Elucidating the function of NF2 in NF1 mutant peripheral nervous system tumors.

Schwann cell tumors are the most common peripheral nervous system (PNS) tumors, and people with neurofibromatosis type I (NF-1) or neurofibromatosis type II (NF-2) are at significantly increased risk to develop PNS tumors. NF-1 is caused by loss of the NF1 tumor suppressor gene while NF-2 is caused by loss of the NF2 tumor suppressor gene, but a functional link between these two neurofibromatosis tumors required for Schwann cell tumorigenesis has not been well described. Our work recently showed that NF2 is mutated in NF1 mutant malignant peripheral nerve sheath tumors (MPNSTs), an aggressive PNS tumor that is the most common cause of death in adults with NF-1. However, we do not understand if NF2 is required or sufficient for NF1 PNS tumor malignant transformation or the key signaling pathways engaged by NF2 in NF1 mutant tumors, constituting a key knowledge gap that impedes the development of better therapies for people with neurofibromatosis associated tumors. This proposal focuses on investigating if NF2 cooperates with NF1 in the Schwann cell lineage in vertebrate model organisms or tumor systems and defining whether Hippo signaling, which is dysregulated upon NF2 loss in NF1 mutant tumors, is a viable therapeutic approach for people with MPNSTs. To do so, our proposal incorporates novel mouse and zebrafish models with recently developed pharmacologic inhibitors of Hippo dysregulation and human patient MPNST samples to test the hypothesis that NF2 loss promotes NF1 PNS tumor malignant transformation through Hippo signaling. We will test this hypothesis by first determining whether Nf1/Nf2 conditional mutant mice develop MPNSTs, as Nf1 or Nf2 conditional loss alone is not sufficient for MPNST formation in mice. For added rigor and validation in an orthogonal vertebrate neurofibromatosis model, we will further evaluate whether nf1/nf2 mutant zebrafish develop MPNSTs. To complement these loss of function experiments, we will then perform inducible Nf2 overexpression in MPNST tumor models to determine whether NF2 reconstitution blocks MPNST growth in vivo. Finally, we will test the therapeutic efficacy of targeting Hippo pathway dysregulation across a range of MPNST models and aim to develop a clinical biomarker of Hippo pathway dysregulation in MPNSTs using a multi-institutional cohort with the goal of identifying a signature to predict which patients might benefit from targeting Hippo signaling. We have assembled a multidisciplinary team of biologists, oncologists, and pathologists to carry out this work comprising multiple model systems and technical approaches. The long-term goal of this research is to identify new treatment strategies for MPNSTs, which currently lack any effective therapeutic interventions, and our work will potentially establish the preclinical rationale for future clinical trials targeting Hippo signaling in these tumors. Project Number: 1R01CA304081-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Harish Vasudevan | Institution: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, SAN FRANCISCO, CA | Award Amount: $681,070 | Activity Code: R01 | Study Section: Mechanisms of Cancer Therapeutics A Study Section[MCTA] View on NIH RePORTER: https://reporter.nih.gov/project-details/11449271