TGFβ-dependent signaling drives tumor growth and aberrant extracellular matrix dynamics in NF1-associated plexiform neurofibroma
- Mohannad Abu-Sultanah
- Zhuan Zhou
- Chunhui Jiang
- Dana K. Mitchell
- Waylan K. Bessler
- Li Jiang
- Xiaohong Li
- Shaomin Qian
- Abbi E. Smith
- Henry E. Mang
- Emily E. White
- Marisa D. Ciesielski
- Brooke E. Hickey
- Kylee M. Brewster
- George E. Sandusky
- Andi Masters
- Steven P. Angus
- D. Wade Clapp
- Lu Q. Le
- Steven D. Rhodes
2025-06-20
Plexiform 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.