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Targeting eIF4A-dependent translation in soft tissue sarcoma

ABSTRACT: Well-differentiated and dedifferentiated liposarcoma (WD/DDLS), myxofibrosarcoma (MFS), and undifferentiated pleomorphic sarcoma (UPS) are the most common types of genetically complex sarcoma. There is an urgent need to develop effective targeted therapy for the over 50% of patients who eventually die of disease. Despite their genetic complexity, all four sarcoma types rely on the oncogenic translation of Hippo pathway proteins, which requires the RNA helicase eIF4A (DDX2). Pharmacological inhibition of eIF4A using CR-1-31B effectively suppressed tumor growth and induced apoptosis in DDLS, MFS, and UPS patient-derived cell lines and mouse xenografts. Transcriptome-scale ribosome footprinting identified eIF4A-dependent mRNAs in DDLS, MFS, and UPS cell lines. These include Hippo pathway effectors such as YAP1, WWTR1 (TAZ), and TEAD1. Combined knockdown of YAP and TAZ induced apoptosis in DDLS, MFS, and UPS cell lines, implicating them as critical targets. Hence, DDLS, MFS, and UPS rely on the eIF4A-dependent and CR-1-31B-sensitive translation of Hippo pathway oncogenes such as YAP, TAZ, and TEAD. eIF4A thus represents a new, promising therapeutic target for these incurable forms of soft tissue sarcoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE227676 | GEO | 2025/12/14

REPOSITORIES: GEO

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			Action	DRS
		Other
	GSE227676_sarcoma_count_tab_RNA_run1_rm0row.txt.gz	Txt
	GSE227676_sarcoma_ribodiff_run1.genename.txt.gz	Txt

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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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Targeting eIF4A-dependent translation in soft tissue sarcoma

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