50% Effort. Molecular dissection of the pathway linking growth factor receptors to the nucleus: their role in normal cell growth and cancer. The emerging mutational landscape of G-proteins and G-protein coupled receptors in cancer. The presence of genetic alterations in G proteins and GPCRs were initially restricted to only few neoplastic lesions in endocrine tumors. However, we have recently reported the widespread presence and high frequency of mutations in GPCRs and G proteins in most tumor types. Specifically, in a recent in depth analysis of the human oncogenome we have found that a striking 4.2% of all tumor sequences exhibit activating mutations in GNAS (encoding Gαs), including thyroid and pituitary tumors, as well as colon cancer, hepatocellular carcinoma, and parathyroid, ovarian, endometrial, biliary tract, and pancreatic tumors. Mutually exclusive activating mutations in GNAQ or GNA11 (encoding Gαq family members) occur in 5.6% of tumors, including >66% of ocular melanomas, thus providing a clear example of a human malignancy that is initiated by gain of function mutations in Gαq and G11 proteins. GNAQ and GNA11 mutations are also found in tumors arising from the meninges (59%), in most blue nevi of the skin (83%), and in a subset of cutaneous melanomas (6%). Surprisingly, nearly 20% of human cancers harbor mutations in GPCRs, including frequent mutations in thyroid-stimulating hormone receptor (TSHR), smoothened (SMO), glutamate receptors (GRMs), members of the adhesion family of GPCRs, and receptors for lysophosphatidic acid (LPA) and sphingosine 1 phosphate (S1P). Overall, as GPCRs are the target of >25% drugs in the market, we expect that this information can be exploited for the development of novel strategies targeting GPCRs, G proteins, or their aberrant signaling circuitry for cancer prevention and treatment. Hippo-Independent activation of YAP by the GNAQ uveal melanoma oncogene through a Trio-regulated Rho GTPase signaling circuitry. Uveal melanoma is the most frequent ocular malignancy in adults, for which no effective systemic therapies are currently available. Recent findings revealed that activating mutations in GNAQ and GNA11, encoding members of the Gαq family of G protein α subunits, drive uveal melanoma oncogenesis. Approximately 6% of skin melanomas also express GNAQ oncogenes, hence rendering these melanomas insensitive to BRAF inhibitors in the clinic. However, the molecular events underlying these GNAQ-driven malignancies are not yet defined, thus limiting the ability to develop cancer-targeted therapies. Recently, we focused on the transcriptional co-activator YAP, a critical component of the Hippo signaling pathway that controls organ size. We found that Gαq stimulates YAP through a novel Trio-Rho/Rac signaling circuitry promoting actin polymerization, independently of PLCβ and the canonical Hippo pathway. Furthermore, we show that Gαq promotes the YAP-dependent growth of uveal melanoma cells, thereby identifying YAP as a novel therapeutic target in uveal melanoma, the first described GNAQ/GNA11-initiated human malignancy. This cancer vulnerability can now be exploited for the development of new precision molecular therapies for GNAQ-driven human malignancies. Blockade of mTORC1 is sufficient to decrease CXCR4-mediated directional migration and metastasis. The migration of tumor cells bearing CXCR4 receptors toward the chemokine SDF-1 (CXCL12), which accumulates in lymph nodes and secondary cancer colonization sites, has been implicated in lymphatic and organ-specific metastasis in many human malignancies. The growth promoting PI3K/mTOR pathway is deregulated in many cancer types, hence mTOR inhibitors, represent suitable therapeutic agents for multiple tumor types that are addicted to this signaling route. However, the underlining mechanisms by which mTOR activation contribute to tumor progression and metastasis are still poorly understood. Using a recently developed animal model for CXCR4-mediated spontaneous metastasis, we found that inhibition of the mTORC1 complex by knocking down its obligatory component, Raptor, or by the use of rapamycin is sufficient to decrease CXCR4-mediated migration and metastasis. These data suggest that mTOR inhibition may halt the metastatic process in patients diagnosed with aggressive malignancies. 30% Effort. Molecular basis of developmental and tumor-induced angiogenesis. The disruption of the vascular endothelial barrier is a frequent event in many inflammatory conditions and in tumor cell intra- and extravasation and metastasis. Histamine is one of the most potent inducers of vascular permeability, a process that underlies many highly prevalent human diseases. By the use of genetically defined animal models, pharmacologic inhibitors, and a synthetic biology approach we have found that the small GTPase RhoA mediates histamine-induced endothelial permeability. Furthermore, small molecule Rho kinase inhibitors prevent histamine-induced vascular leakage, and can rescue mice from active systemic anaphylaxis and death. Ongoing experiments using conditional deletion of RhoA in endothelial cells in vivo further support the key biological role for this GTPase in histamine-induced endothelial permeability, thereby identifying novel pharmacological targets for the treatment of a myriad of human diseases characterized by aberrant vascular leakage. Molecular mechanisms by which Semaphorins and Plexins control angiogenesis and lymphangiogenesis: Semaphorin 3E (Sema3E) and its receptor Plexin-D1 control the patterning of the developing vasculature. However, it was not known whether Sema3E-Plexin-D1 signals in adult and in pathological angiogenesis. We have recently observed that Sema3E behaves as a potent natural anti-lymphangiogenic molecule in a number of in vivo models of developmental and tumor-induced lymphangiogenesis. We have also focused in the possibility that another semaphorin, Sema3F, may represent an anti-lymphangiogenic metastasis suppressor gene, given that one of its co-receptors, NRP2, is expressed primarily in lymphatic endothelial cells, and that SEAM3F gene loss is a frequent event in advanced HNSCC lesions. Indeed, we found that. SEMA3F, which is localized to 3p21, is one of the earliest and most frequently deleted loci in HNSCC. We observed that heterozygous deletion and decreased expression of SEMA3F correlates with poor clinical outcome, increased vascularity, and metastasis. SEMA3F negatively regulates the function of lymphatic endothelial cells and blocks lymphangiogenesis in vivo through multiple Neuropilin 2/Plexin A coreceptor complexes. We also provided direct evidence that SEMA3F functions as an antilymphangiogenic tumor and metastasis suppressor in HNSCC through autocrine and paracrine signaling pathways, thus representing a useful biomarker and possible therapeutic target in HNSCC. 20% effort. AIDS-associated Kaposis sarcoma: molecular mechanisms. Activation of YAP/TAZ by KSHV vGPCR in sarcomagenesis: Building on our prior studies on uveal melanoma and transforming GPCRs, we have recently contributed to the discovery that vGPCR activates the YAP/TAZ transcription co-activators, which are inhibited by the Hippo tumor suppressor pathway. Down-regulation of YAP/TAZ blocks vGPCR-induced cell proliferation and tumorigenesis. Furthermore, we found that YAP/TAZ are activated in Kaposis sarcoma and correlates with KSHV markers. Our observations indicate that YAP/TAZ mediate the oncogenic function of vGPCR in Kaposis sarcoma tumorigenesis.
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