TY - JOUR
T1 - Comprehensive functional characterization of cancer-testis antigens defines obligate participation in multiple hallmarks of cancer
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.
N1 - Funding Information:
We thank Brian Golitz and Noah Sciaky for technical assistance with screening; Robin Frink for assistance with animal studies; L.O. for SK-OV-6 and SK-MEL-37 cell lines; K.E.M. and P.J.T. were supported by general medicine training grant T32GM007040-37. P.J.T. was supported by F30CA183464. The Simmons Cancer Center Support Grant (5P30 CA142543-05) supported shared resources used in this study at UTSW. This study was supported by Stand Up to Cancer (IRG1211) and the National Cancer Institute (CA154699).
Publisher Copyright:
© 2015, Nature Publishing Group. All rights reserved.
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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U2 - 10.1038/ncomms9840
DO - 10.1038/ncomms9840
M3 - Article
C2 - 26567849
AN - SCOPUS:84947294079
SN - 2041-1723
VL - 6
JO - Nature communications
JF - Nature communications
M1 - 8840
ER -