Comprehensive functional characterization of cancer-testis antigens defines obligate participation in multiple hallmarks of cancer

Kimberly E Maxfield; Patrick J Taus; Kathleen Corcoran; Joshua Wooten; Jennifer Macion; Yunyun Zhou; Mark Borromeo; Rahul K Kollipara; Jingsheng Yan; Yang Xie; Xian-Jin Xie; Angelique W Whitehurst

doi:10.1038/ncomms9840

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Comprehensive functional characterization of cancer-testis antigens defines obligate participation in multiple hallmarks of cancer

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Open access

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Comprehensive functional characterization of cancer-testis antigens defines obligate participation in multiple hallmarks of cancer

Kimberly E Maxfield, Patrick J Taus, Kathleen Corcoran, Joshua Wooten, Jennifer Macion, Yunyun Zhou, Mark Borromeo, Rahul K Kollipara, Jingsheng Yan, Yang Xie, …

Nature communications, Vol.6(1), 8840

11/16/2015

DOI: 10.1038/ncomms9840

PMCID: PMC4660212

PMID: 26567849

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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.

Signal Transduction

Neoplasm Transplantation

Prognosis

Adenocarcinoma of Lung

Lung Neoplasms - mortality

Colorectal Neoplasms - genetics

Humans

Gene Expression Regulation, Neoplastic

Immunoblotting

Triple Negative Breast Neoplasms - immunology

Neoplasms - genetics

HEK293 Cells

Apoptosis Regulatory Proteins - genetics

Adenocarcinoma - genetics

Smad7 Protein - genetics

Real-Time Polymerase Chain Reaction

Wnt Signaling Pathway

Colorectal Neoplasms - mortality

Lung Neoplasms - genetics

Transforming Growth Factor beta - immunology

Antigens, Neoplasm - genetics

Cell Line

Cell Survival

Membrane Proteins - genetics

Adenocarcinoma - immunology

HCT116 Cells

Carcinogenesis - genetics

Proportional Hazards Models

Neoplasms - mortality

Triple Negative Breast Neoplasms - mortality

Transcription Factors - genetics

DNA-Binding Proteins - genetics

Lung Neoplasms - immunology

Animals

Colorectal Neoplasms - immunology

Transforming Growth Factor beta - genetics

Triple Negative Breast Neoplasms - genetics

Neoplasms - immunology

Fluorescent Antibody Technique

Cell Line, Tumor

Mice, Inbred NOD

In Vitro Techniques

Ubiquitin-Protein Ligases - genetics

Adenocarcinoma - mortality

Details

Title: Subtitle: Comprehensive functional characterization of cancer-testis antigens defines obligate participation in multiple hallmarks of cancer
Creators: Kimberly E Maxfield - Simmons Comprehensive Cancer Center, UT-Southwestern Medical Center, Dallas, Texas 75390, USA
Patrick J Taus - Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
Kathleen Corcoran - Department of Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
Joshua Wooten - Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
Jennifer Macion - Simmons Comprehensive Cancer Center, UT-Southwestern Medical Center, Dallas, Texas 75390, USA
Yunyun Zhou - Department of Clinical Science, UT-Southwestern Medical Center, Dallas, Texas 75390, USA
Mark Borromeo - Department of Neuroscience, UT-Southwestern Medical Center, Dallas, Texas 75390, USA
Rahul K Kollipara - Eugene McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
Jingsheng Yan - Simmons Comprehensive Cancer Center, UT-Southwestern Medical Center, Dallas, Texas 75390, USA
Yang Xie - Department of Clinical Science, UT-Southwestern Medical Center, Dallas, Texas 75390, USA
Xian-Jin Xie - Department of Clinical Science, UT-Southwestern Medical Center, Dallas, Texas 75390, USA
Angelique W Whitehurst - Simmons Comprehensive Cancer Center, UT-Southwestern Medical Center, Dallas, Texas 75390, USA
Resource Type: Journal article
Publication Details: Nature communications, Vol.6(1), 8840
DOI: 10.1038/ncomms9840
PMID: 26567849
PMCID: PMC4660212
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Publisher: England
Grant note: CA154699 / NCI NIH HHS R01 CA154699 / NCI NIH HHS T32GM007040-37 / NIGMS NIH HHS 5P30 CA142543-05 / NCI NIH HHS P30 CA142543 / NCI NIH HHS T32 GM007040 / NIGMS NIH HHS F30 CA183464 / NCI NIH HHS F30CA183464 / NCI NIH HHS
Language: English
Date published: 11/16/2015
Academic Unit: Preventive and Community Dentistry; Biostatistics; Dental Research
Record Identifier: 9983917772802771

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