OSCR

RAC1 regulates Sonic Hedgehog-medulloblastoma growth via GLI-mediated transcription.

Overview

Authors: Nitish Jangde1, Mi-Hye Lee1, Luz Ruiz1, Isabelle Egan1, Anna M Jermakowicz1, Rishika Chowdary1, Jonathan Chu1, Daniel T Wynn1, Erik Goka1,2, Marc Lippman1, David J Robbins1, Nagi G Ayad1
ORCID iDs: Nitish Jangde, Mi-Hye Lee, Isabelle Egan, Anna M Jermakowicz, Daniel T Wynn, Nagi G Ayad
  1. Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Georgetown University, Washington, DC, USA
  2. Revere Pharmaceuticals, San Diego, CA, USA (E.G.)
Institutions: Georgetown University (United States); Georgetown University Medical Center (United States); Georgetown Lombardi Comprehensive Cancer Center
Journal: Neuro-oncology, volume 28, issue 6, pages 1527-1540
Dates: received 10 June 2025; accepted 13 March 2026; published online 19 March 2026; in print June 2026
Type: Research article · Language: English
License: CC BY-NC
Identifiers: DOI 10.1093/neuonc/noag057 · PMID 41857757 · PMCID PMC13233070 · OpenAlex W7138838724
Open access: hybrid, a free copy (OpenAlex)
Status: data only
Categories: human (organism), mouse (organism), rat (organism), other condition (population), cellular / molecular (subfield)
Keywords: cell migration, cytoskeleton, medulloblastoma, proliferation, RAC1 GTPase, targeted therapy
MeSH: Cerebellar Neoplasms*, Hedgehog Proteins*, Medulloblastoma*, rac1 GTP-Binding Protein*, Zinc Finger Protein GLI1*, Animals, Cell Movement, Cell Proliferation, Gene Expression Regulation, Neoplastic, Humans, Mice, Rats, Transcription, Genetic (* major topic)
Topic: Hedgehog Signaling Pathway Studies (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: Cure Childhood Cancer (F31CA291046, 1305140); NIH HHS (NS118023, NS110591, NS135506); NINDS NIH HHS (R21 NS135506); NCI NIH HHS (T32 CA009686); BellRinger Foundation at Lombardi Comprehensive Cancer Center of Georgetown University
Citations: not cited yet (Europe PMC); 64 references in the paper
Research resources: DNMT1 RRID:AB_10548197, UHRF1 RRID:AB_10947236, GLI2 RRID:AB_2111902, GLI1 RRID:AB_2247710

Abstract

Background: Medulloblastoma (MB) is the most common malignant brain tumor of childhood, and current treatments cannot sufficiently inhibit tumoral growth, leptomeningeal dissemination, and metastasis. Ras-related C3 botulinum toxin substrate 1 (RAC1), a low molecular weight GTPase involved in cytoskeletal regulation and cell migration, is established to facilitate tumorigenesis in other neoplasia, but RAC1 is unexplored in MB and has no targeted therapies.

Methods: We examined RAC1 activity in Sonic Hedgehog (SHH)-subtype MB using human and mouse Ptch1−/− cell models, RNAi knockdown, pharmacologic inhibition with GYS32661, transcript profiling, chromatin immunoprecipitation, and cytotoxicity assays in primary human astrocytes. We also determined the efficacy, brain penetration, and toxicity of GYS32661 in orthotopic spheroid Ptch1−/− mouse and rat models.

Results: RAC1 activity was markedly increased in the MB tissue compared to the normal cerebellum. RAC1 depletion suppressed the proliferation and migration of SHH-MB cells. Mechanistically, RAC1 regulated GLI1 and GLI2 expression and bound the upstream loci of GLI1 and DNMT1, revealing a novel mechanism of SHH transcriptional regulation. GYS32661, a brain-permeable RAC1 inhibitor, was not toxic to normal astrocytes, suppressed SHH-MB tumor growth, and improved survival in vivo without toxicity in rats.

Conclusion: RAC1 functions as a critical transcriptional regulator of SHH signaling and epigenetic mediators in medulloblastoma, highlighting its potential as a druggable target in SHH-dependent MB. Our findings also characterize the RAC1 inhibitor GYS32661 as a promising drug candidate for the treatment of SHH-MB.

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

The paper's code and data availability statement is in the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none, so it has no map.

Data

Datasets cited

Data Availability

Raw experimental data of the presented study are available from the corresponding author upon reasonable request. The datasets analyzed are publicly available in the Gene Expression Omnibus (GEO) with the accession codes GSE119926 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE119926), GSE67835 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE67835), microarray dataset (de Bont et al 2008) Gliovis (http://gliovis.bioinfo.cnio.es/) by Bowman et al (2017).

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 12 authors, 6 keywords, 13 MeSH terms, 5 funders, 64 references, 4 RRIDs.

Cite

This paper

Jangde, N., Lee, M.-H., Ruiz, L., Egan, I., Jermakowicz, A. M., Chowdary, R., Chu, J., Wynn, D. T., Goka, E., Lippman, M., Robbins, D. J., & Ayad, N. G. (2026). RAC1 regulates Sonic Hedgehog-medulloblastoma growth via GLI-mediated transcription. Neuro-oncology, 28(6), 1527-1540. https://doi.org/10.1093/neuonc/noag057

BibTeX

@article{jangde2026rac1,
author = {Jangde, Nitish and Lee, Mi-Hye and Ruiz, Luz and Egan, Isabelle and Jermakowicz, Anna M and Chowdary, Rishika and Chu, Jonathan and Wynn, Daniel T and Goka, Erik and Lippman, Marc and Robbins, David J and Ayad, Nagi G},
title = {{RAC1 regulates Sonic Hedgehog-medulloblastoma growth via GLI-mediated transcription}},
journal = {Neuro-oncology},
year = {2026},
month = jun,
volume = {28},
number = {6},
pages = {1527--1540},
publisher = {Oxford University Press},
issn = {1522-8517},
doi = {10.1093/neuonc/noag057},
url = {https://doi.org/10.1093/neuonc/noag057},
pmid = {41857757},
pmcid = {PMC13233070}
}

RIS

TY - JOUR
AU - Jangde, Nitish
AU - Lee, Mi-Hye
AU - Ruiz, Luz
AU - Egan, Isabelle
AU - Jermakowicz, Anna M
AU - Chowdary, Rishika
AU - Chu, Jonathan
AU - Wynn, Daniel T
AU - Goka, Erik
AU - Lippman, Marc
AU - Robbins, David J
AU - Ayad, Nagi G
TI - RAC1 regulates Sonic Hedgehog-medulloblastoma growth via GLI-mediated transcription
T2 - Neuro-oncology
J2 - Neuro Oncol
PY - 2026
DA - 2026/06/01
VL - 28
IS - 6
SP - 1527
EP - 1540
SN - 1522-8517
PB - Oxford University Press
DO - 10.1093/neuonc/noag057
UR - https://doi.org/10.1093/neuonc/noag057
LA - en
ER -

CSL-JSON

{
"id": "10.1093/neuonc/noag057",
"type": "article-journal",
"title": "RAC1 regulates Sonic Hedgehog-medulloblastoma growth via GLI-mediated transcription",
"container-title": "Neuro-oncology",
"author": [
{
"family": "Jangde",
"given": "Nitish"
},
{
"family": "Lee",
"given": "Mi-Hye"
},
{
"family": "Ruiz",
"given": "Luz"
},
{
"family": "Egan",
"given": "Isabelle"
},
{
"family": "Jermakowicz",
"given": "Anna M"
},
{
"family": "Chowdary",
"given": "Rishika"
},
{
"family": "Chu",
"given": "Jonathan"
},
{
"family": "Wynn",
"given": "Daniel T"
},
{
"family": "Goka",
"given": "Erik"
},
{
"family": "Lippman",
"given": "Marc"
},
{
"family": "Robbins",
"given": "David J"
},
{
"family": "Ayad",
"given": "Nagi G"
}
],
"container-title-short": "Neuro Oncol",
"volume": "28",
"issue": "6",
"page": "1527-1540",
"DOI": "10.1093/neuonc/noag057",
"PMID": "41857757",
"PMCID": "PMC13233070",
"ISSN": "1522-8517",
"publisher": "Oxford University Press",
"URL": "https://doi.org/10.1093/neuonc/noag057",
"language": "en",
"issued": {
"date-parts": [
[
2026,
6,
1
]
]
}
}

Similar papers

The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.

[1] doi:10.1007/s12017-026-08935-8
Subgroup-Specific Associations of GRIA Genes Encoding AMPA Glutamate Receptor Subunits with Patient Survival in Medulloblastoma.
Journal: Neuromolecular medicine
In common: other condition, cellular / molecular, 1 reference
[2] doi:10.1038/s12276-026-01732-0
Comprehensive proteogenomic characterization reveals clinically relevant molecular subtypes associated with medulloblastoma progression.
Journal: Experimental & molecular medicine
In common: other condition, cellular / molecular, 1 reference
[3] doi:10.1126/sciadv.aed5548 [code]
In situ proteomics unveils specialized domains for extrasynaptic signaling on neuronal cilia.
Journal: Science advances
In common: mouse, cellular / molecular, 1 reference
[4] doi:10.1038/s41467-026-72598-z [code]
Functional impact of genetic background on variable expressivity in neurodevelopmental disorders.
Journal: Nature communications
In common: other condition, 1 reference
[5] doi:10.3389/fgene.2026.1807347 [code]
Epigenetic regulators are preferentially coordinated with protocadherin gene expression across the human brain: a genome-wide co-expression analysis.
Journal: Frontiers in genetics
In common: other condition, cellular / molecular, 1 reference
[6] doi:10.1038/s41467-026-74037-5
Microglial CD31 suppresses Aβ clearance and promotes Alzheimer pathology in 5×FAD mice.
Journal: Nature communications
In common: mouse, cellular / molecular, 1 reference
[7] doi:10.1038/s41586-026-10299-9 [code]
A µ-opioid receptor superagonist analgesic with minimal adverse effects.
Journal: Nature
In common: rat, other condition, mouse, 1 other category
[8] doi:10.1038/s41586-026-10414-w [code]
Focal white matter lesions drive grey matter inflammation and synapse loss.
Journal: Nature
In common: rat, other condition, mouse, 1 other category
[9] doi:10.3390/ijms27073253
S-equol Modulates T3-Induced Transcription and Neurite Outgrowth in Neuronal Cells.
Journal: International journal of molecular sciences
In common: rat, other condition, mouse, 1 other category
[10] doi:10.1038/s41467-026-73505-2 [code]
Light- and chemical-induced ciliary signaling governs dorsal/ventral regionalization of human telencephalic organoids.
Journal: Nature communications
In common: 1 reference

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Sign in with ORCID to claim this paper as one of its authors, correct its record or validate its tracing map: when the paper's metadata lists your ORCID iD, you are recognized at once. Maintainers of its code: sign in with GitHub, then claim the repository on your account page.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion, reproductions, activity

Discussion: questions and error reports about this paper and its code, from signed-in readers and its authors. It opens with sign-in.

Reproductions: reports from readers who ran the authors' code: what they reproduced, with which environment, commit and data. It opens with sign-in.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.