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

Autor(es)

Alencastro Veiga Cruzeiro, Gustavo ^{[1, 2, 3]} ; de Almeida Magalhaes, Taciani ^{[4, 5]} ; Ribeiro de Sousa, Graziella ^[4] ; Bonfim Silva, Ricardo ^[4] ; Alberto Oliveira de Biagi Junior, Carlos ^[4] ; Ferreira das Chagas, Pablo ^[4] ; Gomes de Paula Queiroz, Rosane ^[2] ; Alberto Scrideli, Carlos ^[2] ; Gonzaga Tone, Luiz ^[2] ; Terci Valera, Elvis ^[2]

Afiliação do(s) autor(es)

^[1] Broad Inst Harvard & MIT, Cambridge, MA 02142 - USA

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Hosp Clin Ribeirao Preto, Dept Pediat, Av Bandeirantes 3900, BR-05468901 Ribeirao Preto, SP - Brazil

^[3] Harvard Med Sch, Dana Farber Boston Childrens Canc & Blood Disorde, Dept Pediat Oncol, 450 Brookline Ave, Boston, MA 02215 - USA

^[4] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Genet, Av Bandeirantes 3900, BR-05468901 Ribeirao Preto, SP - Brazil

^[5] Harvard Med Sch, Dept Cell Biol, 240 Longwood Ave, Boston, MA 02115 - USA

• Tipo de documento: Artigo Científico
• Fonte: CANCERS; v. 13, n. 24 DEC 2021.
• Citações Web of Science: 0

Resumo

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. 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. (AU)

• Processo FAPESP: 14/20341-0 - Interação entre alvos terapêuticos emergentes e vias de desenvolvimento associadas à tumorigênese: ênfase em neoplasias da criança e do adolescente
• Beneficiário: Luiz Gonzaga Tone
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 17/06511-8 - Investigação do complexo Smad2/3-YAP como fator quimioresistente em meduloblastoma SHH TP53 mutante
• Beneficiário: Gustavo Alencastro Veiga Cruzeiro
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 18/20635-4 - Novas estratégias e alvos terapêuticos explorando o microambiente tumoral através de modelos in vivo de meduloblastoma subgrupo SHH e Group 3
• Beneficiário: Gustavo Alencastro Veiga Cruzeiro
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado