{"doi":"10.1093/neuonc/noac147","title":"Activation of Hedgehog signaling by the oncogenic RELA fusion reveals a primary cilia-dependent vulnerability in supratentorial ependymoma","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.","journal":"Neuro-Oncology","year":2022,"id":271825,"datarank":0.38474240361923057,"base_score":2.5649493574615367,"endowment":2.5649493574615367,"self_citation_contribution":0.38474240361923057,"citation_network_contribution":0.0,"self_endowment_contribution":0.38474240361923057,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9604,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":937256,"name":"Gustavo Alencastro Veiga Cruzeiro","orcid":"0000-0002-0005-3984","position":1,"is_corresponding":false},{"id":937257,"name":"Graziella Ribeiro de Sousa","orcid":"0000-0003-1809-8539","position":2,"is_corresponding":false},{"id":25316,"name":"Bernhard Englinger","orcid":"0000-0002-9701-2600","position":3,"is_corresponding":false},{"id":937258,"name":"Luís Fernando Peinado Nagano","orcid":"0000-0003-4313-9347","position":4,"is_corresponding":false},{"id":679386,"name":"Mathew Ancliffe","orcid":null,"position":5,"is_corresponding":false},{"id":937259,"name":"Keteryne Rodrigues da Silva","orcid":"0000-0002-8260-6377","position":6,"is_corresponding":false},{"id":25317,"name":"Li Jiang","orcid":"0000-0001-7320-5283","position":7,"is_corresponding":false},{"id":5535,"name":"Johannes Gojo","orcid":"0000-0002-8113-3416","position":8,"is_corresponding":false},{"id":895054,"name":"Yulu Cherry Liu","orcid":"0000-0003-4861-6915","position":9,"is_corresponding":false},{"id":678491,"name":"Brooke Carline","orcid":"0000-0002-8061-4170","position":10,"is_corresponding":false},{"id":678489,"name":"Mani Kuchibhotla","orcid":"0000-0002-6348-4087","position":11,"is_corresponding":false},{"id":937260,"name":"Fabiano Pinto Saggioro","orcid":"0000-0003-3879-7142","position":12,"is_corresponding":false},{"id":71359,"name":"Suely Kazue Nagahashi Marie","orcid":"0000-0003-4419-7928","position":13,"is_corresponding":false},{"id":607789,"name":"Sueli Mieko Oba‐Shinjo","orcid":"0000-0002-1650-5973","position":14,"is_corresponding":false},{"id":771779,"name":"José Andrés Yunes","orcid":"0000-0002-1316-3525","position":15,"is_corresponding":false},{"id":937664,"name":"Rosane Gomes de Paula Queiróz","orcid":null,"position":16,"is_corresponding":false},{"id":937261,"name":"Carlos Alberto Scrideli","orcid":"0000-0001-6618-789X","position":17,"is_corresponding":false},{"id":371168,"name":"Raelene Endersby","orcid":"0000-0003-3554-2769","position":18,"is_corresponding":false},{"id":1408,"name":"Mariella G. Filbin","orcid":"0000-0002-2613-8126","position":19,"is_corresponding":false},{"id":310373,"name":"Kleiton Silva Borges","orcid":"0000-0003-0356-922X","position":20,"is_corresponding":false},{"id":294013,"name":"Adrian Salic","orcid":"0000-0002-0748-9545","position":21,"is_corresponding":false},{"id":752613,"name":"Luíz Gonzaga Tone","orcid":"0000-0001-8821-4211","position":22,"is_corresponding":false},{"id":937262,"name":"Elvis Terci Valera","orcid":"0000-0002-4434-429X","position":23,"is_corresponding":false},{"id":937255,"name":"Taciani de Almeida Magalhães","orcid":"0000-0002-6743-1003","position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:27:39.717534Z","pmid":"35640920","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}