Evidence map›Paper›PMID 35640920›Full record

ArticleNeuro-oncology2023

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

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 and 14 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neuro-oncology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
1.2field-weighted citation impact, top 22% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

5 citing papers in PubMed, 12 citations in OpenAlex.

  1. Article
  2. Article
  3. Frontiers in oncology · 2024
    Review
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

24 authors at 7 institutions in 4 countries.

Taciani de Almeida MagalhãesDepartment of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Gustavo Alencastro Veiga CruzeiroDepartment of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.ORCID 0000-0002-0005-3984
Graziella Ribeiro de SousaDepartment of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Bernhard EnglingerDepartment of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts, USA.
Luis Fernando Peinado NaganoDepartment of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Mathew AncliffeBrain Tumour Research Program, Telethon Kids Institute and the University of Western Australia, Nedlands, Western Australia, Australia.
Keteryne Rodrigues da SilvaDepartment of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Li JiangDepartment of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts, USA.
Johannes GojoDepartment of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts, USA.
Yulu Cherry LiuDepartment of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Brooke CarlineBrain Tumour Research Program, Telethon Kids Institute and the University of Western Australia, Nedlands, Western Australia, Australia.
Mani KuchibhotlaBrain Tumour Research Program, Telethon Kids Institute and the University of Western Australia, Nedlands, Western Australia, Australia.
Fabiano Pinto SaggioroDepartment of Pathology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Suely Kazue Nagahashi MarieCellular and Molecular Biology Laboratory, Department of Neurology, Faculdade de Medicina (FMUSP), University of São Paulo, São Paulo, Brazil.
Sueli Mieko Oba-ShinjoCellular and Molecular Biology Laboratory, Department of Neurology, Faculdade de Medicina (FMUSP), University of São Paulo, São Paulo, Brazil.
José Andres YunesMolecular Biology Laboratory, Boldrini Children's Center, Campinas, São Paulo, Brazil.
Rosane Gomes de Paula QueirozDepartment of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Carlos Alberto ScrideliDepartment of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Raelene EndersbyBrain Tumour Research Program, Telethon Kids Institute and the University of Western Australia, Nedlands, Western Australia, Australia.ORCID 0000-0003-3554-2769
Mariella G FilbinDepartment of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts, USA.
Kleiton Silva BorgesDepartment of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Adrian SalicDepartment of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Luiz Gonzaga ToneDepartment of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Elvis Terci ValeraDepartment of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.ORCID 0000-0002-4434-429X
Universidade de São Paulo · BRThe Kids Research Institute Australia · AUBroad Institute · USHarvard University · USBoston Children's Hospital · USCentro Infantil Boldrini · BRDana-Farber/Boston Children's Cancer and Blood Disorders Center · US

Funding

Sending and receiving Hedgehog signalsR01GM122920 · NIGMS · HARVARD MEDICAL SCHOOL · PI SALIC, ADRIAN · 2018 to 2023
$2.7M
Transducing Hedgehog signals across the plasma membraneR01GM135262 · NIGMS · HARVARD MEDICAL SCHOOL · PI SALIC, ADRIAN · 2020 to 2023
$1.7M
NIGMS NIH HHS R01 GM122920NIGMS NIH HHS R01 GM135262
6 · The paper itself

Abstract

backgroundSupratentorial 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.

methodsGene 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.

resultsHh 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.

conclusionOur 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.

Indexed as

EpendymomaSupratentorial NeoplasmsAurora Kinase ABiphenyl CompoundsCiliaHedgehog ProteinsHumansPyridinesTranscription Factor RelAAurora Kinase ABiphenyl CompoundsHedgehog ProteinsPyridinesRELA protein, humansonidegibTranscription Factor RelAAlisertibHedgehog pathwayPrimary ciliaSonidegibST-RELA ependymoma

Identifiers

PMID35640920
PMCPMC9825332
OpenAlexW4282928866

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.