regulatory Proteins / genetics
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Carcinogenesis / genetics*
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Cell Line
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Cell Line, Tumor
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Cell Survival
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / immunology
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Colorectal Neoplasms / mortality
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DNA-Binding Proteins / genetics*
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Fluorescent Antibody Technique
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Gene Expression Regulation, Neoplastic*
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HCT116 Cells
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HEK293 Cells
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Humans
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Immunoblotting
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In Vitro Techniques
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Lung Neoplasms / genetics
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Lung Neoplasms / immunology
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Lung Neoplasms / mortality
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Membrane Proteins / genetics
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Mice, Inbred NOD
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Mitochondrial Proteins
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Neoplasm Transplantation
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Neoplasms / genetics*
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Neoplasms / immunology
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Neoplasms / mortality
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Prognosis
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Proportional Hazards Models
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Real-Time Polymerase Chain Reaction
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Signal Transduction
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Smad7 Protein / genetics
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Transcription Factors / genetics*
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Transforming Growth Factor beta / genetics*
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Transforming Growth Factor beta / immunology
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Triple Negative Breast Neoplasms / genetics
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Triple Negative Breast Neoplasms / immunology
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Triple Negative Breast Neoplasms / mortality
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Ubiquitin-Protein Ligases / genetics
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Wnt Signaling Pathway
Substances
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Antigens, Neoplasm
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Apoptosis Regulatory Proteins
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BIK protein, human
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DNA-Binding Proteins
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FATE1 protein, human
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Membrane Proteins
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Mitochondrial Proteins
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PMEPA1 protein, human
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SMAD7 protein, human
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Smad7 Protein
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Transcription Factors
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Transforming Growth Factor beta
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ZNF165 protein, human
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SMURF2 protein, human
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Ubiquitin-Protein Ligases