CELL BIOLOGY AND MOLECULAR CARCINOGENESIS GROUP

AREAS OF EXPERTISE

  • Primary cell culture
  • Three-dimensional spheroid modeling of normal and cancer cells
  • shRNA, CRISPR/Cas9 gene knockdown
  • Lentiviral induced gene overexpression
  • Neoplastic phenotyping assays
  • Chemotherapeutic assays
  • CRISPR/Cas9 genome editing of genetic variants
  • CRISPR/Cas9 functional screens
  • Epigenome biology
  • LncRNA biology
  • Chromatin immunoprecipitation sequencing
  • RNA sequencing

TEAM MEMBERS

Simon Gayther, PhD. Professor and Director of Molecular Epidemiology at Cedar-Sinai Medical Center (simon.gayther@cshs.org)

Simon Gayther, PhD. 

Dr. Gayther’s research program is largely focused on understanding the underlying causes of ovarian cancer initiation and development. Dr Gayther has a long established track record in defining the heritable component of ovarian cancer, and the functional role of both common and rare risk variants and their target susceptibility genes in the early stage disease pathogenesis.The overall approach of this research program is to integrate genomics and epigenomics analyses to identify molecular markers associated with disease, with cell biology modeling studies to validate the role of novel molecular markers in disease biology. The goal is to translate the findings from these studies into the clinical arena to improve risk prediction and prevention strategies, early stage screening and disease diagnosis and targeted therapeutics

 

Justyna Kanska, PhD.

Justyna Kanska, PhD.- Postdoctoral Scientist - Center for Bioinformatics and Functional Genomics at Cedar-Sinai Medical Center (justyna.kanska@cshs.org)

Dr. Kanska’s postdoctoral research career has so far focused on novel mechanistic studies of ovarian cancer development. Initially, she studied signaling pathways that increase ovarian cancer cell plasticity and heterogeneity upon glucose starvation, leading to the identification of a novel ZEB1/NNMT signaling axis and the metabolic enzyme NNMT in ovarian cancer.Since joining Dr. Gayther’s lab in June 2016, Dr. Kanska has developed mutant TP53- mediated early stage transformation models of normal ovarian and breast precursor cells with the primary goal of establishing the functional consequences of genetic variants and candidate genes. These models will be the primary research tool in understanding a host of functional mechanisms in ovarian/breast cancer pathogenesis and for the identification of novel early stage clinical biomarkers and therapeutic targets.

 

Norma I. Rodríguez-Malavé, PhD.

Norma I. Rodríguez-Malavé, PhD. - Postdoctoral Scientist - Center for Bioinformatics and Functional Genomics at Cedar-Sinai Medical Center (Norma.Rodriguez-Malave@cshs.org)

Dr. Rodríguez-Malavé joined Dr. Gayther’s laboratory as a postdoctoral research scientist after completing her PhD at Dr. Dinesh Rao’s laboratory at University of California, Los Angeles (UCLA) where she was studying the role of lncRNAs in B-cell malignancies and their possible role as clinical biomarkers and therapeutic targets.Dr. Rodríguez-Malavé has extensive experience in in vitro and in vivo approaches to delineate the role of lncRNAs in cancer cell survival.Her current research is focused on lncRNA and transcription factor mechanisms in ovarian cancer development, in particular analysis of the role of the Wilms Tumor 1 anti-sense (WT1-AS) lncRNA and its sense gene product Wilm’s Tumor 1 (WT1) transcription factor. She is investigating the role of WT1-AS specifically in the high-grade serous histotype of ovarian cancer and the interplay between this lncRNA and WT1, an important biomarker for high-grade serous ovarian cancer.

 

Kruttika Dabke

Kruttika Dabke, MS - Research Associate I- Center for Bioinformatics and Functional Genomics at Cedar-Sinai Medical Center  (Kruttika.Dabke@cshs.org)

Kruttika Dabke completed her Masters in Molecular Pharmacology and Toxicology from the University of Southern California where she worked with Dr. Swenson in Dr. Markland’s lab on canine osteosarcoma. She performed various assays to determine the efficacy of vicrostatin (a drug engineered in the Markland lab) against canine osteosarcoma. She used various molecular biology techniques like western blot, IHC, cell migration and adhesion assays to determine the effects of vicrostatin in vitro. Along with Dr. Swenson, she helped develop a xenograft mouse model for canine osteosarcoma to study the effect of vicrostatin in vivo. She joined Dr. Kanska’s group in Dr. Gayther’s lab as a Research Associate I and is involved in functional studies of the oncogenic function of different genetic variants. She is involved in developing various cancer cell lines as models for CRISPR screens to identify potential causal targets for breast and ovarian cancer.

 

Ivetth Corona de la Fuente, PhD.

Ivetth Corona de la Fuente, PhD - Post-Doctoral Scientist - Bioinformatics and Functional Genomics at Cedars-Sinai Medical Center (Rosario.CoronadelaFuente@cshs.org

Ivetth has a Bachelor's degree in Electric and Computer Engineering from CETYS Universidad, Mexico and a M.Sc. in Computer Science from CICESE, Mexico. She was first introduced to Computational Biology during her master’s, where she studied protein structure prediction. Continuing in the Structural Bioinformatics field, she did her Ph.D. analyzing protein-DNA complexes and characterized structural features that account for DNA-binding specificity. She then completed an internship at Takeda Pharmaceuticals, Cambridge, MA, where she studied cancer genomics for the first time. Now, under the direction of Drs. Lawrenson and Gayther, she is a Computational Biologist studying the interplay between transcription factors and somatic and germline variants that contribute to the development of ovarian cancer.

PUBLICATIONS

GENETIC DISCOVERY

Phelan C, Kuchenbaecker KB, Tyrer JP, Kar S, Lawrenson K, et al. Genome wide association studies identify 12 novel susceptibility loci for different histological subtypes of epithelial ovarian cancer Nature Genetics 2016 (in press) 

Kar SP, Beesley J, Amin Al Olama A et al. Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types. Cancer Discov. 2016 6:1052-67 

Pharoah PD, Song H, Dicks E et al J. PPM1D Mosaic Truncating Variants in Ovarian Cancer Cases May Be Treatment-Related Somatic Mutations. J Natl Cancer Inst. 2016 108(3) 

Ramus SJ, Song H, Dicks E, Tyrer JP et al. Mutations in the BRIP1, BARD1, PALB2and NBNgenes in women with ovarian cancer. J. Nat. Cancer Inst. 2015, 107(11) 

Kelemen, LE, Lawrence K, Tyrer J, Li, Q et al. Genome-wide significant risk associations for mucinous epithelial ovarian carcinoma. Nat. Genet. 2015, 47:888-97 

Song H, Dicks E, Ramus SJ, Tyrer JP et al. Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population. J Clin Oncol. 2015, 33:2901-7 

Kuchenbaecker KB, Ramus SJ, Tyrer J, Lee A et al. Identification of six new susceptibility loci for invasive epithelial ovarian cancer. Nat Genet. 2015 47:164-71 

Song H, Cicek MS, Dicks E, Harrington P, Ramus SJ, et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Genet. 2014 23:4703-9 

Permuth-Wey J, Lawrenson K, Shen HC, Velkova A, Tyrer JP et al. Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31. Nat Commun. 2013 4:1627 

Shen H, Fridley BL, Song H, Lawrenson K, Cunningham JM, et al. Epigenetic Analysis Leads to Identification of HNF1B as a Subtype-Specific Susceptibility Gene for Ovarian Cancer. Nat Commun. 2013 4:1628 

Bojesen SE, Pooley KA, Johnatty SE, Beesley J, Michailidou K et al. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. Nat Genet. 2013 45:371-84 

Pharoah PD, Tsai YY, Ramus SJ, Phelan CM, Goode  et al GWAS meta-analysis and replication identifies three novel common susceptibility loci for ovarian cancer Nat Genet. 2013 45:362-70 

Goode EL, Chenevix-Trench G, Song H, Ramus SJ, Notaridou M et al. A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nat Genet 2010; 42:874-879 

Bolton KL, Tyrer J, Song H, Ramus SJ, Notaridou M et al. Common variants at 19p13 are associated with susceptibility to ovarian cancer. Nat Genet 2010; 42:880-884 

Song H, Ramus SJ, Tyrer J, Bolton KL, Gentry-Maharaj A et al. A genome-wide association study identifies a novel ovarian cancer susceptibility locus on 9p22.2. Nat Genet 2009; 41:996-1000 

Soegaard M, Kjaer SK, Cox M, Wozniak E, Høgdall E, et al. Contribution Of BRCA1 and BRCA2 Mutations and Clinical Characteristics in Ovarian Cancer Cases From Danish Population Clin Cancer Res 2008; 14:3761-3767 

Ramus SJ, Harrington PA, Pye C, Dicioccio RA, Cox MJ, et al. The contribution of BRCA1 and BRCA2 mutations to inherited ovarian cancer. Hum Mutation 2007; 28:1207-1215 

Gayther SA, Batley S, Linger L, Bannister A, Thorpe K, et al. Mutations truncating the EP300 acetylase in human cancers. Nat. Genet. 2000, 43:851-857 

Gayther SA, Russell P, Harrington P, Antoniou AC, Easton DF, Ponder BA. The contribution of germline BRCA1 and BRCA2 mutations to familial ovarian cancer: no evidence for other ovarian cancer-susceptibility genes. Am J Hum Genet 1999; 65:1021-1029 

Gayther SA, Mangion J. Russell P, Seal S, Barfoot R, et al. Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet 1997,15:103-105 

Foster KA, Harrington P, Kerr J, Russell P, DiCioccio RA, et al. Somatic and germline mutations of the BRCA2 gene in sporadic ovarian cancer. Cancer Res. 1996; 56:3622-3625 

Gayther SA, Warren W, Mazoyer S, Russell PA, Harrington PA, et al. Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation. Nat Genet 1995, 11:428-433 

CLINICAL EPIDEMIOLOGY

Candido Dos Reis FJ, Song H, Goode EL, Cunningham JM, Fridley BL, et al. Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer. Clin Cancer Res. 2015 21:652-657 

Trabert B, Ness RB, Lo-Ciganic WH, Murphy MA, et al. Aspirin, Nonaspirin Nonsteroidal Anti-inflammatory Drug, and Acetaminophen Use and Risk of Invasive Epithelial Ovarian Cancer: A Pooled Analysis in the Ovarian Cancer Association Consortium. J Natl Cancer Inst. 2014 106:djt431 

Faber MT, Kjær SK, Dehlendorff C, Chang-Claude J, Andersen KK, et al. Cigarette smoking and risk of ovarian cancer: a pooled analysis of 21 case-control studies. Cancer Causes Control 2013 24:989-1004 

Olsen CM, Nagle CM, Whiteman DC, Ness R, Pearce CL, et al. Obesity and risk of ovarian cancer subtypes: evidence from the Ovarian Cancer Association Consortium. Endocr Relat Cancer. 2013 20:251-262 

Pearce CL, Templeman C, Rossing MA, Lee A, Near AM, et al. Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies. Lancet Oncol. 2012 13:385-94 

Bolton KL, Chenevix-Trench G, Goh C, Sadetzki S, Ramus SJ, et al.  Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA 2012, 307:382-90 

Pharoah PD, Easton D, Stockton DL, Gayther SA, Ponder BA. Survival in familial, BRCA1-associated, and BRCA2-associated epithelial ovarian cancer. United Kingdom Coordinating Committee for Cancer Research (UKCCCR) Familial Ovarian Cancer Study Group. Cancer Res 1999; 59:868-871 

MOLECULAR CARCINOGENESIS

Kanska J, Zakhour M, Taylor-Harding B, Karlan BY, Wiedemeyer WR. Cyclin E as a potential therapeutic target in high grade serous ovarian cancer. Gynecologic Oncology. 2016 July 23.  

Coetzee S, Shen H, Hazelett D, Lawrenson K, Li Q, et al. Fine mapping and regulatory profiling of ovarian cancer susceptibility loci discovered by GWAS. Hum Mol Genet. 2015 24:3595-607 

Adler EK, Mhawech-Fauceglia P, Gayther SA, Lawrenson, K. Evaluating the Expression of PAX8 in Ovarian Surface Epithelial Cells. Hum Pathol. 2015 46:948-56 

Rodríguez-Malavé NI, Fernando TR, Patel PC, Contreras JR, Palanichamy JK, Tran TM, Anguiano J, Davoren MJ, Sandoval S, Crooks GM, and Rao DS. BALR-6 regulates cell growth and cell survival in B-lymphoblastic leukemia. Mol Can. 2015 14:1, 214  

Fernando TR*, Rodríguez-Malavé NI*, Waters EV, Yan W, Casero D, Basso G, Pigazzi M, and Rao DS. LncRNA expression discriminates karyotype and regulates cell survival in B-lymphoblastic leukemia. Mol Can Res. 2015 13:5, 839-851. *Co-authorship 

Köbel M, Madore J, Ramus SJ, Clarke BA, Pharoah PD, et al. Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study. Br J Cancer. 2014 111:2297-307 

Köbel M, Kalloger SE, Lee S, Duggan MA, Kelemen LE, et al. Biomarker-based ovarian carcinoma typing: a histologic investigation in the ovarian tumor tissue analysis consortium. Cancer Epidemiol Biomarkers Prev. 2013 22:1677-86 

Sieh W, Köbel M, Longacre TA, Bowtell DD, deFazio A et al. Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study. Lancet Oncol. 2013, 14:853-62 

Khalique L, Ayhan A, Jacobs IJ, Gayther SA, Ramus SJ. The clonal evolution of metastases from primary ovarian epithelial cancers. Int J Cancer 2009; 124:1579-1586 

Høgdall EV, Christensen L, Kjaer SK, Blaakaer J, Jarle Christensen I, et al. Protein expression levels of CarcinoEmbryonic Antigen (CEA) in Danish ovarian cancer patients. Pathology 2008; 40:487-492  

Ramus SJ, Elmasry K, Luo Z, Gammerman A, Lu K, et al. A Molecular Genetic Approach to improve the clinical diagnosis and clinical outcome of synchronous ovarian and endometrial cancer. Clin Cancer Res 2008; 14:5840-5848 

Høgdall EV, Christensen L, Høgdall CK, Frederiksen K, Gayther S, et al. Distribution of p53 expression in tissue from 774 Danish ovarian tumour patients and its prognostic significance in ovarian carcinomas APMIS 2008; 116:400-409 

Khalique L, Ayhan A, Weale ME, Jacobs IJ, Ramus SJ, Gayther SA. Genetic Intra Tumour Heterogeneity In Epithelial Ovarian Cancer: The Implications For Molecular Based Clinical Diagnosis Of Tumours J Pathol 2007; 211:286-295 

Högdall EV, Christensen L, Högdall CK, Blaakaer J, Gayther SA, et al. Prognostic value of estrogen receptor and progesterone receptor tumor expression in Danish ovarian cancer patients: From the 'MALOVA' Ovarian Cancer Study. Oncol Rep 2007; 18:1051-1059 

Høgdall EV, Christensen L, Kjaer SK, Blaakaer J, Christensen IJ, et al. Expression level of Wilms tumor 1 (WT1) protein has limited prognostic value in epithelial ovarian cancer From the Danish "MALOVA" Ovarian Cancer Study. Gynecol Oncol 2007; 106:318-324 

Högdall EV, Christensen L, Kjaer SK, Blaakaer J, Kjaerbye-Thygesen A, et al. CA125 expression pattern, prognosis and correlation with serum CA125 in ovarian tumor patients. From The Danish " MALOVA" Ovarian Cancer Study. Gynaecologic Oncology 2007; 104:508-515 

Brinkmann D, Ryan A. Ayhan A, McCluggage WG, Feakins R, Santibanez-Koref MF, Mein CA, Gayther SA, Jacobs IJ. A molecular genetic and statistical approach for the diagnosis of dual-site cancers. JNCI 2004; 96:1441-1446 

Ramus SJ, Pharoah P. Harrington P, Pye C, Werness B, et al. BRCA1/2 mutation status influences somatic genetic progression in inherited and sporadic epithelial ovarian cancer cases. Cancer Res 2003, 63:417-423 

Russell PA, Pharoah PDP, De Foy K, Ramus SJ, Symmonds I, et al. Frequent loss of BRCA1 mRNA and protein expression in sporadic ovarian cancers. Int J Cancer 2000, 87:317-321 

CELL BIOLOGY MODELING

Manek R, Pakzamir E, Mhawech-Fauceglia P, Pejovic T, Sowter H, Gayther SA, Lawrenson K. Targeting Src in endometriosis-associated ovarian cancer. Oncogenesis. 2016 5:e251. 

Lawrenson K, Lee N, Lee J, Rao N, Gayther SA. Src as a Novel Therapeutic Target for Ovarian Endometriosis. Gynecol Oncol. 2014 135:100-7 

Lee J, Mhawech-Fauceglia P, Lee N, Parsanian JC, Lin YG, Gayther SA, Lawrenson K A three-dimensional microenvironment alters protein expression and chemosensitivity of epithelial ovarian cancer cells in vitro. Lab Invest. 2013 93:528-42 

Brueggmann, D, Templeman, C, Starzinski-Powitz, A, Rao, PN, Gayther, SA, Lawrenson, K. Novel Three dimensional in vitroModels of Ovarian Endometriosis. J Ovarian Res. 2014 7(1):17 

Lawrenson K, Notaridou M, Lee N, Benjamin E, Jacobs IJ, et al. In vitro three-dimensional modeling of fallopian tube secretory epithelial cells. BMC Cell Biol 2013, 14:43 

Lawrenson K, Sproul D, Grun B, Notaridou M, Benjamin E, et al. Modeling genetic and clinical heterogeneity in epithelial ovarian cancer. Carcinogenesis 2011, 32:2540-1549  

Lawrenson K; Grun B; Benjamin E; Jacobs IJ; Dafou D; Gayther SA. Senescent Fibroblasts Promote Neoplastic Transformation of Ovarian Epithelial Cells in a Three-Dimensional Model of Early Stage Ovarian Cancer. Neoplasia 2010, 12:317-325 

Lawrenson K; Benjamin E, Jacobs IJ, Gayther SA, Dafou D. In vitro Three-Dimensional Modeling of Human Ovarian Surface Epithelial Cells. Cell Proliferation 2009; 42:385-393  

Grun B, Benjamin E, Sinclair J, Timms, J, Gayther SA, Dafou D. Three dimensional in vitro cell biology models of ovarian and endometrial cancer. Cell Proliferation 2009; 42:219-228 

Li NF, Dafou D, Broad S, Lu YJ , Yang JS, Hagemann T, et al. hTERT immortalised human ovarian surface epithelial cells maintain functional pRb and p53 expression. Cell Proliferation 2007, 40:780-794 

Li NF, Willbanks G, Balkwill F, Jacobs IJ, Dafou D, Gayther SA. A Modified Culture Medium That Significantly Improves the Growth of Human Normal Ovarian Surface Epithelial (NOSE) Cells in Vitro. Lab Invest 2004; 84:923-931 

FUNCTIONAL MECHANISMS

Ross-Adams H, Ball S, Lawrenson K, Halim S, Russell R, et al. HNF1B variants associate with promoter methylation and regulate gene networks activated in prostate and ovarian cancer. Oncotarget. 2016 doi: 10.18632 

Lawrenson, K, Siddhartha Kar, S, McCue, K, Kuchenbaeker, K et al. Functional Mechanisms Underlying Pleiotropic Risk Alleles At The 19p13.1 Breast-Ovarian Cancer Susceptibility Locus. Nat. Comm. 2016 7:12675 

Li, Q, Stram D, Haiman C, Kraft P, Pharoah PDP, Gayther SA, Karr S, Freedman MF. Expression QTL based analyses reveal candidate causal genes and loci across five tumor types. Hum Mol Genet. 2014 23:5294-302 

Notaridou M, Quaye L, Dafou D, Jones C, Song H, et al. Common alleles in candidate susceptibility genes associated with risk and development of epithelial ovarian cancer. Int J Cancer.  2011 128:2063-74 

Spisak S, Lawrenson K, Fu Y, Csabai I, Cottman R, et al.  Establishing functional causality of non-coding GWAS variants using epigenome and genome editing. Nat. Med. 2015, 21:1357-6 

Freedman ML, Monteiro, ANA, Gayther SA, Coetzee GA, et al. Principles for the post-GWAS functional characterization of cancer risk loci. Nat. Genet. 2011, 43:513-518 

Lawrenson K, Li, Q, Kar S, Seo J-H et al. Cis –eQTL Analysis And Functional Validation Of Candidate Susceptibility Genes For High-Grade Serous Ovarian Cancer. Nat. Comm. 2015, 6:8234