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

Maxfield KE, Taus PJ, Corcoran K, Wooten J, Macion J, Zhou Y, Borromeo M, Kollipara RK, Yan J, Xie Y, Xie XJ, Whitehurst AW - Nat Commun (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Simmons Comprehensive Cancer Center, UT-Southwestern Medical Center, Dallas, Texas 75390, USA.

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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Related in: MedlinePlus

Platform for a multidimensional screen to interrogate CTA function.(a) Workflow for siRNA screen. (b) Presence (red) and absence(white) calls for all CTAs in indicated cell lines based on quantitativeexpression analysis. See Supplementary Data 2. (c) Z-scores for each screen werecalculated and plotted for each CTA (left) for each assay and cell line(top, cell lines are hidden). (d–f) SiRNAs weretransfected into cell lines, and 96 h post transfection APO(d), EdU (e) and CTG (f) assays were performed.Bars represent the average mean (n=2)±range.Grey line indicates activity of control siRNA. Numbers indicate independentsiRNA sequences.
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f1: Platform for a multidimensional screen to interrogate CTA function.(a) Workflow for siRNA screen. (b) Presence (red) and absence(white) calls for all CTAs in indicated cell lines based on quantitativeexpression analysis. See Supplementary Data 2. (c) Z-scores for each screen werecalculated and plotted for each CTA (left) for each assay and cell line(top, cell lines are hidden). (d–f) SiRNAs weretransfected into cell lines, and 96 h post transfection APO(d), EdU (e) and CTG (f) assays were performed.Bars represent the average mean (n=2)±range.Grey line indicates activity of control siRNA. Numbers indicate independentsiRNA sequences.

Mentions: We designed an experimental platform to allow for broad-scale investigation ofthe mechanistic contribution of CTAs to tumour cell autonomous behaviours (Fig. 1a). One-hundred forty CTAs with documented expressionin solid tumours were selected for this study (Supplementary Data 1). Given the notoriousheterogeneity in expression of CTAs among tumours, we used quantitativeexpression profiling to identify 11 tumour-derived cell lines providing maximalrepresentation of CTAs (135 CTAs) (Fig. 1b and Supplementary Data 2)1. These cell lines were derived from prostate, breast, ovarian, skin,non-small cell lung cancer (NSCLC) and bone tumours. Each cell line within this‘testbed' exhibited a distinct pattern of CTA expression;however, most CTAs were present in >2 cell lines and 20% wereexpressed in all 11 cell lines (Fig. 1b).


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

Maxfield KE, Taus PJ, Corcoran K, Wooten J, Macion J, Zhou Y, Borromeo M, Kollipara RK, Yan J, Xie Y, Xie XJ, Whitehurst AW - Nat Commun (2015)

Platform for a multidimensional screen to interrogate CTA function.(a) Workflow for siRNA screen. (b) Presence (red) and absence(white) calls for all CTAs in indicated cell lines based on quantitativeexpression analysis. See Supplementary Data 2. (c) Z-scores for each screen werecalculated and plotted for each CTA (left) for each assay and cell line(top, cell lines are hidden). (d–f) SiRNAs weretransfected into cell lines, and 96 h post transfection APO(d), EdU (e) and CTG (f) assays were performed.Bars represent the average mean (n=2)±range.Grey line indicates activity of control siRNA. Numbers indicate independentsiRNA sequences.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4660212&req=5

f1: Platform for a multidimensional screen to interrogate CTA function.(a) Workflow for siRNA screen. (b) Presence (red) and absence(white) calls for all CTAs in indicated cell lines based on quantitativeexpression analysis. See Supplementary Data 2. (c) Z-scores for each screen werecalculated and plotted for each CTA (left) for each assay and cell line(top, cell lines are hidden). (d–f) SiRNAs weretransfected into cell lines, and 96 h post transfection APO(d), EdU (e) and CTG (f) assays were performed.Bars represent the average mean (n=2)±range.Grey line indicates activity of control siRNA. Numbers indicate independentsiRNA sequences.
Mentions: We designed an experimental platform to allow for broad-scale investigation ofthe mechanistic contribution of CTAs to tumour cell autonomous behaviours (Fig. 1a). One-hundred forty CTAs with documented expressionin solid tumours were selected for this study (Supplementary Data 1). Given the notoriousheterogeneity in expression of CTAs among tumours, we used quantitativeexpression profiling to identify 11 tumour-derived cell lines providing maximalrepresentation of CTAs (135 CTAs) (Fig. 1b and Supplementary Data 2)1. These cell lines were derived from prostate, breast, ovarian, skin,non-small cell lung cancer (NSCLC) and bone tumours. Each cell line within this‘testbed' exhibited a distinct pattern of CTA expression;however, most CTAs were present in >2 cell lines and 20% wereexpressed in all 11 cell lines (Fig. 1b).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Simmons Comprehensive Cancer Center, UT-Southwestern Medical Center, Dallas, Texas 75390, USA.

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.

Show MeSH
Related in: MedlinePlus