A5068853971- Neurofibromatosis and Schwannoma Cases
- Neuroblastoma Research and Treatments
- Cancer Mechanisms and Therapy
- Sarcoma Diagnosis and Treatment
- Cancer, Hypoxia, and Metabolism
- Chromatin Remodeling and Cancer
- PI3K/AKT/mTOR signaling in cancer
- Nerve injury and regeneration
- Multiple Myeloma Research and Treatments
- Protein Degradation and Inhibitors
- HER2/EGFR in Cancer Research
- Lung Cancer Treatments and Mutations
- Cellular Mechanics and Interactions
- Cancer therapeutics and mechanisms
- Biochemical and Molecular Research
- NF-κB Signaling Pathways
- Protein Tyrosine Phosphatases
- Glycosylation and Glycoproteins Research
- Immune Cell Function and Interaction
- Cancer Cells and Metastasis
- RNA Research and Splicing
- Protein Kinase Regulation and GTPase Signaling
- Genomics and Chromatin Dynamics
- Monoclonal and Polyclonal Antibodies Research
- interferon and immune responses
Medical University of South Carolina
2014-2024
Brigham and Women's Hospital
2009-2014
Harvard University
2009-2014
University of Southern California
2006-2008
Abstract NF1 encodes a RAS GTPase-activating protein. Accordingly, aberrant activation underlies the pathogenesis of NF1-mutant cancers. Nevertheless, it is unclear which pathway components represent optimal therapeutic targets. Here, we identify mTORC1 as key PI3K effector in nervous system malignancies and conversely show that mTORC2 AKT are dispensable. However, find tumor regression requires sustained inhibition both MEK. Transcriptional profiling studies were therefore used to establish...
Emergingevidence supports the idea that c-Jun N-terminal kinases (JNKs)possess overlapping but distinct functions. The potential roles of theubiquitously expressed JNK1 and JNK2 in regulating expression thecentral transcription initiation factor, TATA-binding protein (TBP),were examined. Relative to wild-type fibroblasts, TBP was decreased inJnk1−/− cellsand increased inJnk2−/−cells. Similarly, reduction human hepatoma cells decreasedTBP expression, whereas enhanced it....
We have found that erbB receptor tyrosine kinases drive Ras hyperactivation and growth in NF1-null malignant peripheral nerve sheath tumors (MPNSTs). However, MPNSTs variably express multiple receptors with distinct functional characteristics it is not clear which of these MPNST pathogenesis. Here, we test the hypothesis altered erbB4 expression promotes pathogenesis by uniquely activating key cytoplasmic signaling cascades. ErbB4 was assessed using immunohistochemistry, immunocytochemistry,...
Chemotherapeutic agents effective against malignant peripheral nerve sheath tumors (MPNSTs) are urgently needed. We recently found that tamoxifen potently impedes xenograft growth. In vitro, inhibits MPNST proliferation and survival in an estrogen receptor-independent manner; these effects phenocopied by the calmodulin inhibitor trifluoperazine. The present study was performed to establish mechanism of action vivo optimize its therapeutic effectiveness. To determine if has receptor-dependent...
The epidermal growth factor receptor (EGFR) family regulates essential biological processes. Various epithelial tumors are linked to EGFR overexpression or expression of variant forms, such as the EGFR1 variant, EGFRvIII. Perturbations in transcription initiation factor, TATA-binding protein (TBP), alter cellular properties. Here we demonstrate that and EGFRvIII, but not HER2, induce TBP at a transcriptional level through distinct mechanisms. enhances phosphorylation function Elk-1,...
Neurofibromin, the tumor suppressor encoded by neurofibromatosis type 1 (NF1) gene, potentially suppresses activation of H-Ras, N-Ras, and K-Ras. However, it is not known whether these classic Ras proteins are hyperactivated in NF1-null nerve sheath tumors, how they contribute to tumorigenesis, what signaling pathways mediate their effects. Here we show that K-Ras coexpressed with activators (guanine nucleotide exchange factors) neurofibromin-null malignant peripheral (MPNST) cells, all 3...
Abstract Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive Schwann cell-derived neoplasms that occur sporadically or in patients with neurofibromatosis type 1 (NF1). Preclinical research on sporadic MPNSTs has been limited as few cell lines exist. We generated and characterized a new MPNST line, 2XSB, which shares the molecular genomic features of parent tumor. These cells have highly complex karyotype extensive chromothripsis. 2XSB show robust invasive 3-dimensional...
Loss of the Ras GTPase-activating protein neurofibromin promotes nervous system tumor pathogenesis in patients with neurofibromatosis type 1 (NF1). Neurofibromin loss potentially hyperactivates classic (H-Ras, N-Ras, K-Ras), M-Ras, and R-Ras (R-Ras, R-Ras2/TC21) subfamily proteins. We have shown that proteins promote proliferation survival, but not migration, malignant peripheral nerve sheath (MPNST) cells. However, it is unclear whether R-Ras, R-Ras2 M-Ras are expressed hyperactivated...
Abstract Schwann cell‐derived neoplasms known as malignant peripheral nerve sheath tumors (MPNSTs) are the most common malignancy and leading cause of death in individuals with neurofibromatosis Type 1. Using genome‐scale shRNA screens, we have previously found evidence suggesting that lysophosphatidic acid receptors (LPARs) essential for MPNST proliferation and/or survival. Here, examine expression mutational status all six LPA MPNSTs, assess role individual play physiology their ability to...
Patients with the autosomal dominant tumor susceptibility syndrome neurofibromatosis type 1 (NF1) commonly develop plexiform neurofibromas (PNs) that subsequently transform into highly aggressive malignant peripheral nerve sheath tumors (MPNSTs). Understanding process by which a PN transforms an MPNST would be facilitated availability of genetically engineered mouse (GEM) models accurately replicate PN-MPNST progression seen in humans NF1. Unfortunately, GEM Nf1 ablation do not fully...
<p>PDF file - 58KB</p>
<p>PDF file - 47KB, Supplementary Figure 1 shows that AKT inhibition does not slow proliferation in a human MPNST cell line.</p>
<p>PDF file - 47KB, Supplementary Figure 1 shows that AKT inhibition does not slow proliferation in a human MPNST cell line.</p>