Cancer Genetics, Gene Discovery, Genomics, Molecular Biology, Tumor Suppressor Genes
Biophysics and Systems Pharmacology [BSP], Cancer Biology [CAB], Genetics and Genomic Sciences [GGS]
BA, Columbia College
MPhil, Cambridge University
MD, PhD, Mount Sinai School of Medicine
MD, Mount Sinai Sch. of Medicine CUNY
Mount Sinai Hospital
Fellowship, Human Genetics
Mount Sinai Hospital
English, Italian, Spanish
The translational research in our laboratory focuses on four major human disease themes: 1. Osteolysis and arthritis; 2. Cancer genetics and cancer syndromes; 3. Metabolic and genetic basis of obesity, and; 4. Hereditary platelet disorders. In each, combinations of genetic, biochemical, genomic, proteomic and model system approaches are used to explore the molecular basis of the disease and then, ultimately, target diagnostic and treatment strategies for patients with these disorders. In collaboration with other clinical and basic science researchers, and across these human diseases, we have used this approach to define novel human syndromes and disease genes and then use these discoveries to understand the biologic basis of the underlying physiology and pathophysiology.
Two examples of current studies are provided. We first characterized and described with colleagues a severe osteolysis and arthritis syndrome [Am J Med Genet. 93:11-18; 2000]. Using a positional cloning strategy, we then localized and identified that the disease was caused by inactivating mutations in the matrix metalloproteinase 2 gene (MMP-2); the first identified MMP deficiency [Nat Genet 28:261-5; 2001]. Counterintuitively, MMP-2 is a member of the matrix metalloproteinase family of proteolytic enzymes which degrade the extracellular matrix (ECM) during tissue remodeling and are involved in various critical cellular processes including cell migration, proliferation, and apoptosis. The overall goal of current ongoing patient, mouse model and biochemical studies is to resolve the apparent paradox created by our original findings in affected individuals: "How does functional loss of a single proteolytic enzyme result in increased bone loss and joint destruction".
A second example is provided by studies in human cancer. We originally demonstrated, in collaboration with Dr. Scott Friedman's laboratory, that KLF6, a member of the Kruppel-like family of zinc finger transcription factors which regulate growth-related signal transduction pathways, mediates growth suppression by a p53-independent, upregulation of p21 and is a tumor suppressor gene [Science 294:2563-6; 2001; Am J Pathol 162:1047-52; 2003]. We have now further demonstrated loss or inactivation of KLF6 in a number of major human cancers including ovarian cancer [Clin Cancer Res. 12:3730-9; 2006], colorectal cancer [Gastroenterology 126:1090-103; 2004], hepatocellular carcinoma [Hepatology. 40:1047-52; 2004], head and neck squamous cell carcinoma [In Press, 2007], and malignant glioma [In Press, 2007].
Beyond this, we recently demonstrated in a multicenter, prostate cancer study of greater than 3,400 men that a prevalent KLF6 germline single nucleotide polymorphism (SNP) is associated with an increased lifetime cancer risk [Cancer Res. 65:1213-22; 2005]. The SNP results in the increased transcription of an alternatively spliced, biologically active KLF6 isoform [Cancer Res. 65:5761-8; 2005]. We are now investigating the co-opted, critical pro-survival functions of KLF6-SV1 in patient samples and genetically engineered tumor cells and mouse and drosophila models and exploring the role of targeted KLF6-SV1 silencing as a potential therapeutic agent in human cancers.
Mosig RA, Martignetti JA, DiFeo A, Ramirez MM, Parker IC, Abe E, Diouri J, Al Aqeel A, Wylie J, Oblander SA, Madri J, Apte SS, Zaidi M, Doty SB, Majeska RJ, Schaffler MB, Dowling O. Loss of MMP-2 disrupts early skeletal and craniofacial development, and results in decreased bone mineralization, joint erosion and defects in osteoblast and osteoclast growth. Human Molecular Genetics 2007;.
Camacho-Vanegas O, Narla G, Teixeira MS, Martignetti JA, Misra A, Friedman SL, Feuerstein BG, DiFeo A. Functional inactivation of the KLF6 tumor suppressor gene by loss of heterozygosity and increased alternative splicing in glioblastoma. Int. J of Onc 2007;.
Teixeira MS, Camacho-Vanegas O, Fernandez Y, Narla G, DiFeo A, Lee B, Martignetti JA, Friedman SL, Schlecht NF, Genden EM, Urken M, Brandwein-Gensler M, Kalir T. KLF6 allelic loss is associated with tumor recurrence and markedly decreased survival in head and neck squamous cell carcinoma. Int. J of Onc 2007;.
DiFeo A, Narla G, Hirshfeld J, Camacho-Vanegas O, Narla J, Rose SL, Martignetti JA, Yao S, Levine A, Birrer MJ, Bonome T, Friedman SL, Buller RE, Kalir T. Roles of KLF6 and KLF6-SV1 in ovarian cancer progression and intraperitoneal dissemination. Clin Cancer Res 2006; 12: 3730-3739.
DiFeo A, Narla G, Camacho-Vanegas O, Nishio H, Martignetti JA, Buller RE, Friedman SL, Walsh MJ, Rose SL. E-cadherin is a novel transcriptional target of the KLF6 tumor suppressor. Oncogene 2006; 25: 6026-6031.
Narla G, DiFeo A, Yao S, Banno A, Hod E, Reeves HL, Martignetti JA, Camacho-Vanegas O, Levine A, Kirschenbaum A, Chan AM, Friedman SL, Qiao RF. Targeted inhibition of the KLF6 splice variant KLF6 SV1 suppresses prostate cancer cell growth and spread. Cancer Res 2005; 65: 5761-5768.
Narla G, Martignetti JA, Reeves HL, Schaid DJ, Hirshfeld J, Hod E, Katz A, Isaacs WB, Hebbring S, Komiya A, McDonnell SK, Wiley KE, Jacobsen SJ, Isaacs SD, Walsh PC, Zheng SL, Chang BL, Friedrichsen DM, Stanford JL, Ostrander EA, Chinnaiyan AM, Rubin MA, Xu J, Thibodeau SN, Friedman SL, Difeo A. A germline DNA polymorphism associated with increased prostate cancer risk enhances alternative splicing of the KLF6 tumor suppressor gene. Cancer Res 2005; 65: 1213-1222.
Dowling O, Martignetti JA, Ramirez MC, Tukel T, Narla G, Bonafe L, Kayserili H, Yuksel-Apak M, Paller AS, Norton K, Teebi AS, Grum-Tokars V, Martin GS, Davis GE, Glucksman MJ, Difeo A. Mutations in capillary morphogenesis gene-2 result in the allelic disorders juvenile hyaline fibromatosis and infantile systemic hyalinosis. Am J Hum Genet 2003; 73: 957-966.
Narla G, Heath KE, Reeves HL, Li D, Giono LE, Kimmelman AC, Friedman SL, Narla J, Eng FJ, Chan AM, Ferrari AC, Martignetti JA, Glucksman MJ. KLF6, a candidate tumor suppressor gene mutated in prostate cancer. Science 2001; 294: 2563-2566.
Martignetti JA, Al Aqeel A, Al Sewairi W, Boumah CE, Kambouris M, Al Mayouf S, Desnick RJ, Al Eid W, Dowling O, Harris J, Glucksman MJ, Bahabri S, Meyer BF, Sheth KV. Mutations in a human matrix metalloproteinase gene cause a multicentric osteolysis and arthritis syndrome. Nat Genet 2001; 28: 261-265.
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