Reviewer #2 (Public Review): VGLL2 and TEAD1 fusion proteins drive YAP/TAZ-independent transcription and tumorigenesis by engaging p300 DOI Open Access

Published: July 1, 2024

Studies on Hippo pathway regulation of tumorigenesis largely center YAP and TAZ, the transcriptional co-regulators TEAD. Here, we present an oncogenic mechanism involving VGLL TEAD fusions that is pathway-related but YAP/TAZ-independent. We characterize two recurrent fusions, VGLL2-NCOA2 TEAD1-NCOA2, recently identified in spindle cell rhabdomyosarcoma. demonstrate that, contrast to VGLL2 TEAD1, fusion proteins are strong activators TEAD-dependent transcription, their function does not require YAP/TAZ. Furthermore, identify TEAD1 engage specific epigenetic by recruiting histone acetyltransferase p300 control TEAD-mediated landscapes. showed small molecule inhibition can suppress proteins-induced transformation both vitro vivo. Overall, our study reveals a molecular basis for involvement cancer provides framework targeting tumors carrying VGLL, TEAD, or NCOA translocations.

Language: Английский

Control of stem cell renewal and fate by YAP and TAZ DOI
Jordan H. Driskill, Duojia Pan

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(12), P. 895 - 911

Published: Aug. 25, 2023

Language: Английский

Citations

72
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
New insights into the ambivalent role of YAP/TAZ in human cancers DOI Creative Commons
Juan Luo, Liang Deng,

Hailin Zou

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 42(1)

Published: May 22, 2023

Abstract Hippo signaling was first identified in Drosophila as a key controller of organ size by regulating cell proliferation and anti-apoptosis. Subsequent studies have shown that this pathway is highly conserved mammals, its dysregulation implicated multiple events cancer development progression. Yes-associated protein (YAP) transcriptional coactivator with PDZ-binding motif (TAZ) (hereafter YAP/TAZ) are the downstream effectors pathway. YAP/TAZ overexpression or activation sufficient to induce tumor initiation progression, well recurrence therapeutic resistance. However, there growing evidence also exert tumor-suppressive function context-dependent manner. Therefore, caution should be taken when targeting clinical trials future. In review article, we will give an overview their oncogenic roles various cancers then systematically summarize functions different contexts. Based on these findings, further discuss implications YAP/TAZ-based targeted therapy potential future directions. Graphical

Language: Английский

Citations

31
New Insights into YAP/TAZ-TEAD-Mediated Gene Regulation and Biological Processes in Cancer DOI Open Access
Yang Zhao,

Marisela Sheldon,

Yutong Sun

et al.

Cancers, Journal Year: 2023, Volume and Issue: 15(23), P. 5497 - 5497

Published: Nov. 21, 2023

The Hippo pathway is conserved across species. Key mammalian kinases, including MST1/2 and LATS1/2, inhibit cellular growth by inactivating the TEAD coactivators, YAP, TAZ. Extensive research has illuminated roles of signaling in cancer, development, regeneration. Notably, dysregulation components not only contributes to tumor metastasis, but also renders tumors resistant therapies. This review delves into recent on YAP/TAZ-TEAD-mediated gene regulation biological processes cancer. We focus several key areas: newly identified molecular patterns YAP/TAZ activation, emerging mechanisms that contribute metastasis cancer therapy resistance, unexpected suppression, advances therapeutic strategies targeting this pathway. Moreover, we provide an updated view YAP/TAZ's functions, discuss ongoing controversies, offer perspectives specific debated topics rapidly evolving field.

Language: Английский

Citations

20
Malignant mesothelioma tumours: molecular pathogenesis, diagnosis, and therapies accompanying clinical studies DOI Creative Commons
Ram Kumar Sahu,

Sakina Ruhi,

Ashok Kumar Jeppu

et al.

Frontiers in Oncology, Journal Year: 2023, Volume and Issue: 13

Published: July 4, 2023

The pathetic malignant mesothelioma (MM) is a extremely uncommon and confrontational tumor that evolves in the mesothelium layer of pleural cavities (inner lining- visceral pleura outer parietal pleura), peritoneum, pericardium, tunica vaginalis highly resistant to standard treatments. In mesothelioma, predominant pattern lesions loss genes limit tumour growth. Despite worldwide ban on manufacture supply asbestos, prevalence continues increase. Mesothelioma presents behaves variety ways, making diagnosis challenging. Most treatments available today for MM are ineffective, median life expectancy between 10 12 months. However, recent years, considerable progress has already been made understanding genetics molecular pathophysiology by addressing hippo signaling pathway. development progression related many important genetic alterations. This NF2 and/or LATS2 mutations activate transcriptional coactivator YAP. X-rays, CT scans, MRIs, PET scans used diagnose MM. treated with surgery, chemotherapy, first-line combination second-line treatment, radiation therapy, adoptive T-cell targeted cancer vaccines. Recent clinical trials investigating function surgery have led innovative approaches treatment associated effusions as well introduction medications. An interdisciplinary collaborative approach needed effective care persons who because rising intricacy treatment. article highlights key findings pathogenesis special emphasis management mesothelioma.

Language: Английский

Citations

16
Fibroblast-derived EGF ligand neuregulin 1 induces fetal-like reprogramming of the intestinal epithelium without supporting tumorigenic growth DOI Creative Commons
Toni T Lemmetyinen, Emma W Viitala,

Linnea Wartiovaara

et al.

Disease Models & Mechanisms, Journal Year: 2023, Volume and Issue: 16(4)

Published: March 13, 2023

ABSTRACT Growth factors secreted by stromal fibroblasts regulate the intestinal epithelium. Stroma-derived epidermal growth factor (EGF) family ligands are implicated in epithelial regeneration and tumorigenesis, but their specific contributions associated mechanisms remain unclear. Here, we use primary organoids modeling homeostatic, injured tumorigenic epithelia to assess how fibroblast-derived EGF neuregulin 1 (NRG1) epiregulin (EREG) NRG1 was expressed exclusively stroma, robustly increased crypt budding protected from radiation-induced damage. also induced regenerative features epithelium, including a fetal-like transcriptome, suppression of Lgr5+ stem cell pool remodeling actin cytoskeleton. Intriguingly, unlike EREG, failed support pre-tumorigenic lacking tumor suppressor Apc, commonly mutated human colorectal cancer (CRC). Interestingly, high expression with improved survival CRC cohorts, suggesting tumor-suppressive function. Our results highlight power transcriptional reprogramming protection epithelium radiation injury without promoting tumorigenesis.

Language: Английский

Citations

15
K48-linked deubiquitination of VGLL4 by USP15 enhances the efficacy of tumor immunotherapy in triple-negative breast cancer DOI
Xuehui Wang,

Xiaochong Deng,

Jiashu Hu

et al.

Cancer Letters, Journal Year: 2024, Volume and Issue: 588, P. 216764 - 216764

Published: Feb. 29, 2024

Language: Английский

Citations

5
VGLL2 and TEAD1 fusion proteins drive YAP/TAZ-independent tumorigenesis by engaging p300 DOI Open Access
Susu Guo, Xiaodi Hu, Jennifer L. Cotton

et al.

Published: April 15, 2025

Studies on Hippo pathway regulation of tumorigenesis largely center YAP and TAZ, the transcriptional co-regulators TEAD. Here, we present an oncogenic mechanism involving VGLL TEAD fusions that is pathway-related but YAP/TAZ-independent. We characterize two recurrent fusions, VGLL2-NCOA2 TEAD1-NCOA2, recently identified in spindle cell rhabdomyosarcoma. demonstrate contrast to VGLL2 TEAD1, fusion proteins are strong activators TEAD-dependent transcription, their function does not require YAP/TAZ. Furthermore, identify TEAD1 engage specific epigenetic by recruiting histone acetyltransferase p300 control TEAD-mediated landscapes. showed small molecule inhibition can suppress proteins-induced transformation both vitro vivo . Overall, our study reveals a molecular basis for involvement cancer provides framework targeting tumors carrying VGLL, TEAD, or NCOA translocations.

Language: Английский

Citations

0
miR-603 Mediates Thyroid Cancer Progression by Inhibiting HACE1-Dependent YAP1 Degradation DOI

Tangya Li,

Jian Chu,

Zhou Guangjun

et al.

Archives of Biochemistry and Biophysics, Journal Year: 2025, Volume and Issue: unknown, P. 110453 - 110453

Published: May 1, 2025

Language: Английский

Citations

0
VGLL2 and TEAD1 fusion proteins identified in human sarcoma drive YAP/TAZ-independent tumorigenesis by engaging EP300 DOI Creative Commons
Susu Guo, Xiaodi Hu, Jennifer L. Cotton

et al.

eLife, Journal Year: 2025, Volume and Issue: 13

Published: May 8, 2025

Studies on Hippo pathway regulation of tumorigenesis largely center YAP and TAZ, the transcriptional co-regulators TEADs. Here, we present an oncogenic mechanism involving VGLL TEAD fusions that is pathway-related but YAP/TAZ-independent. We characterize two recurrent fusions, VGLL2-NCOA2 TEAD1-NCOA2 , recently identified in human spindle cell rhabdomyosarcoma. demonstrate contrast to VGLL2 TEAD1 fusion proteins are potent activators TEAD-dependent transcription, function these does not require YAP/TAZ. Furthermore, identify engage specific epigenetic by recruiting histone acetyltransferase EP300 control TEAD-mediated landscapes. show small-molecule inhibition can suppress protein-induced transformation both vitro vivo mouse models. Overall, our study reveals a molecular basis for involvement cancer provides framework targeting tumors carrying or NCOA translocations.

Language: Английский

Citations

0