| Full text | |
| Author(s): Show less - |
Magalhaes, Taciani de Almeida
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Veiga Cruzeiro, Gustavo Alencastro
;
de Sousa, Graziella Ribeiro
;
Englinger, Bernhard
;
Peinado Nagano, Luis Fernando
;
Ancliffe, Mathew
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da Silva, Keteryne Rodrigues
;
Jiang, Li
;
Gojo, Johannes
;
Liu, Yulu Cherry
;
Carline, Brooke
;
Kuchibhotla, Mani
;
Saggioro, Fabiano Pinto
;
Nagahashi Marie, Suely Kazue
;
Oba-Shinjo, Sueli Mieko
;
Yunes, Jose Andres
;
de Paula Queiroz, Rosane Gomes
;
Scrideli, Carlos Alberto
;
Endersby, Raelene
;
Filbin, Mariella G.
;
Borges, Kleiton Silva
;
Salic, Adrian
;
Tone, Luiz Gonzaga
;
Valera, Elvis Terci
Total Authors: 24
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| Document type: | Journal article |
| Source: | NEURO-ONCOLOGY; v. 25, n. 1, p. 14-pg., 2022-05-31. |
| Abstract | |
Background Supratentorial RELA fusion (ST-RELA) ependymomas (EPNs) are resistant tumors without an approved chemotherapeutic treatment. Unfortunately, the molecular mechanisms that lead to chemoresistance traits of ST-RELA remain elusive. The aim of this study was to assess RELA fusion-dependent signaling modules, specifically the role of the Hedgehog (Hh) pathway as a novel targetable vulnerability in ST-RELA. Methods Gene expression was analyzed in EPN from patient cohorts, by microarray, RNA-seq, qRT-PCR, and scRNA-seq. Inhibitors against Smoothened (SMO) (Sonidegib) and Aurora kinase A (AURKA) (Alisertib) were evaluated. Protein expression, primary cilia formation, and drug effects were assessed by immunoblot, immunofluorescence, and immunohistochemistry. Results Hh components were selectively overexpressed in EPNs induced by the RELA fusion. Single-cell analysis showed that the Hh signature was primarily confined to undifferentiated, stem-like cell subpopulations. Sonidegib exhibited potent growth-inhibitory effects on ST-RELA cells, suggesting a key role in active Hh signaling; importantly, the effect of Sonidegib was reversed by primary cilia loss. We, thus, tested the effect of AURKA inhibition by Alisertib, to induce cilia stabilization/reassembly. Strikingly, Alisertib rescued ciliogenesis and synergized with Sonidegib in killing ST-RELA cells. Using a xenograft model, we show that cilia loss is a mechanism for acquiring resistance to the inhibitory effect of Sonidegib. However, Alisertib fails to rescue cilia and highlights the need for other strategies to promote cilia reassembly, for treating ST-RELA tumors. Conclusion Our study reveals a crucial role for the Hh pathway in ST-RELA tumor growth, and suggests that rescue of primary cilia represents a vulnerability of the ST-RELA EPNs. (AU) | |
| FAPESP's process: | 18/18842-1 - The role of the Hedgehog signaling pathway in ependymoma |
| Grantee: | Taciani de Almeida Magalhães |
| Support Opportunities: | Scholarships abroad - Research Internship - Doctorate |
| FAPESP's process: | 16/19820-6 - Investigation of new therapeutic targets from transcriptional networks of genes of the mitotic spindle associated with embryonic developmental pathways in the ependymoma: focus on molecular subgroups of worst outcome |
| Grantee: | Taciani de Almeida Magalhães |
| Support Opportunities: | Scholarships in Brazil - Doctorate |
| FAPESP's process: | 14/20341-0 - Interactions between emerging therapeutic targets and developmental pathways associated with tumorigenesis: emphasis on pediatric malignancies |
| Grantee: | Luiz Gonzaga Tone |
| Support Opportunities: | Research Projects - Thematic Grants |