Browsing by Author "Brewster, Kylee M."

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    TGFβ-dependent signaling drives tumor growth and aberrant extracellular matrix dynamics in NF1-associated plexiform neurofibroma
    (American Association for the Advancement of Science, 2025) Abu-Sultanah, Mohannad; Zhou, Zhuan; Jiang, Chunhui; Mitchell, Dana K.; Bessler, Waylan K.; Jiang, Li; Li, Xiaohong; Qian, Shaomin; Smith, Abbi E.; Mang, Henry E.; White, Emily E.; Ciesielski, Marisa D.; Hickey, Brooke E.; Brewster, Kylee M.; Sandusky, George E.; Masters, Andi; Angus, Steven P.; Clapp, D. Wade; Le, Lu Q.; Rhodes, Steven D.; Pediatrics, School of Medicine
    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.