Details

Autor(en) / Beteiligte

• de Almeida Magalhães, Taciani
• Alencastro Veiga Cruzeiro, Gustavo
• Ribeiro de Sousa, Graziella
• Englinger, Bernhard
• Fernando Peinado Nagano, Luis
• Ancliffe, Mathew
• Rodrigues da Silva, Keteryne
• Jiang, Li
• Gojo, Johannes
• Cherry Liu, Yulu
• Carline, Brooke
• Kuchibhotla, Mani
• Pinto Saggioro, Fabiano
• Kazue Nagahashi Marie, Suely
• Mieko Oba-Shinjo, Sueli
• Andres Yunes, José
• Gomes de Paula Queiroz, Rosane
• Alberto Scrideli, Carlos
• Endersby, Raelene
• Filbin, Mariella G
• Silva Borges, Kleiton
• Salic, Adrian
• Gonzaga Tone, Luiz
• Valera, Elvis Terci

Titel

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

Ist Teil von

• Neuro-oncology (Charlottesville, Va.), 2023-01, Vol.25 (1), p.185-198

Ort / Verlag

England: Oxford University Press

Erscheinungsjahr

2023

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• 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. 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. 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. 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.