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

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

Research output: Contribution to journal › Article › peer-review

91 Scopus citations

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.

Original language	English
Article number	8840
Pages (from-to)	8840
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms9840
State	Published - Nov 16 2015
Externally published	Yes

Keywords

Neoplasm Transplantation
Prognosis
Adenocarcinoma of Lung
Humans
Gene Expression Regulation, Neoplastic
Membrane Proteins/genetics
Immunoblotting
Mitochondrial Proteins
Neoplasms/genetics
Lung Neoplasms/genetics
HEK293 Cells
Adenocarcinoma/genetics
Real-Time Polymerase Chain Reaction
Wnt Signaling Pathway
Cell Line
Smad7 Protein/genetics
Signal Transduction
Cell Survival
HCT116 Cells
Proportional Hazards Models
Colorectal Neoplasms/genetics
Transcription Factors/genetics
Animals
DNA-Binding Proteins/genetics
Fluorescent Antibody Technique
Antigens, Neoplasm/genetics
Cell Line, Tumor
Apoptosis Regulatory Proteins/genetics
Mice, Inbred NOD
In Vitro Techniques
Ubiquitin-Protein Ligases/genetics
Transforming Growth Factor beta/genetics
Carcinogenesis/genetics
Triple Negative Breast Neoplasms/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ncomms9840

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Maxfield, K. E., Taus, P. J., Corcoran, K., Wooten, J., MacIon, J., Zhou, Y., Borromeo, M., Kollipara, R. K., Yan, J., Xie, Y., Xie, X. J., & Whitehurst, A. W. (2015). Comprehensive functional characterization of cancer-testis antigens defines obligate participation in multiple hallmarks of cancer. Nature Communications, 6, 8840. Article 8840. https://doi.org/10.1038/ncomms9840

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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.",

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author = "Maxfield, {Kimberly E.} and Taus, {Patrick J.} and Kathleen Corcoran and Joshua Wooten and Jennifer MacIon and Yunyun Zhou and Mark Borromeo and Kollipara, {Rahul K.} and Jingsheng Yan and Yang Xie and Xie, {Xian Jin} and Whitehurst, {Angelique W.}",

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doi = "10.1038/ncomms9840",

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AU - Maxfield, Kimberly E.

AU - Taus, Patrick J.

AU - Corcoran, Kathleen

AU - Wooten, Joshua

AU - MacIon, Jennifer

AU - Zhou, Yunyun

AU - Borromeo, Mark

AU - Kollipara, Rahul K.

AU - Yan, Jingsheng

AU - Xie, Yang

AU - Xie, Xian Jin

AU - Whitehurst, Angelique W.

PY - 2015/11/16

Y1 - 2015/11/16

N2 - 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.

AB - 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.

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KW - Immunoblotting

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KW - Neoplasms/genetics

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KW - HEK293 Cells

KW - Adenocarcinoma/genetics

KW - Real-Time Polymerase Chain Reaction

KW - Wnt Signaling Pathway

KW - Cell Line

KW - Smad7 Protein/genetics

KW - Signal Transduction

KW - Cell Survival

KW - HCT116 Cells

KW - Proportional Hazards Models

KW - Colorectal Neoplasms/genetics

KW - Transcription Factors/genetics

KW - Animals

KW - DNA-Binding Proteins/genetics

KW - Fluorescent Antibody Technique

KW - Antigens, Neoplasm/genetics

KW - Cell Line, Tumor

KW - Apoptosis Regulatory Proteins/genetics

KW - Mice, Inbred NOD

KW - In Vitro Techniques

KW - Ubiquitin-Protein Ligases/genetics

KW - Transforming Growth Factor beta/genetics

KW - Carcinogenesis/genetics

KW - Triple Negative Breast Neoplasms/genetics

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U2 - 10.1038/ncomms9840

DO - 10.1038/ncomms9840

M3 - Article

C2 - 26567849

SN - 2041-1723

VL - 6

SP - 8840

JO - Nature Communications

JF - Nature Communications

M1 - 8840

ER -

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

Abstract

Keywords

UN SDGs

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