Professor Silvia Montaner, PhD, MPH
The growth of abnormal blood vessels is a hallmark of many human pathologies, ranging from cancer to diseases affecting the eye. Therapies targeting the growth of these pathological blood vessels (pathological angiogenesis) could therefore have an impact on the treatment of many human disorders. My laboratory examines the molecular mechanisms regulating pathological angiogenesis and vessel hyperpermeability. We have focused our studies on two diseases: 1) Kaposi’s sarcoma (KS), a vascular tumor caused by infection with the Kaposi’s sarcoma associated herpesvirus (KSHV) and a model of dysregulated angiogenesis and vascular permeability; and 2) ischemic retinal disease, a common cause of visual impairment and blindness.
Our work on KS has helped identify important signaling pathways activated by a single gene encoded by KSHV, the KSHV G protein-coupled receptor (vGPCR), which is a critical viral gene that is necessary for KS development. We have reported that vGPCR activates the AKT/TSC/mTOR/HIF pathway to promote direct and paracrine endothelial cell transformation. We have further identified Angiopoietin-like 4 (ANGPTL4) as a hypoxia-inducible factor (HIF-1)-regulated, vasoactive molecule that promotes vascular permeability and pathological angiogenesis in KS. Our work helped provide the foundation for clinical studies interrogating the use of inhibitors of mTOR for KS treatment.
In collaboration with Dr. Akrit Sodhi’s lab at the Wilmer Eye Institute (Johns Hopkins University), we have also identified ANGPTL4 as a critical vascular hyperpermeability and angiogenic factor for patients with diabetic eye disease. We have observed that ANGPTL4 promotes angiogenesis by inducing endothelial cell migration and differentiation and vessel leakage through the destabilization of endothelial tight and adherens junctions and the activation of RhoA GTPase. Diabetic eye disease is the most common cause of severe vision impairment in working-age Americans. Our studies have important clinical implications for the treatment of this vision-threating disease.
Sodhi A, Montaner S. JAMA Ophthalmology. 2015 Dec;133(12):1375-6.
Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy. Babapoor-Farrokhran S, Jee K, Puchner B, Hassan SJ, Xin X, Rodrigues M, Kashiwabuchi F, Ma T, Hu K, Deshpande M, Daoud Y, Solomon S, Wenick A, Lutty GA, Semenza GL, Montaner S, Sodhi A. Proc Natl Acad Sci U S A. 2015 Jun 9;112(23):E3030-9.
KSHV induces aerobic glycolysis and angiogenesis through HIF-1-dependent upregulation of pyruvate kinase 2 in Kaposi's sarcoma. Ma T, Patel H, Babapoor-Farrokhran S, Franklin R, Semenza GL, Sodhi A, Montaner S. Angiogenesis. 2015 Oct;18(4):477-88.
Hypoxic retinal Muller cells promote vascular permeability by HIF-1-dependent up-regulation of angiopoietin-like 4. Xin X, Rodrigues M, Umapathi M, Kashiwabuchi F, Ma T, Babapoor-Farrokhran S, Wang S, Hu J, Bhutto I, Welsbie DS, Duh EJ, Handa JT, Eberhart CG, Lutty G, Semenza GL, Montaner S, Sodhi A. Proc Natl Acad Sci U S A. 2013 Sep 3;110(36):E3425-34.
Molecular mechanisms deployed by virally encoded G protein-coupled receptors in human diseases. Montaner S, Kufareva I, Abagyan R, Gutkind JS. Annu Rev Pharmacol Toxicol. 2013;53:331-54.
VEGF secreted by hypoxic Müller cells induces MMP-2 expression and activity in endothelial cells to promote retinal neovascularization in proliferative diabetic retinopathy. Rodrigues M, Xin X, Jee K, Babapoor-Farrokhran S, Kashiwabuchi F, Ma T, Bhutto I, Hassan SJ, Daoud Y, Baranano D, Solomon S, Lutty G, Semenza GL, Montaner S, Sodhi A. Diabetes. 2013 Nov;62(11):3863-73.
Amplification of the angiogenic signal through the activation of the TSC/mTOR/HIF axis by the KSHV vGPCR in Kaposi's sarcoma. Jham BC, Ma T, Hu J, Chaisuparat R, Friedman ER, Pandolfi PP, Schneider A, Sodhi A, Montaner S. PLoS One. 2011 Apr 29;6(4):e19103.
Angiopoietin-like 4: a novel molecular hallmark in oral Kaposi's sarcoma. Hu J, Jham BC, Ma T, Friedman ER, Ferreira L, Wright JM, Accurso B, Allen CM, Basile JR, Montaner S. Oral Oncology. 2011 May;47(5):371-5.
Viral G protein-coupled receptor up-regulates Angiopoietin-like 4 promoting angiogenesis and vascular permeability in Kaposi's sarcoma. Ma T, Jham BC, Hu J, Friedman ER, Basile JR, Molinolo A, Sodhi A, Montaner S. Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14363-8.
The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor: Lessons on dysregulated angiogenesis from a viral oncogene. Jham BC, Montaner S. J Cellular Biochemistry. 2010 May;110(1):1-9.
Dual inhibition of PI3Kalpha and mTOR as an alternative treatment for Kaposi's sarcoma. Chaisuparat R, Hu J, Jham BC, Knight ZA, Shokat KM, Montaner S. Cancer Research. 2008 Oct 15;68(20):8361-8.
An NF-kappaB gene expression signature contributes to Kaposi's sarcoma virus vGPCR-induced direct and paracrine neoplasia. Martin D, Galisteo R, Ji Y, Montaner S, Gutkind JS. Oncogene. 2008 Mar 20;27(13):1844-52.
Akt/TSC/mTOR activation by the KSHV G protein-coupled receptor: emerging insights into the molecular oncogenesis and treatment of Kaposi's sarcoma. Montaner S. Cell Cycle. 2007 Feb 15;6(4):438-43.
The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor. Sodhi A, Chaisuparat R, Hu J, Ramsdell AK, Manning BD, Sausville EA, Sawai ET, Molinolo A, Gutkind JS, Montaner S. Cancer Cell. 2006 Aug;10(2):133-43.
Viral hijacking of G-protein-coupled-receptor signalling networks. Sodhi A, Montaner S, Gutkind JS. Nat Rev Mol Cell Biol. 2004 Dec;5(12):998-1012.
EDUCATION AND TRAINING:
- PhD, Biochemistry and Molecular Biology: Universidad Autónoma, Madrid, Spain.
- Master in Public Health: Universidad Pontificia Comillas, Madrid, Spain.
- Fellowship: National Institutes of Health, Bethesda, MD.