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Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are soft tissue sarcomas that arise in connective tissue surrounding peripheral nerves. They occur sporadically in a subset of patients with Neurofibromatosis type-1 (NF1). MPNSTs are highly aggressive, therapeutically resistant, and typically fatal. Using comparative transcriptome analysis, we identified CXCR4, a G protein-coupled receptor, as highly expressed in mouse models of NF1-deficient MPNSTs, but not in non-transformed precursor cells. The chemokine receptor CXCR4 and its ligand, CXCL12, promote MPNST growth by stimulating cyclin D1 expression and cell cycle progression through PI3-Kinase (PI3K) and β-catenin signaling. Suppression of CXCR4 activity, either by shRNA or pharmacological inhibition decreases MPNST cell growth in culture and inhibits tumorigenesis in allografts and in spontaneous genetic mouse models of MPNST. We further demonstrate conservation of these activated molecular pathways in human MPNSTs. Our findings indicate a role for CXCR4 in NF1-associated MPNST development, and identify a novel therapeutic target.

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Summary Neurofibromatosis type 1 is a tumor-predisposing genetic disorder. Plexiform neurofibromas are common NF1 tumors carrying a risk of malignant transformation, which is typically fatal. Little is known about mechanisms mediating initiation and identity of specific cell-type that gives rise to neurofibromas. Using cell-lineage tracing, we identify a population of GAP43+ PLP+ precursors in embryonic nerve roots as the cells of origin for these tumors and report a non-germline model of neurofibroma for preclinical drug screening to identify effective therapies. The identity of tumor cell-of-origin and facility for isolation and expansion provides fertile ground for continued analysis to define intrinsic and extrinsic factors critical for neurofibromagenesis. It also provides unique approaches to develop therapies to prevent neurofibroma formation in NF1 patients.

Summary Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are highly aggressive sarcomas that develop sporadically or in Neurofibromatosis type 1 (NF1) patients. There is no effective treatment for MPNSTs and they are typically fatal. To gain insights into MPNST pathogenesis, we utilized a novel MPNST mouse model that allowed us to study the evolution of these tumors at the transcriptome level. Strikingly, in MPNSTs we found upregulation of chromatin regulator Brd4, and show that BRD4 inhibition profoundly suppresses both growth and tumorigenesis. Our findings reveal new roles for BET bromodomains in MPNST development, and report a novel mechanism by which bromodomain inhibition induces apoptosis through induction of pro-apoptotic Bim, which may represent a paradigm shift in therapy for MPNST patients. Moreover, these findings indicate novel epigenetic mechanisms underlying the balance of anti-/pro-apoptotic molecules, and that bromodomain inhibition can shift this balance in favor of cancer cell apoptosis.

Neurofibromatosis Type 1 (NF1) is an autosomal disorder that affects neural crest-derived tissues, leading to a wide spectrum of clinical presentations. Patients commonly present with plexiform neurofibromas, benign but debilitating growths that can transform into malignant peripheral nerve sheath tumors (MPNSTs), a main cause of mortality. Currently, surgery is the primary course of treatment for MPNST, but with the limitation that these tumors are highly invasive. Radiation therapy is another treatment option, but is undesirable because it can induce additional mutations. MPNST patients may also receive doxorubicin as therapy, but this DNA-intercalating agent has relatively low tumor specificity and limited efficacy. In this study, we exploited a robust genetically-engineered mouse model of MPNST that recapitulates human NF1 associated MPNST to identify a novel small chemical compound that inhibits tumor cell growth. Compound 21 (Cpd21) inhibits growth of all available in vitro models of MPNST and human MPNST cell lines, while remaining non-toxic to normally-dividing Schwann cells or mouse embryonic fibroblasts. We show that this compound delays the cell cycle and leads to cellular apoptosis. Moreover, Cpd21 can reduce MPNST burden in a mouse allograft model, underscoring the compound’s potential as a novel chemotherapeutic agent.

In India, women appear to have a higher prevalence of hypertension, diabetes, obesity, and family history of CHD. Yet women get invasive treatments less often than men. Depression is also more common in women and is associated with poor QoL and early mortality than men.

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