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.
Highlights
Tumours frequently activate genes whose expression is otherwise biased to the testis, collectively known as cancer–testis antigens (CTAs)
Each cell line within this ‘testbed’ exhibited a distinct pattern of CTA expression; most CTAs were present in 42 cell lines and 20% were expressed in all 11 cell lines (Fig. 1b)
To examine the consequences of Foetal and Adult Testis Expressed 1 (FATE1) expression in patient tumours, we examined the Cancer Genome Atlas (TCGA) colorectal data set, given that depletion of FATE1 was most potent in the HCT116 colorectal cell line
Summary
Tumours frequently activate genes whose expression is otherwise biased to the testis, collectively known as cancer–testis antigens (CTAs). A handful of CTAs have been implicated in centrosomal clustering, regulation of microtubule dynamics, p53 silencing and deflection of differentiation signalling[8,9,10,11] Based on these nascent indications that individual CTAs have tumorigenic activities, in this study we constructed an investigational pipeline to define the frequency and nature of CTA participation in tumorigenic behaviours. ZNF165 drives the unrestrained activation of transforming growth factor b (TGFb) signalling by directly inactivating the expression of negative feedback pathway regulators, SMURF2, SMAD7 and PMEPA1 These findings indicate extraordinary flexibility in tumour cell regulatory networks, rendering them vulnerable to corruption on aberrant expression of primordial gene-regulatory programmes
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