Targeting NF-κB prevents Schwann cell reprogramming and plexiform neurofibroma initiation in mouse model of Nf1

Plexiform neurofibromas arise in approximately half of all individuals with Neurofibromatosis Type I (NF1). Genetic lesions apart from NF1 pathogenic variants are not present in NF1 mutant Schwann cells, suggesting that tumorigenesis may instead require cellular rewiring. To identify putatively re-wired tumor cells, we used multiplex imaging and flow cytometry to delineate markers that distinguish tumor Schwann cell from non-tumor Schwann cells. We identified tumor Schwann cells as CD44+;CD49f+ cells that show increased transcription of epithelial to mesenchymal plasticity (EMP)- associated genes. CD44+;CD49f+ expression was induced by treating Nf1-/- Schwann cells with stressors or by direct NF-κB pathway activation via IKK2; treated Schwann cells increased secretion of NF-κB targets and immune cell chemoattractants CCL2 and CCL3. In established tumors, MEK inhibition plus NF-κB blockade diminished tumor cell proliferation, tumor Schwann cells, immune cell populations, tumor cytokines and tumor number. Notably, transient single agent NF-κB pathway blockade was sufficient to significantly delay tumor formation in mice. Thus, Nf1 loss in Schwann cells is followed by NF-κB activation and cellular reprogramming that drives tumor initiation and targeting NF-κB activation can reduce NF1-deficient tumor formation.