TGFβ-dependent signaling drives tumor growth and aberrant extracellular matrix dynamics in NF1-associated plexiform neurofibroma

dc.contributor.authorAbu-Sultanah, Mohannad
dc.contributor.authorZhou, Zhuan
dc.contributor.authorJiang, Chunhui
dc.contributor.authorMitchell, Dana K.
dc.contributor.authorBessler, Waylan K.
dc.contributor.authorJiang, Li
dc.contributor.authorLi, Xiaohong
dc.contributor.authorQian, Shaomin
dc.contributor.authorSmith, Abbi E.
dc.contributor.authorMang, Henry E.
dc.contributor.authorWhite, Emily E.
dc.contributor.authorCiesielski, Marisa D.
dc.contributor.authorHickey, Brooke E.
dc.contributor.authorBrewster, Kylee M.
dc.contributor.authorSandusky, George E.
dc.contributor.authorMasters, Andi
dc.contributor.authorAngus, Steven P.
dc.contributor.authorClapp, D. Wade
dc.contributor.authorLe, Lu Q.
dc.contributor.authorRhodes, Steven D.
dc.contributor.departmentPediatrics, School of Medicine
dc.date.accessioned2025-07-17T11:35:08Z
dc.date.available2025-07-17T11:35:08Z
dc.date.issued2025
dc.description.abstractPlexiform neurofibromas (PNFs) are benign tumors of the peripheral nervous system that represent a major source of morbidity in neurofibromatosis type 1 (NF1). A substantial proportion of patients do not respond to current therapies or experience intolerable side effects. Transcriptomic characterization of murine and human PNF at bulk and single-cell resolution identified transforming growth factor-β (TGFβ) signaling as a key upstream regulator, driving aberrant basement membrane (BM) protein production by neoplastic Schwann cells and Fbs. Conditional TGFβ1 overexpression in Nf1-deficient Schwann cells driven by Hoxb7-Cre promoted PNF growth and malignant transformation in vivo. Conversely, pharmacologic inhibition of the type I TGFβ receptor (TGFβRI) reduced PNF tumor burden in Nf1 mutant mice. Proteomic characterization of the extracellular matrix (ECM) showed reduced BM proteins upon TGFβRI inhibition. These findings implicate TGFβ as a potential therapeutic target in PNF and provide insights into the role of TGFβ signaling in orchestrating ECM dynamics in the PNF microenvironment.
dc.eprint.versionFinal published version
dc.identifier.citationAbu-Sultanah M, Zhou Z, Jiang C, et al. TGFβ-dependent signaling drives tumor growth and aberrant extracellular matrix dynamics in NF1-associated plexiform neurofibroma. Sci Adv. 2025;11(25):eadu0772. doi:10.1126/sciadv.adu0772
dc.identifier.urihttps://hdl.handle.net/1805/49548
dc.language.isoen_US
dc.publisherAmerican Association for the Advancement of Science
dc.relation.isversionof10.1126/sciadv.adu0772
dc.relation.journalScience Advances
dc.rightsAttribution-NonCommercial 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.sourcePMC
dc.subjectNeurofibromatosis 1
dc.subjectPlexiform neurofibroma
dc.subjectSchwann cells
dc.subjectCell proliferation
dc.titleTGFβ-dependent signaling drives tumor growth and aberrant extracellular matrix dynamics in NF1-associated plexiform neurofibroma
dc.typeArticle
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