TEAD inhibition alters the lung immune microenvironment and attenuates metastasis. DOI Open Access
Raneen Rahhal, Marcel O. Schmidt,

Maha Moussa

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

The Hippo pathway signaling mediated through YAP/TAZ, and the transcription factor TEAD is known to be involved in primary tumor progression. Here we report that novel inhibitors (iTEAD) cause a significant reduction outgrowth of lung metastases from triple negative breast cancer (TNBC) models predominantly changes stromal immune signaling. inhibition did not affect proliferation TNBC cells vitro or growth vivo . In normal mice were treated with iTEAD absence tumors, lungs showed decrease pro-tumor inflammatory pathways. However, IL12 was enhanced its production isolated tissue resident macrophages, but bone marrow derived elevated. syngeneic mouse models, suppressed inflammation M2-like macrophage phenotype tissues, increased infiltration CD8+ T into as well Th1 CD4+ cells, restoring an responsive microenvironment. iTEAD-treated cytotoxicity degranulation when co-cultured via IL-2 activity. Furthermore, knockdown, T-cell crosstalk anti-tumor activity 3D tumorspheres which reversed by neutralizing antibodies. Our data supports multifaceted model on innate adaptive they respond cell signals reveals important could reverse suppression eliminate seeded lungs.

Language: Английский

Transfer learning enables predictions in network biology DOI
Christina V. Theodoris, Ling Xiao,

Anant Chopra

et al.

Nature, Journal Year: 2023, Volume and Issue: 618(7965), P. 616 - 624

Published: May 31, 2023

Language: Английский

Citations

388
Therapeutic targeting of TEAD transcription factors in cancer DOI
Ajaybabu V. Pobbati, Ramesh Kumar, Brian P. Rubin

et al.

Trends in Biochemical Sciences, Journal Year: 2023, Volume and Issue: 48(5), P. 450 - 462

Published: Jan. 26, 2023

Language: Английский

Citations

82
XIST directly regulates X-linked and autosomal genes in naive human pluripotent cells DOI Creative Commons
Iris Dror, Tsotne Chitiashvili, Shawn Y.X. Tan

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(1), P. 110 - 129.e31

Published: Jan. 1, 2024

X chromosome inactivation (XCI) serves as a paradigm for RNA-mediated regulation of gene expression, wherein the long non-coding RNA XIST spreads across in cis to mediate silencing chromosome-wide. In female naive human pluripotent stem cells (hPSCs), is dispersed configuration, and XCI does not occur, raising questions about XIST's function. We found that induces dampening X-linked expression hPSCs. Surprisingly, also targets specific autosomal regions, where it repressive chromatin changes dampening. Thereby, equalizes dosage between male while inducing differences autosomes. The Xist configuration localization occur transiently during initiation mouse PSCs. Together, our study identifies regulator dampening, uncovers an evolutionarily conserved trans-acting role XIST/Xist, reveals correlation XIST/Xist dispersal targeting.

Language: Английский

Citations

36
Direct and selective pharmacological disruption of the YAP–TEAD interface by IAG933 inhibits Hippo-dependent and RAS–MAPK-altered cancers DOI Creative Commons
Emilie A. Chapeau, Laurent Sansregret, Giorgio Giacomo Galli

et al.

Nature Cancer, Journal Year: 2024, Volume and Issue: 5(7), P. 1102 - 1120

Published: April 2, 2024

The YAP-TEAD protein-protein interaction mediates YAP oncogenic functions downstream of the Hippo pathway. To date, available pharmacologic agents bind into lipid pocket TEAD, targeting indirectly via allosteric changes. However, consequences a direct pharmacological disruption interface between and TEADs remain largely unexplored. Here, we present IAG933 its analogs as potent first-in-class selective disruptors with suitable properties to enter clinical trials. Pharmacologic abrogation all four TEAD paralogs resulted in eviction from chromatin reduced Hippo-mediated transcription induction cell death. In vivo, deep tumor regression was observed Hippo-driven mesothelioma xenografts at tolerated doses animal models well Hippo-altered cancer outside mesothelioma. Importantly this also extended larger indications, such lung, pancreatic colorectal cancer, combination RTK, KRAS-mutant MAPK inhibitors, leading more efficacious durable responses. Clinical evaluation is underway.

Language: Английский

Citations

36
Systems-based identification of the Hippo pathway for promoting fibrotic mesenchymal differentiation in systemic sclerosis DOI Creative Commons
Feiyang Ma, Pei‐Suen Tsou, Mehrnaz Gharaee‐Kermani

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 3, 2024

Abstract Systemic sclerosis (SSc) is a devastating autoimmune disease characterized by excessive production and accumulation of extracellular matrix, leading to fibrosis skin other internal organs. However, the main cellular participants in SSc remain incompletely understood. Here using differentiation trajectories at single cell level, we demonstrate dual source matrix deposition from both myofibroblasts endothelial-to-mesenchymal-transitioning cells (EndoMT). We further define central role Hippo pathway effectors homeostasis myofibroblast EndoMT, respectively, show that EndoMTs function as communication hubs drive key pro-fibrotic signaling pathways SSc. Together, our data help characterize EndoMT phenotypes skin, hint modulation may contribute reversing EndoMTs.

Language: Английский

Citations

22
Recent Therapeutic Approaches to Modulate the Hippo Pathway in Oncology and Regenerative Medicine DOI Creative Commons

Evan Barry,

Vladimir Simov,

Iris Valtingojer

et al.

Cells, Journal Year: 2021, Volume and Issue: 10(10), P. 2715 - 2715

Published: Oct. 11, 2021

The Hippo pathway is an evolutionary conserved signaling network that regulates essential processes such as organ size, cell proliferation, migration, stemness and apoptosis. Alterations in this are commonly found solid tumors can lead to hyperproliferation, resistance chemotherapy, compensation for mKRAS tumor immune evasion. As the terminal effectors of pathway, transcriptional coactivators YAP1/TAZ transcription factors TEAD1–4 present exciting opportunities pharmacologically modulate biology cancer settings, inflammation regenerative medicine. This review will provide overview progress current strategies directly indirectly target protein–protein interaction (PPI) with across multiple modalities, focus on recent small molecules able selectively bind TEAD, block its autopalmitoylation inhibit YAP1/TAZ–TEAD-dependent cancer.

Language: Английский

Citations

60
YAP antagonizes TEAD‐mediated AR signaling and prostate cancer growth DOI
Xu Li, Shu Zhuo, Yong Suk Cho

et al.

The EMBO Journal, Journal Year: 2023, Volume and Issue: 42(4)

Published: Jan. 2, 2023

Language: Английский

Citations

26
AR and YAP crosstalk: impacts on therapeutic strategies in prostate cancer DOI Creative Commons

Guansong Zheng,

Zhaojie Yan,

Junrong Zou

et al.

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 15

Published: Feb. 3, 2025

Prostate cancer ranks as one of the most common types affecting men worldwide, and its progression is shaped by a diverse array influencing factors. The AR signaling pathway plays pivotal role in pathogenesis prostate cancer. While existing anti-androgen treatments show initial efficacy, they ultimately do not succeed halting advancement to CRPC. Recent studies have identified alterations Hippo-YAP within cancer, highlighting intricate crosstalk with pathway. In this review, we examine interactions underlying mechanisms between YAP, key molecules these two pathways. regulates stability function YAP modulating transcription, translation, phosphorylation status, while exerts both promotional inhibitory regulatory effects on AR. Based findings, paper investigates their significant roles onset, progression, therapeutic resistance discusses clinical potential treatment.

Language: Английский

Citations

1
The N6-methyladenosine reader protein YTHDC2 promotes gastric cancer progression via enhancing YAP mRNA translation DOI Creative Commons

Wei Yuan,

Shiqiang Chen, Bo Li

et al.

Translational Oncology, Journal Year: 2021, Volume and Issue: 16, P. 101308 - 101308

Published: Dec. 12, 2021

N6-methyladenosine (m6A) modification is the most prevalent internal in eukaryotic mRNA. YTH domain containing 2 (YTHDC2), a m6A binding protein, has recently been identified as key player human cancer. However, its contribution to gastric cancer (GC) remains unknown. Herein, we found that YTHDC2 was significantly upregulated GC tissues and associated with poor prognosis. CRISPR-Cas9 mediated knockout notably inhibited cell viability, proliferation invasion. Transcriptome analysis coupled mechanism experiments revealed yes-associated protein (YAP), well-known oncogene, target of cells. Specifically, recognized m6A-modified YAP mRNA at 5`-UTR, resulting enhancing translation efficiency YAP, without affecting level. In turn, YAP/TEAD directly targeted -843∼-831 region on promoter activated transcription YTHDC2, thus forming positive regulatory loop. Further, using xenograft tumor model, markedly reduced size lung metastasis nodules vivo. And high strongly positively correlated clinical tissues. Collectively, our data demonstrate novel oncogene GC, which provides theoretical basis for strategy targeting patients.

Language: Английский

Citations

42
Regulatory enhancer profiling of mesenchymal-type gastric cancer reveals subtype-specific epigenomic landscapes and targetable vulnerabilities DOI
Shamaine Wei Ting Ho,

Taotao Sheng,

Manjie Xing

et al.

Gut, Journal Year: 2022, Volume and Issue: 72(2), P. 226 - 241

Published: July 11, 2022

Objective Gastric cancer (GC) comprises multiple molecular subtypes. Recent studies have highlighted mesenchymal-subtype GC (Mes-GC) as a clinically aggressive subtype with few treatment options. Combining studies, we derived and applied consensus Mes-GC classifier to define the enhancer landscape revealing disease vulnerabilities. Design Transcriptomic profiles of ~1000 primary GCs cell lines were analysed derive classifier. Clinical genomic associations performed across >1200 patients GC. Genome-wide epigenomic (H3K27ac, H3K4me1 assay for transposase-accessible chromatin sequencing (ATAC-seq)) 49 generated identify Mes-GC-specific landscapes. Upstream regulators downstream targets enhancers interrogated using immunoprecipitation followed by (ChIP-seq), RNA sequencing, CRISPR/Cas9 editing, functional assays pharmacological inhibition. Results We identified validated 993-gene cancer-cell intrinsic applicable retrospective cohorts or prospective single samples. Multicohort analysis Mes-GCs confirmed poor patient survival, therapy resistance targetable alterations. Analysis revealed distinctive landscape, TEAD1 master regulator exhibiting preferential sensitivity super-enhancers also NUAK1 kinase target, synergistic effects observed between inhibition cisplatin treatment. Conclusion Our results establish transcriptomic scenarios. exhibit distinct combinatorial inhibition/cisplatin may represent potential

Language: Английский

Citations

34