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YAP and TAZ Dictate Binary Pan-Cancer Superclasses

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. We defined pan-cancer binary classes based on distinct expression of YAP (and its paralog TAZ/ WWTR1) and YAP-responsive adhesion regulators. Combining informatics with in vivo and in vitro gain- and loss-of-function studies across multiple murine and human tumor types, we showed that opposite pro- or anti-cancer YAP activity functionally defines binary YAPon or YAPoff cancer classes that express or silence YAP, respectively. Essentially all leukemia and lymphoma fall into the YAPoff class, as do multiple neural and neuroendocrine YAPoff solid cancers. YAPoff solid cancers are frequently RB1-/-, such as retinoblastoma, small cell lung cancer and neuroendocrine prostate cancer. YAP-silencing was intrinsic to the cell-of-origin, or acquired with lineage-switching and drug-resistance. The binary cancer groups exhibit distinct YAP-dependent adhesive behavior, and pharmaceutical vulnerabilities, underscoring clinical relevance. Mechanistically, whereas YAP induces cell cycle genes in YAPon cancers, extensive RNAseq data showed that forced YAP expression in YAPoff cancers instead activated adhesion genes that are normally co-silenced with YAP. YAP regulates both of these anti-cancer adhesive or pro-cancer cell cycle programs through the TEAD DNA binding family (TEAD1-4). YAP/TEAD targets AP1-bound enhancers in YAPon cancers, but Chipseq studies revealed that in YAPoff cancers, YAP/TEAD instead targeted elements co-bound with neural and neuroendocrine lineage-defining basic helix-loop-helix (bHLH) and Homeobox transcription factors (e.g. NEUROD, ASCL1, NKX2, OTX2). A CRISPR screen revealed that, among the adhesion regulators, ITGAV/ITGB5 pair are required for YAP induced cytostasis in YAPoff cancers. YAP is thus pivotal across all cancer, but in opposite pro- or anti-cancer ways, which define contrasting genetic and drug sensitivities.

ORGANISM(S): Homo sapiens

PROVIDER: GSE144975 | GEO | 2021/06/21

REPOSITORIES: GEO

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Project description:Uncontrolled Transforming growth factor-beta (TGFβ) signaling promotes aggressive metastatic properties in late-stage breast cancers. However, how TGFβ-mediated cues are directed to induce late-stage tumorigenic events is poorly understood, particularly given that TGFβ has clear tumor suppressing activity in other contexts. Here we demonstrate that the transcriptional regulators TAZ and YAP (TAZ/YAP), key effectors of the Hippo pathway, are necessary to promote and maintain TGFβ-induced tumorigenic phenotypes in breast cancer cells. Interactions between TAZ/YAP, TGFβ-activated SMAD2/3, and TEAD transcription factors reveal convergent roles for these factors in the nucleus. Genome-wide expression analyses indicate that TAZ/YAP, TEADs and TGFβ-induced signals coordinate a specific pro-tumorigenic transcriptional program. Importantly, genes cooperatively regulated by TAZ/YAP, TEAD, and TGFβ, such as the novel targets NEGR1 and UCA1, are necessary for maintaining tumorigenic activity in metastatic breast cancer cells. Nuclear TAZ/YAP also cooperate with TGFβ signaling to promote phenotypic and transcriptional changes in non-tumorigenic cells to overcome TGFβ repressive effects. Our work thus identifies crosstalk between nuclear TAZ/YAP and TGFβ signaling in breast cancer cells, revealing novel insight into late-stage disease-driving mechanisms. Expression profiling was conducted following the repression of the transcriptional regulators TAZ and YAP (TAZ/YAP), the TEAD family of transcription factors (TEAD1/2/3/4), or the TGFb signaling pathway (with SB-431542, an inhibitor of the TBRI recpeptor) in human MDA-MB-231-LM2 breast cancer cells treated with TGFβ1. Human MDA-MB-231-LM2-4 breast cancer cells were transfected with control siRNA, or siRNAs targeting TAZ/YAP or all four TEADs and were treated 24 hours later with 500pM TGFβ1 or 5mM SB-431542 for an additional 24 hours. Total RNA was isolated and twelve microarrays in total were performed, with each condition carried out three times on separate days. The Boston University Microarray Core generated the data using the Affymetrix Human Gene 1.0 St Array.

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YAP and TAZ Dictate Binary Pan-Cancer Superclasses

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