Abstract
ObjectiveIndividuals with the neurofibromatosis type 2 (NF2) cancer predisposition syndrome develop spinal cord glial tumors (ependymomas) that likely originate from neural progenitor cells. Whereas many spinal ependymomas exhibit indolent behavior, the only treatment option for clinically symptomatic tumors is surgery. In this regard, medical therapies are unfortunately lacking due to an incomplete understanding of the critical growth control pathways that govern the function of spinal cord (SC) neural progenitor cells (NPCs).MethodsTo identify potential therapeutic targets for these tumors, we leveraged primary mouse Nf2-deficient spinal cord neural progenitor cells.ResultsWe demonstrate that the Nf2 protein, merlin, negatively regulates spinal neural progenitor cell survival and glial differentiation in an ErbB2-dependent manner, and that NF2-associated spinal ependymomas exhibit increased ErbB2 activation. Moreover, we show that Nf2-deficient SC NPC ErbB2 activation results from Rac1-mediated ErbB2 retention at the plasma membrane.SignificanceCollectively, these findings establish ErbB2 as a potential rational therapeutic target for NF2-associated spinal ependymoma.
Highlights
Spinal cord (SC) ependymomas are well-delineated gliomas characterized by prominent glial fibrillary acidic protein (GFAP) expression [1]
Since spinal cord ependymomas are hypothesized to originate from radial glial-like stem/progenitor cells [2,3] expressing the fatty acid binding protein-7 (Fig. S1A), initial studies employed genetically-engineered mice in which the neurofibromatosis type 2 (NF2) gene was conditionally deleted in BLBP+ cells (Nf2BLBPCKO mice) using a previously published BLBP-Cre strain [19]
Since over 75% of pediatric ependymomas express ErbB2 [26] and increased ErbB family receptor tyrosine kinase signaling has been reported in the hallmark NF2-associated tumor [27,28] we examined ErbB2 activation in normal human spinal cord and in two representative spinal ependymomas from individuals with a confirmed diagnosis of NF2
Summary
Spinal cord (SC) ependymomas are well-delineated gliomas characterized by prominent glial fibrillary acidic protein (GFAP) expression [1]. Potential insights into the molecular pathogenesis of ependymoma are likely to derive from studies focused on familial syndromes in which affected individuals are prone to these tumors. One such syndrome, neurofibromatosis type 2 (NF2) is an autosomal dominant inherited cancer predisposition syndrome, caused by a germline mutation in the NF2 tumor suppressor gene: 35–53% of individuals with NF2 develop ependymoma [7], with a striking predilection for the cervical or thoracic spinal cord (62– 86% of tumors) [8]. The majority of ependymomas exhibiting NF2 loss occur in the spinal cord [12] For these reasons, NF2 represents a tractable genetic model system to identify potential therapeutic targets for spinal ependymoma
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