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YAP1 Is a Potential Predictive Molecular Biomarker for Response to SMO Inhibitor in Medulloblastoma Cells

SIMPLE SUMMARY: Medulloblastoma (MB) is the most common malignant brain tumor in childhood. Currently, MB is assigned in four molecular subgroups (SHH, WNT, Group 3, and Group 4) and subtyped in 12 variants. The alpha subtype of the SHH subgroup bears TP53 mutation and is considered very high risk b...

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Autores principales: Alencastro Veiga Cruzeiro, Gustavo, de Almeida Magalhães, Taciani, Ribeiro de Sousa, Graziella, Bonfim Silva, Ricardo, Alberto Oliveira de Biagi Junior, Carlos, Ferreira das Chagas, Pablo, Gomes de Paula Queiroz, Rosane, Alberto Scrideli, Carlos, Gonzaga Tone, Luiz, Terci Valera, Elvis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8699675/
https://www.ncbi.nlm.nih.gov/pubmed/34944872
http://dx.doi.org/10.3390/cancers13246249
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author Alencastro Veiga Cruzeiro, Gustavo
de Almeida Magalhães, Taciani
Ribeiro de Sousa, Graziella
Bonfim Silva, Ricardo
Alberto Oliveira de Biagi Junior, Carlos
Ferreira das Chagas, Pablo
Gomes de Paula Queiroz, Rosane
Alberto Scrideli, Carlos
Gonzaga Tone, Luiz
Terci Valera, Elvis
author_facet Alencastro Veiga Cruzeiro, Gustavo
de Almeida Magalhães, Taciani
Ribeiro de Sousa, Graziella
Bonfim Silva, Ricardo
Alberto Oliveira de Biagi Junior, Carlos
Ferreira das Chagas, Pablo
Gomes de Paula Queiroz, Rosane
Alberto Scrideli, Carlos
Gonzaga Tone, Luiz
Terci Valera, Elvis
author_sort Alencastro Veiga Cruzeiro, Gustavo
collection PubMed
description SIMPLE SUMMARY: Medulloblastoma (MB) is the most common malignant brain tumor in childhood. Currently, MB is assigned in four molecular subgroups (SHH, WNT, Group 3, and Group 4) and subtyped in 12 variants. The alpha subtype of the SHH subgroup bears TP53 mutation and is considered very high risk by the World Health Organization (WHO). In the current study, we have investigated the role of YAP1 expression in SHH MBs. Herein, we show: (1) SHH MB patients genotypically profiled as resistant to SMOi and the aggressive alpha subtype overexpress YAP1; (2) SHH-like cell lines bearing TP53 mutation show improved responsiveness to SMOi upon YAP1 depletion; (3) Sonidegib (smoothened inhibitor) and Verteporfin (YAP1 inhibitor) synergize at specific doses; (4) distinct cell populations in the single-cell RNA-seq patient setting express YAP1 and SMO. ABSTRACT: Advances in genomics have led to the identification of twelve relevant molecular subtypes within medulloblastoma (MB). The alpha subtype of Sonic hedgehog-driven MB is resistant to therapy (including smoothened inhibitors) due to activation of genes from the non-canonical SHH pathway, such as MYCN, YAP1, or TP53. Using retrospective cohort microarray data, we found that YAP1 is overexpressed in SHH alpha MB and patients profiled as resistant to SMO inhibitors compared to good responders. Here, we performed YAP1 depletion via CRISPR/Cas9 in two in vitro models of SHH-like MB cells and found that this protein is involved in responsiveness to the SMO inhibitor regarding proliferation, apoptosis, and colony formation. Further, considering the synergic combination of YAP1 depletion with SMO inhibition, we assessed single-cell RNA-seq data from five patients and found that SMO and YAP1 are enriched within cells of SHH MB. Importantly, our data suggest that YAP1 is not only a reliable biomarker for cellular response to SMOi but may indicate prospective testing of combination therapy using YAP1 and SMO inhibitors in preclinical models of SHH MB.
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spelling pubmed-86996752021-12-24 YAP1 Is a Potential Predictive Molecular Biomarker for Response to SMO Inhibitor in Medulloblastoma Cells Alencastro Veiga Cruzeiro, Gustavo de Almeida Magalhães, Taciani Ribeiro de Sousa, Graziella Bonfim Silva, Ricardo Alberto Oliveira de Biagi Junior, Carlos Ferreira das Chagas, Pablo Gomes de Paula Queiroz, Rosane Alberto Scrideli, Carlos Gonzaga Tone, Luiz Terci Valera, Elvis Cancers (Basel) Communication SIMPLE SUMMARY: Medulloblastoma (MB) is the most common malignant brain tumor in childhood. Currently, MB is assigned in four molecular subgroups (SHH, WNT, Group 3, and Group 4) and subtyped in 12 variants. The alpha subtype of the SHH subgroup bears TP53 mutation and is considered very high risk by the World Health Organization (WHO). In the current study, we have investigated the role of YAP1 expression in SHH MBs. Herein, we show: (1) SHH MB patients genotypically profiled as resistant to SMOi and the aggressive alpha subtype overexpress YAP1; (2) SHH-like cell lines bearing TP53 mutation show improved responsiveness to SMOi upon YAP1 depletion; (3) Sonidegib (smoothened inhibitor) and Verteporfin (YAP1 inhibitor) synergize at specific doses; (4) distinct cell populations in the single-cell RNA-seq patient setting express YAP1 and SMO. ABSTRACT: Advances in genomics have led to the identification of twelve relevant molecular subtypes within medulloblastoma (MB). The alpha subtype of Sonic hedgehog-driven MB is resistant to therapy (including smoothened inhibitors) due to activation of genes from the non-canonical SHH pathway, such as MYCN, YAP1, or TP53. Using retrospective cohort microarray data, we found that YAP1 is overexpressed in SHH alpha MB and patients profiled as resistant to SMO inhibitors compared to good responders. Here, we performed YAP1 depletion via CRISPR/Cas9 in two in vitro models of SHH-like MB cells and found that this protein is involved in responsiveness to the SMO inhibitor regarding proliferation, apoptosis, and colony formation. Further, considering the synergic combination of YAP1 depletion with SMO inhibition, we assessed single-cell RNA-seq data from five patients and found that SMO and YAP1 are enriched within cells of SHH MB. Importantly, our data suggest that YAP1 is not only a reliable biomarker for cellular response to SMOi but may indicate prospective testing of combination therapy using YAP1 and SMO inhibitors in preclinical models of SHH MB. MDPI 2021-12-13 /pmc/articles/PMC8699675/ /pubmed/34944872 http://dx.doi.org/10.3390/cancers13246249 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Communication
Alencastro Veiga Cruzeiro, Gustavo
de Almeida Magalhães, Taciani
Ribeiro de Sousa, Graziella
Bonfim Silva, Ricardo
Alberto Oliveira de Biagi Junior, Carlos
Ferreira das Chagas, Pablo
Gomes de Paula Queiroz, Rosane
Alberto Scrideli, Carlos
Gonzaga Tone, Luiz
Terci Valera, Elvis
YAP1 Is a Potential Predictive Molecular Biomarker for Response to SMO Inhibitor in Medulloblastoma Cells
title YAP1 Is a Potential Predictive Molecular Biomarker for Response to SMO Inhibitor in Medulloblastoma Cells
title_full YAP1 Is a Potential Predictive Molecular Biomarker for Response to SMO Inhibitor in Medulloblastoma Cells
title_fullStr YAP1 Is a Potential Predictive Molecular Biomarker for Response to SMO Inhibitor in Medulloblastoma Cells
title_full_unstemmed YAP1 Is a Potential Predictive Molecular Biomarker for Response to SMO Inhibitor in Medulloblastoma Cells
title_short YAP1 Is a Potential Predictive Molecular Biomarker for Response to SMO Inhibitor in Medulloblastoma Cells
title_sort yap1 is a potential predictive molecular biomarker for response to smo inhibitor in medulloblastoma cells
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8699675/
https://www.ncbi.nlm.nih.gov/pubmed/34944872
http://dx.doi.org/10.3390/cancers13246249
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