NF2 (neurofibromatosis type 2)-related schwannomatosis (NF2-SWN) is a cancer predisposition syndrome characterized by the development of bilateral vestibular (VS) and spinal schwannomas. While benign, these tumors can cause substantial morbidity, and effective pharmacological treatments remain limited. Here, we demonstrate that genetic ablation of focal adhesion kinase (Fak/Ptk2) impairs tumor formation and preserves hearing in a murine model of NF2. Mechanistically, we show that Fak deletion decreases macrophage infiltration, attenuates nucleotide-binding oligomerization domain-containing protein 2-, leucine rich repeats (LRR)- and pyrin domain-containing protein 3 inflammasome activation, and suppresses the hepatocyte growth factor-MET axis. Pharmacological inhibition of FAK with single agent VS-4718 did not significantly reduce macroscopic tumor volume; however, its use in combination with the mitogen-activated protein kinase kinase (MEK) inhibitor selumetinib resulted in both a significant reduction in tumor volume and the preservation of dorsal root ganglion architecture. Our findings establish a critical role for FAK in schwannoma development and provide rationale for evaluation of combination FAK plus MEK inhibition in future clinical trials for NF2-associated SWN.

TCGA MPNST vs GTEX Normal Nerve DEGS

In vitro experimentation in MPNST cell lines

TCGA GOBP 2023 Downregulated genes

Table of mice enrolled in drug study

Kaplan Meier Survival Curve and Tolerability

PURPOSE:Malignant peripheral nerve sheath tumor (MPNST) is the leading cause of premature death among individuals with neurofibromatosis type 1 (NF1), and the transcriptional aberrations that precede malignant transformation and contribute to MPNST tumorigenesis remain poorly defined. Alterations involving CDKN2A and components of PRC2 have been implicated as early drivers of peripheral nerve sheath tumor (PNST) evolution, but these events do not occur in all MPNST. Accordingly, emerging data have begun to highlight the importance of molecular-based stratification to improve outcomes in patients with NF1-PNST. EXPERIMENTAL DESIGN:In this study, we perform an integrated analysis of multiple, independent datasets obtained from human patients with NF1 to gain critical insights into PNST evolution and MPNST heterogeneity. RESULTS:We show that delta-like noncanonical Notch ligand 1 (DLK1) is significantly increased in MPNST and provide evidence that DLK1 overexpression may precede histologic changes consistent with malignancy. In complementary analyses, we find that serum levels of DLK1 are significantly higher in both mice and humans harboring MPNST compared with those without malignancy. Importantly, although DLK1 expression is increased in MPNST overall, through the integration of multiple, independent datasets, we demonstrate that divergent levels of DLK1 expression distinguish MPNST subsets characterized by unique molecular programs and potential therapeutic vulnerabilities. Specifically, we show that overexpression of DLK1 is associated with the reactivation of embryonic signatures, an immunosuppressive microenvironment, and a worse overall survival in patients with NF1-MPNST. CONCLUSIONS:Collectively, our findings provide critical insights into MPNST tumorigenesis and support prospective studies evaluating the utility of DLK1 tissue and serum levels in augmenting diagnosis, risk assessment, and therapeutic stratification in the setting of NF1-PNST.

JH MPNST vs Benign Neurofibroma DEGS

Gene set enrichment analysis of RAS signatures

Reactome G1 Phase Heatmap and Top DEGs

Raw log2LFQ values for kinases profiled by MIB/MS

PathView normalized signature scores for biological pathways relevant to tumor progression, immune response and tumor microenvironment for each sample.

Normalized count matrix. Probes with raw counts below threshold were excluded.