Activation of Hedgehog signaling by the oncogenic RELA fusion reveals a primary cilia-dependent vulnerability in supratentorial ependymoma

Autor: Taciani de Almeida Magalhães, Gustavo Alencastro Veiga Cruzeiro, Graziella Ribeiro de Sousa, Bernhard Englinger, Luis Fernando Peinado Nagano, Mathew Ancliffe, Keteryne Rodrigues da Silva, Li Jiang, Johannes Gojo, Yulu Cherry Liu, Brooke Carline, Mani Kuchibhotla, Fabiano Pinto Saggioro, Suely Kazue Nagahashi Marie, Sueli Mieko Oba-Shinjo, José Andres Yunes, Rosane Gomes de Paula Queiroz, Carlos Alberto Scrideli, Raelene Endersby, Mariella G Filbin, Kleiton Silva Borges, Adrian Salic, Luiz Gonzaga Tone, Elvis Terci Valera
Rok vydání: 2022
Předmět:
Zdroj: Neuro Oncol
ISSN: 1523-5866
1522-8517
DOI: 10.1093/neuonc/noac147
Popis: 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.
Databáze: OpenAIRE
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