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PolyA-enriched RNA-seq of primary human hepatocyte spheroids treated with small molecule inhibitors targeting TEAD

ABSTRACT: TEAD1 emerged as an estrogen-sensitive gene that was upregulated in a HFD mouse model and in NAFLD patients. We investigated the roles of TEAD in NAFLD by treating primary human hepatocyte spheroids with two small molecule inhibitors blocking the TEAD/YAP interaction. One small molecule blocks the interaction by inhibiting TEAD autopalmitoylation (TEADap), the second small molecule blocks the interaction by binding to the surface of the TEAD protein (TEADsf).

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Homo sapiens

SUBMITTER:

PROVIDER: E-MTAB-13207 | biostudies-arrayexpress |

SECONDARY ACCESSION(S): E-MTAB-11833

REPOSITORIES: biostudies-arrayexpress

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TEAD1 ChIP-seq on on MDA-MB-231 and Detroit X1 562 cells

Project description:The Hippo Pathway is a critical signaling network that regulates organ size and cellular proliferation in metazoans. The transcriptional enhanced associate domain (TEAD) family of transcription factors serve as the receptors for the downstream effectors of the Hippo pathway, YAP and TAZ, to upregulate expression of multiple genes involved in proliferation, cell-fate determination, polarity, and survival1. Recent work revealed that TEAD proteins are palmitoylated at a conserved cysteine with the lipid tail extending into the hydrophobic core of the protein2. Mutagenic and covalent modulation of the palmitoylation site disrupts Hippo signaling2,3; however, an understanding of why TEAD proteins require this seemingly essential modification and the therapeutic implications of modulating TEAD palmitoylation has remained elusive. Here we report the identification and optimization of a potent pan-TEAD small molecule that binds the TEAD lipid pocket (LP), blocks palmitoylation, and dysregulates TEAD activity in multiple cancer cell lines. Cellular and biochemical data interrogating the mechanism of action for our compound reveal TEAD palmitoylation to function as a checkpoint that regulates TEAD homeostasis. We show that bypassing this checkpoint with a small molecule increases TEAD protein levels thereby decreasing the ability of YAP/TAZ to activate downstream target gene transcription in a dominant-negative manner. Our study demonstrates a new role for lipidation in protein signaling and establishes the TEAD LP as a bona fide therapeutic site for modulation of the Hippo Pathway.

2020-06-03 | GSE139951 | GEO

Next Generation Sequencing Quantitative Analysis of TEAD Palmitoylation Inhibitor MGH-CP1 in Breast Cancer Cell Line

Project description:Purpose: The goal of this study is to understand the signaling pathway alteration in cancer cell line treated with TEAD palmitoylation inhibitor MGH-CP1, and to further validate TEAD inhibitor for specifity in TEAD-YAP interuption. Methods:Breast cancer cell line MDA-MB-231 was chosen to be treated with TEAD palmitoylation inhibitor MGH-CP1 at 10μM for 24 hours. Total RNA was isolated for the analysis. RNA samples were sent to Novogen for library construction, RNA sequencing and raw data process. Results: MGH-CP1 specifically blocks TEAD transcriptional activity compared with YAP/TAZ siRNA in MDA-MB-231 cells. Conclusions: Our study privides gene expression profiling evidence to validate our TEAD palmitoylation inhibitor MGH-CP1 as specific small molecule to block TEAD transcriptional activity. We report the application of next generation sequencing technology for high-throughput profiling of TEAD palmitoylation inhibitor MGH-CP1 in breast cancer cells.

2021-05-11 | GSE140396 | GEO

Multicellular spheroids treated with the compound VLX600

Project description:Microarray based mRNA profiling was used to charactarize the response to the compound VLX600 in cells grown as spheroids. Cells used was colon cancer cells HCT116 and HCT116HIF1a knock-out. We identify the small molecule VLX600 as a drug that is preferentially active against quiescent cells in colon cancer 3-D microtissues. The anticancer activity is associated with reduced mitochondrial respiration, leading to a bioenergetic catastrophe and tumor cell death. VLX600 shows enhanced cytotoxic activity under conditions of nutrient starvation. Microarray based mRNA profiling was used to charactarize the response to the compound VLX600 in cells grown as spheroids. Cells used was colon cancer cells HCT116 and HCT116HIF1a knock-out cells.

2014-02-17 | E-GEOD-53777 | biostudies-arrayexpress

An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance

Project description:The Hippo pathway is a key growth-control pathway conserved across species. The downstream effectors of the Hippo pathway YAP/TAZ are frequently activated in cancer cells by a diverse array of mechanisms to drive proliferation and survival. Based on the premise that sustained interactions between YAP/TAZ and TEADs are central to their transcriptional activities, we discovered a potent small molecule inhibitor (SMI) GNE-7883 that allosterically blocks the interactions between YAP/TAZ and all four TEAD paralogs in human cells through binding to the TEAD lipid pocket. GNE-7883 effectively reduces chromatin accessibility specifically at TEAD motifs, suppresses cell proliferation in a variety of cell line models, and achieved strong anti-tumor efficacy in vivo. Furthermore, we uncovered that GNE-7883 effectively overcomes resistance to the recently approved KRAS G12C inhibitor sotorasib in both treatment-refractory and acquired resistance cell line models, providing strong proof-of-concept of TEAD SMIs in targeting YAP/TAZ-mediated KRAS inhibitor resistance. Taken together, this work demonstrates activities of TEAD SMIs in YAP/TAZ-dependent cancers and highlights their potential broad applications in precision oncology and therapy resistance.

2023-04-26 | GSE229071 | GEO

Identification of resistance mechanisms to small-molecule inhibition of YAP/TEAD-regulated transcription [RNA-seq]

Project description:The Hippo tumour suppressor pathway controls transcription by regulating nuclear abundance of YAP and TAZ, which activate transcription with the TEAD1-TEAD4 DNA-binding proteins. Recently, several small-molecule inhibitors of YAP and TEADs have been reported, with some now entering clinical trials for different cancers. Here, we investigated the cellular response to TEAD palmitoylation inhibitors, using genomic and genetic strategies. Genome-wide CRISPR/Cas9 screens revealed that mutations in genes from the Hippo, MAPK and JAK-STAT signaling pathways all modulate the cellular response to TEAD inhibition. Inhibition of TEAD palmitoylation strongly reduced YAP/TEAD target expression, whilst only mildly impacting YAP/TEAD genome binding. Additionally, expression of MAPK pathway genes was induced upon inhibition of TEAD palmitoylation, which coincided with YAP/TEAD redistribution to AP-1 transcription factor binding sites. Consistent with this, combined inhibition of TEAD and the MAPK protein MEK, synergistically blocked proliferation of several mesothelioma and lung cancer cell lines and more potently reduced the growth of patient-derived lung cancers in vivo. Collectively, we reveal mechanisms by which cells can overcome small-molecule inhibition of TEAD palmitoylation and potential strategies to enhance the anti-tumor activity of emerging Hippo pathway targeted therapies.

2024-07-08 | GSE269899 | GEO

Next Generation Sequencing Quantitative Analysis of TEAD Palmitoylation Inhibitor TM2 in NCI-H226 cells

Project description:Purpose: The goal of this study is to understand the signaling pathway alteration in NCI-H226 cells treated with new TEAD autopalmitoylation inhibitor TM2, and to further validate TEAD inhibitor for specifity in TEAD-YAP interuption. Methods: Mesothelioma cell line NCI-H226 was chosen to be treated with TEAD palmitoylation inhibitor TM2 at 1μM for 24 hours. Total RNA was isolated for the analysis. RNA samples were sent to Novogen for library construction, RNA sequencing and raw data process. Conclusions: Our study privides gene expression profiling evidence to validate our TEAD palmitoylation inhibitor TM2 as specific small molecule to block TEAD transcriptional activity in mesothelioma cells.

2024-05-01 | GSE203421 | GEO

Next Generation Sequencing Quantitative Analysis of TEAD Palmitoylation Inhibitor MGH-CP1 in MDA-MB-231 cells

Project description:Purpose: The goal of this study is to understand the signaling pathway alteration inMDA-MB-231cells treated with TEAD autopalmitoylation inhibitor MGH-CP1, and to further validate TEAD inhibitor for specifity in TEAD-YAP interuption. Methods:Breast cancer cell line MDA-MB-231 was chosen to be treated with TEAD palmitoylation inhibitor MGH-CP1 at 10μM for 24 hours. Total RNA was isolated for the analysis. RNA samples were sent to Novogen for library construction, RNA sequencing and raw data process. Conclusions: Our study privides gene expression profiling evidence to validate our TEAD palmitoylation inhibitor MGH-CP1 as specific small molecule to block TEAD transcriptional activity.

2022-09-11 | GSE177052 | GEO

Identification of resistance mechanisms to small-molecule inhibition of YAP/TEAD-regulated transcription

Project description:Identification of resistance mechanisms to small-molecule inhibition of YAP/TEAD-regulated transcription

| PRJNA1124085 | ENA

Proteomics profiling of research models for studying pancreatic ductal adenocarcinoma

Project description:Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a five-year survival rate of 10-15% due to late-stage diagnosis and limited efficacy of existing treatments. This study utilized proteomics-based system modelling to generate multimodal datasets from various research models, including PDAC cells, spheroids, organoids, and tissues derived from murine and human samples. Identical mass spectrometry-based proteomics was applied across the different models. Preparation and validation of the research models and the proteomics were described in detail. The assembly datasets we present here may contribute to the data collection on PDAC, which will be useful for systems modeling, data mining, knowledge discovery in databases, and bioinformatics of individual models. Further data analysis may lead to generation of research hypotheses, predictions of targets for diagnosis and treatment and relationships between data variables. bridging the gap between preclinical research and clinical trials, thus enhancing the possibilities for discovering early diagnostic biomarkers and effective therapeutic targets.

2024-12-18 | PXD057804 | Pride

Targeting YAP/TAZ-TEAD as a precision therapy approach in head and neck squamous cell carcinoma

Project description:Dysregulation of the Hippo pathway and the consequent activation of its downstream targets, the transcriptional co-activators YAP and TAZ (YAP/TAZ), drives oncogenic transcriptional programs upon binding TEAD transcription factors in multiple human malignancies. The recent development of small molecule TEAD inhibitors (smTEADi) provides an opportunity to therapeutically target Hippo pathway dysregulation in cancer. In this regard, HPV-negative head and neck squamous cell carcinoma (HNSCC) harbor multiple genetic alterations that promote YAP/TAZ hyperactivation, raising the possibility that HNSCC cells might be dependent on YAP/TAZ-TEAD driven oncogenic transcriptional programs. To test this hypothesis, we examined the antitumor activity of the novel smTEADi, SW-682 and genetically encoded TEAD inhibitor peptide (pTEADi) in Cal33 HPV-negative HNSCC cell line-derived xenograft model. To elucidate the transcriptomic changes upon YAP/TAZ-TEAD inhibition, RNA extracted from xenograft tumors treated with SW-682 or pTEADi, as well as control, was subjected to RNA sequencing.

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