GOUTHAM NARLA, MD, PhD
Oncogenes / Tumor Suppressor Genes
Mouse Models of cancer
transcriptional regulation of oncogene signaling; mouse models of cancer metastasis; small molecule based drug discovery; alternative splicing in regulation gene function in cancer metastasis; signal transduction and the role of transcription factors and protein phosphatases in regulating oncogene signaling
The focus of the Narla laboratory is to understand the role of negative regulators of oncogene signaling, specifically transcription factors and protein phosphatases, in cancer development and progression using both cell culture and in vivo models of the disease. In addition, the group is focused on developing and validating small molecule based therapies to reactivate these networks to treat cancer. Recent efforts have identified a series of novel small molecule activators of protein phosphatase 2A (PP2A), a major negative regulator of oncogenic AKT and ERK signaling that have broad activity in cancer cell lines and xenograft and transgenic mouse models of lung cancer.
In addition, the laboratory studies the role of dysregulated alternative splicing as a mechanism to regulate tumor suppressor gene function and as a driver of cancer progression, metastasis and chemotherapy resistance. Recent studies have identified a splice variant of the KLF6 gene, KLF6-SV1 to a major driver of prostate and breast cancer metastasis in cell culture and in vivo models of the disease. Further studies in the laboratory are directed at targeting this splice variant for cancer treatment and further understanding the molecular mechanisms that drive aberrant splice site selection.
Dr. Narla has received numerous awards including an early career award from the Howard Hughes Medical Institute (HHMI), and was recently named a Harrington Distinguished Scholar (Early Career Award). Dr. Narla has over 40 publications in the fields of cancer genetics and biology, including papers in Nature Genetics, Science, The Journal of Clinical Investigation, and Science Translational Medicine. Dr. Narla is a Medical Geneticist at University Hospitals and cares for high-risk breast cancer patients at the Seidman Cancer Center.
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The Young Scientist Foundation
Frazer KA, Narla G, Zhang JL, Rubin EM. The apolipoprotein(a) gene is regulated by sex hormones and acute phase inducers in YAC transgenic mice. Nat Genet 1995;9:424-31.
Narla G, Heath KE, Reeves HL, Li D, Giono LE, Kimmelman AC, Glucksman MJ, Narla J, Eng FJ, Chan AM, Ferrari AC, Martignetti JA, Friedman SL. KLF6, a candidate tumor suppressor gene in prostate cancer. Science 2001;21:2563-6.
Narla G, DiFeo A, 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, Martignetti JA. A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk. Cancer Res 2005;65:1213-22.
Narla G, DiFeo A, Yao S, Banno A, Hod E, Reeves H, Qiao RF, Camacho-Vanegas O, Levine A, Kirschenbaum A, Chan AM, Friedman SL, Martignetti JA. Targeted inhibition of the KLF6 splice variant KLF6SV1 suppresses prostate cancer growth and spread. Cancer Res 2005;65:5761-8.
Narla G, Kremer-Tal S, Matsumoto N, Zhao X, Yao S, Kelley K, Tarocchi M, Friedman SL. In vivo Regulation of p21 by the KLF6 Tumor Suppressor Gene in Mouse Liver and Human Hepatocellular Carcinoma. Oncogene 2007;26:4428-34.
DiFeo A, Feld L, Rodriguez E, Wang C, Beer DG, Martignetti JA, Narla G. A functional role for KLF6-SV1 in lung adenocarcinoma prognosis and chemotherapy response. Cancer Res 2008;68:965-70.
Narla G, DiFeo A, Fernandez Y, Dhanasekaran S, Huang F, Sangodkar J, Hod E, Leake D, Friedman SL, Hall S, Chinnaiyan AM, Gerald WL, Rubin MA, Martignetti JA. KLF6-SV1 is a key regulator of metastasis and survival in prostate cancer. J Clin Invest 2008;118:2711-2721. PMCID: 2441856.
Sangodkar J, Katz S, Melville H, Narla G. Lung adenocarcinoma: lessons in translation from bench to bedside. Mt Sinai J Med. 2010;77:597-605.
Vetter D, Cohen-Naftaly M, Villaneuva A, Lee YA, Kocabayoglu P, Narla G, LLovet JM, Thung SN, Friedman SL. Enhanced hepatocarcinogenesis in mouse models and human HCC by coordinate KLF6 depletion and increased mRNA splicing. Hepatology. 2012.
Mallipattu SK, Liu R, Zheng F, Narla G, Ma’ayan A, Dikman S, Jain MK, Saleem M, D’agati V, Klotman P, Chuang PY, He JC. Kruppel-like factor 15 (KLF15) is a key regulator of podocyte differentiation. J Biol Chem. 287(23):19122-35; 2012.
Sangodkar J, Dhawan N, Melville H, Singh V, Katz S, Albano T, Farrington C, Rana H, Yuan E, Arnovitz P, Galsky M, Olhmeyer M, Burstein D, Zhang D, Politi K, Difeo A, and Narla G. The FOXO1/KLF6 transcriptional network negatively regulates activated EGFR signaling and modulates response to anti-EGFR based therapy. J Clin Invest 2012;122:2637-51.
Hatami R, Sieuwerts AM, Izadmehr S, Yao Z, Qiao R, Papa L, Look MP, Smid M, Ohlssen J, Levine AC, Germain D, Burstein D, Kirschenbaum A, DiFeo A, Foekens JA, and Narla G. An oncogenic splice variant of the KLF6 gene is associated with poor survival and a potent driver of breast cancer metastasis. Science Translational Medicine 2013.
Das TK, Sangodkar J, Negre N, Narla G, and Cagan RL. Drosophila Sin3a mediates cancer-like invasion through multiple pathways. Oncogene 2013.