David Wong

1. My laboratory spearheads the use of genome-wide and proteome-wide high-throughput technologies to harness the diagnostic and biological determinants pertaining to the pathogenesis of oral/head and neck cancer. In particular we are focusing on the genomic and proteomic determinants of oral cancer progression. Using a patient-based genome/proteome-wide approach; we are harnessing the genomic and proteomic determinants that distinguish progressing from non-progression oral precancers. For genomic defects, a concurrent approach to identify gene copy number abnormalities (CNA) by cDNA microarray comparative genomic hybridization (CGH) as well as SNP-based loss of heterozygosity (LOH) using the Affymetrix 100K SNP-based Mapping Arrays. For expression analysis, the Affymetrix 133+ 2 and all exon high-density oligonucleotide arrays are used. For proteomic analysis, LC-MS/MS as well as single cell proteomics are creatively being integrated. A key component to a systems approach (Weighted-Gene Co-Expression Network Analysis, WGCNA) is to seek out molecular concordance of detectable molecular defects. a. Das S, Ansel KM, Bitzer M, Breakefield XO, Charest A, Galas DJ, Gerstein MB, Gupta M, Milosavljevic A, McManus MT, Patel T, Raffai RL, Rozowsky J, Roth ME, Saugstad JA, Van Keuren-Jensen K, Weaver AM, Laurent LC. The Extracellular RNA Communication Consortium: Establishing Foundational Knowledge and Technologies for Extracellular RNA Research. Cell. 2019 Apr 4;177(2):231-242. PubMed Central PMCID: PMC6601620. b. Yu T, Ye H, Sun W, Li KC, Chen Z, Jacobs S, Bailey DK, Wong DT, Zhou X. A forward-backward fragment assembling algorithm for the identification of genomic amplification and deletion breakpoints using high-density single nucleotide polymorphism (SNP) array. BMC Bioinformatics. 2007 May 3;8:145. PubMed Central PMCID: PMC1868765. c. Zhou X, Temam S, Chen Z, Ye H, Mao L, Wong DT. Allelic imbalance analysis of oral tongue squamous cell carcinoma by high-density single nucleotide polymorphism arrays using whole-genome amplified DNA. Hum Genet. 2005 Dec;118(3-4):504-7. PubMed PMID: 16193324. d. Zhou X, Mok SC, Chen Z, Li Y, Wong DT. Concurrent analysis of loss of heterozygosity (LOH) and copy number abnormality (CNA) for oral premalignancy progression using the Affymetrix 10K SNP mapping array. Hum Genet. 2004 Sep;115(4):327-30. PubMed PMID: 15290239. 2. We subscribe to the belief that a central defect in human cancer lies in the dysregulation of cell cycle control. Establishing a molecular database of cell cycle regulatory genes dysregulated in head and neck cancer and understanding the molecular and biochemical pathways of these genes are areas of prime interest. Using differential expression screening assays we have identified a number of cellular genes that are differentially expressed in squamous cell carcinoma. CDK2-AP1 is a differentially expressed cellular gene that is currently being studied. CDK2-AP1 is a novel gene exhibiting growth suppressor properties. CDK2-AP1 exerts its growth suppressor function by negatively regulating the activities of DNA polymerase- /primase and cyclin-dependent kinase 2 (CDK2). CDK2-AP1 associates with DNA polymerase-/primase suppressing DNA replication, affecting predominantly the initiation step. CDK2-AP1 has been found to associates with the monomeric non-phosphorylated form of CDK2, suppressing CDK2-associated kinase activities and cell cycle progression. CDK2-AP1 also targets CDK2 for proteolysis. We are investigating the detailed biochemical and genetic mechanisms of CDK2-AP1 in cell cycle regulation, normal development and carcinogenesis. The recent excitement of this research includes finding that CDK2-AP1 -nulled mice are embryonically lethal and that CDK2-AP1 is an epigenetic regulator for differentiation competency for mouse embryonic stem cells, placing this gene at a pivotal juncture of stem cell differentiation and development. a. Kim JJ, Khalid O, Vo S, Sun HH, Wong DT, Kim Y. A novel regulatory factor recruits the nucleosome remodeling complex to wingless integrated (Wnt) signaling gene promoters in mouse embryonic stem cells. J Biol Chem. 2012 Nov 30;287(49):41103-17. PubMed Central PMCID: PMC3510811. b. Kim Y, Deshpande A, Dai Y, Kim JJ, Lindgren A, Conway A, Clark AT, Wong DT. Cyclin-dependent kinase 2-associating protein 1 commits murine embryonic stem cell differentiation through retinoblastoma protein regulation. J Biol Chem. 2009 Aug 28;284(35):23405-14. PubMed Central PMCID: PMC2749114. c. Deshpande AM, Dai YS, Kim Y, Kim J, Kimlin L, Gao K, Wong DT. Cdk2ap1 is required for epigenetic silencing of Oct4 during murine embryonic stem cell differentiation. J Biol Chem. 2009 Mar 6;284(10):6043-7. PubMed Central PMCID: PMC2649091. d. Shintani S, Ohyama H, Zhang X, McBride J, Matsuo K, Tsuji T, Hu MG, Hu G, Kohno Y, Lerman M, Todd R, Wong DT. p12(DOC-1) is a novel cyclin-dependent kinase 2-associated protein. Mol Cell Biol. 2000 Sep;20(17):6300-7. PubMed Central PMCID: PMC86104. 3. The early detection of cancer by non-invasive means has been the holy grail for cancer researchers. My research group has been spearheading a series of concerted efforts to spearhead the scientific and translational frontiers of salivary diagnostics. The use of saliva, a non-invasive biofluid, for oral and systemic disease detection, for disease progression, and for therapeutic monitoring are highly desirable goals. We have harnessed and defined five diagnostic alphabets from human saliva: salivary proteome, transcriptome, micro-RNA, metabolome and microbiome. The availability of these diagnostic alphabets greatly enhanced the translational utilities of saliva. In parallel to the biomarker efforts, point-of-care technologies are being developed for clinical applications. The “Oral Fluid NanoSensor Test (OFNASET)” is a prototype nanotechnology-based point-of-care sensor that will have the ability to detect multiplex analytes in saliva for disease detection. Two additional highly impactful outcomes emerged from these initiatives. One is the discovery of salivary extracellular RNA in saliva, including a previously unnoticed landscape of non-coding RNA. This project by the NIH Common Fund on “Extracellular RNA Communication Consortium” opened a new horizon of saliva biology. A second facet of excitement is the finding that saliva is an optimal biofluid for liquid biopsy (saliva liquid biopsy, sLB) for detection of actionable mutations in human cancers. Using an electrochemical technology called electric field-induced release and measurement (EFIRM), circulating tumor DNA (ctDNA) was detectable in lung cancer patients with near perfect concordance with tissue based biopsy genotyping. a. Murillo OD, Thistlethwaite W, Rozowsky J, Subramanian SL, Lucero R, Shah N, Jackson AR, Srinivasan S, Chung A, Laurent CD, Kitchen RR, Galeev T, Warrell J, Diao JA, Welsh JA, Hanspers K, Riutta A, Burgstaller-Muehlbacher S, Shah RV, Yeri A, Jenkins LM, Ahsen ME, Cordon-Cardo C, Dogra N, Gifford SM, Smith JT, Stolovitzky G, Tewari AK, Wunsch BH, Yadav KK, Danielson KM, Filant J, Moeller C, Nejad P, Paul A, Simonson B, Wong DK, Zhang X, Balaj L, Gandhi R, Sood AK, Alexander RP, Wang L, Wu C, Wong DTW, Galas DJ, Van Keuren-Jensen K, Patel T, Jones JC, Das S, Cheung KH, Pico AR, Su AI, Raffai RL, Laurent LC, Roth ME, Gerstein MB, Milosavljevic A. exRNA Atlas Analysis Reveals Distinct Extracellular RNA Cargo Types and Their Carriers Present across Human Biofluids. Cell. 2019 Apr 4;177(2):463-477.e15. PubMed Central PMCID: PMC6616370. b. Wei F, Lin CC, Joon A, Feng Z, Troche G, Lira ME, Chia D, Mao M, Ho CL, Su WC, Wong DT. Noninvasive saliva-based EGFR gene mutation detection in patients with lung cancer. Am J Respir Crit Care Med. 2014 Nov 15;190(10):1117-26. PubMed Central PMCID: PMC5447327. c. Li Y, Elashoff D, Oh M, Sinha U, St John MA, Zhou X, Abemayor E, Wong DT. Serum circulating human mRNA profiling and its utility for oral cancer detection. J Clin Oncol. 2006 Apr 10;24(11):1754-60. PubMed PMID: 16505414. d. Li Y, St John MA, Zhou X, Kim Y, Sinha U, Jordan RC, Eisele D, Abemayor E, Elashoff D, Park NH, Wong DT. Salivary transcriptome diagnostics for oral cancer detection. Clin Cancer Res. 2004 Dec 15;10(24):8442-50. PubMed PMID: 15623624.

Websites:

W Lab

Publications:

Salfer B, Havo D, Kuppinger S, Wong DTW, Li F, Zhang L. Evaluating Pre-Analytical Variables for Saliva Cell-Free DNA Liquid Biopsy. Diagnostics (Basel). 2023 May 09; 13(10). view on PubMed

Kaczor-Urbanowicz KE, Wong DTW. RNA Sequencing Analysis of Saliva exRNA. Methods Mol Biol. 2023; 2588:3-11. view on PubMed

Tavanasefat H, Li F, Koyano K, Gourtani BK, Marty V, Mulpuri Y, Lee SH, Shin KH, Wong DTW, Xiao X, Spigelman I, Kim Y. Molecular consequences of fetal alcohol exposure on amniotic exosomal miRNAs with functional implications for stem cell potency and differentiation. PLoS One. 2020; 15(11):e0242276. view on PubMed

Tu M, Cheng J, Chen YL, Jea WC, Chen WL, Chen CJ, Ho CL, Huang WL, Lin CC, Su WC, Ye Q, Deignan J, Grody W, Li F, Chia D, Wei F, Liao W, Wong DTW, Strom CM. Electric Field-Induced Release and Measurement (EFIRM): Characterization and Technical Validation of a Novel Liquid Biopsy Platform in Plasma and Saliva. J Mol Diagn. 2020 08; 22(8):1050-1062. view on PubMed

Kaczor-Urbanowicz KE, Wei F, Rao SL, Kim J, Shin H, Cheng J, Tu M, Wong DTW, Kim Y. Clinical validity of saliva and novel technology for cancer detection. Biochim Biophys Acta Rev Cancer. 2019 08; 1872(1):49-59. view on PubMed

Cheng J, Nonaka T, Wong DTW. Salivary Exosomes as Nanocarriers for Cancer Biomarker Delivery. Materials (Basel). 2019 Feb 21; 12(4). view on PubMed

Kaczor-Urbanowicz KE, Trivedi HM, Lima PO, Camargo PM, Giannobile WV, Grogan TR, Gleber-Netto FO, Whiteman Y, Li F, Lee HJ, Dharia K, Aro K, Martin Carreras-Presas C, Amuthan S, Vartak M, Akin D, Al-Adbullah H, Bembey K, Klokkevold PR, Elashoff D, Barnes VM, Richter R, DeVizio W, Masters JG, Wong DTW. Salivary exRNA biomarkers to detect gingivitis and monitor disease regression. J Clin Periodontol. 2018 07; 45(7):806-817. view on PubMed

Katsiougiannis S, Wong DT. The Proteomics of Saliva in Sjögren's Syndrome. Rheum Dis Clin North Am. 2016 08; 42(3):449-56. view on PubMed

Chiang SH, Thomas GA, Liao W, Grogan T, Buck RL, Fuentes L, Yakob M, Laughlin MJ, Schafer C, Nazmul-Hossain A, Wei F, Elashoff D, Slowey PD, Wong DT. RNAPro•SAL: a device for rapid and standardized collection of saliva RNA and proteins. Biotechniques. 2015 Feb; 58(2):69-76. view on PubMed

Yakob M, Fuentes L, Wang MB, Abemayor E, Wong DT. Salivary biomarkers for detection of oral squamous cell carcinoma - current state and recent advances. Curr Oral Health Rep. 2014 Jun 01; 1(2):133-141. view on PubMed

Schafer CA, Schafer JJ, Yakob M, Lima P, Camargo P, Wong DT. Saliva diagnostics: utilizing oral fluids to determine health status. Monogr Oral Sci. 2014; 24:88-98. view on PubMed

Yoshizawa JM, Schafer CA, Schafer JJ, Farrell JJ, Paster BJ, Wong DT. Salivary biomarkers: toward future clinical and diagnostic utilities. Clin Microbiol Rev. 2013 Oct; 26(4):781-91. view on PubMed

Lau C, Kim Y, Chia D, Spielmann N, Eibl G, Elashoff D, Wei F, Lin YL, Moro A, Grogan T, Chiang S, Feinstein E, Schafer C, Farrell J, Wong DT. Role of pancreatic cancer-derived exosomes in salivary biomarker development. J Biol Chem. 2013 Sep 13; 288(37):26888-97. view on PubMed

Wei F, Yang J, Wong DT. Detection of exosomal biomarker by electric field-induced release and measurement (EFIRM). Biosens Bioelectron. 2013 Jun 15; 44:115-21. view on PubMed

Yoshizawa JM, Wong DT. Salivary microRNAs and oral cancer detection. Methods Mol Biol. 2013; 936:313-24. view on PubMed

Bonne NJ, Wong DT. Salivary biomarker development using genomic, proteomic and metabolomic approaches. Genome Med. 2012; 4(10):82. view on PubMed

Wong DT. Salivaomics. J Am Dent Assoc. 2012 Oct; 143(10 Suppl):19S-24S. view on PubMed

Spielmann N, Ilsley D, Gu J, Lea K, Brockman J, Heater S, Setterquist R, Wong DT. The human salivary RNA transcriptome revealed by massively parallel sequencing. Clin Chem. 2012 Sep; 58(9):1314-21. view on PubMed

Deshpande AM, Khalid O, Kim JJ, Kim Y, Lindgren A, Clark AT, Wong DT. Cdk2ap2 is a novel regulator for self-renewal of murine embryonic stem cells. Stem Cells Dev. 2012 Nov 01; 21(16):3010-8. view on PubMed

Zhang L, Xiao H, Zhou H, Santiago S, Lee JM, Garon EB, Yang J, Brinkmann O, Yan X, Akin D, Chia D, Elashoff D, Park NH, Wong DTW. Development of transcriptomic biomarker signature in human saliva to detect lung cancer. Cell Mol Life Sci. 2012 Oct; 69(19):3341-3350. view on PubMed

Elashoff D, Zhou H, Reiss J, Wang J, Xiao H, Henson B, Hu S, Arellano M, Sinha U, Le A, Messadi D, Wang M, Nabili V, Lingen M, Morris D, Randolph T, Feng Z, Akin D, Kastratovic DA, Chia D, Abemayor E, Wong DT. Prevalidation of salivary biomarkers for oral cancer detection. Cancer Epidemiol Biomarkers Prev. 2012 Apr; 21(4):664-72. view on PubMed

Farrell JJ, Zhang L, Zhou H, Chia D, Elashoff D, Akin D, Paster BJ, Joshipura K, Wong DT. Variations of oral microbiota are associated with pancreatic diseases including pancreatic cancer. Gut. 2012 Apr; 61(4):582-8. view on PubMed

Brinkmann O, Zhang L, Giannobile WV, Wong DT. Salivary biomarkers for periodontal disease diagnostics. Expert Opin Med Diagn. 2011 Jan; 5(1):25-35. view on PubMed

Brinkmann O, Kastratovic DA, Dimitrijevic MV, Konstantinovic VS, Jelovac DB, Antic J, Nesic VS, Markovic SZ, Martinovic ZR, Akin D, Spielmann N, Zhou H, Wong DT. Oral squamous cell carcinoma detection by salivary biomarkers in a Serbian population. Oral Oncol. 2011 Jan; 47(1):51-5. view on PubMed

Ai J, Smith B, Wong DT. Saliva Ontology: an ontology-based framework for a Salivaomics Knowledge Base. BMC Bioinformatics. 2010 Jun 03; 11:302. view on PubMed

Wei F, Liao W, Xu Z, Yang Y, Wong DT, Ho CM. Bio/abiotic interface constructed from nanoscale DNA dendrimer and conducting polymer for ultrasensitive biomolecular diagnosis. Small. 2009 Aug 03; 5(15):1784-90. view on PubMed

Kim Y, Deshpande A, Dai Y, Kim JJ, Lindgren A, Conway A, Clark AT, Wong DT. Cyclin-dependent kinase 2-associating protein 1 commits murine embryonic stem cell differentiation through retinoblastoma protein regulation. J Biol Chem. 2009 Aug 28; 284(35):23405-14. view on PubMed

Hu S, Wong DT. Lectin microarray. Proteomics Clin Appl. 2009 Feb; 3(2):148-54. view on PubMed

Hu S, Zhou M, Jiang J, Wang J, Elashoff D, Gorr S, Michie SA, Spijkervet FK, Bootsma H, Kallenberg CG, Vissink A, Horvath S, Wong DT. Systems biology analysis of Sjögren's syndrome and mucosa-associated lymphoid tissue lymphoma in parotid glands. Arthritis Rheum. 2009 Jan; 60(1):81-92. view on PubMed

Deshpande AM, Dai YS, Kim Y, Kim J, Kimlin L, Gao K, Wong DT. Cdk2ap1 is required for epigenetic silencing of Oct4 during murine embryonic stem cell differentiation. J Biol Chem. 2009 Mar 06; 284(10):6043-7. view on PubMed

Jiang J, Park NJ, Hu S, Wong DT. A universal pre-analytic solution for concurrent stabilization of salivary proteins, RNA and DNA at ambient temperature. Arch Oral Biol. 2009 Mar; 54(3):268-73. view on PubMed

Hu S, Arellano M, Boontheung P, Wang J, Zhou H, Jiang J, Elashoff D, Wei R, Loo JA, Wong DT. Salivary proteomics for oral cancer biomarker discovery. Clin Cancer Res. 2008 Oct 01; 14(19):6246-52. view on PubMed

Brooks MN, Wang J, Li Y, Zhang R, Elashoff D, Wong DT. Salivary protein factors are elevated in breast cancer patients. Mol Med Rep. 2008 May-Jun; 1(3):375-8. view on PubMed

Hu Z, Zimmermann BG, Zhou H, Wang J, Henson BS, Yu W, Elashoff D, Krupp G, Wong DT. Exon-level expression profiling: a comprehensive transcriptome analysis of oral fluids. Clin Chem. 2008 May; 54(5):824-32. view on PubMed

Wong DT. Salivary Diagnostics: Amazing as it might seem, doctors can detect and monitor diseases using molecules found in a sample of spit. Am Sci. 2008 Jan 01; 96(1):37-43. view on PubMed

Zimmermann BG, Wong DT. Salivary mRNA targets for cancer diagnostics. Oral Oncol. 2008 May; 44(5):425-9. view on PubMed

Hu S, Yen Y, Ann D, Wong DT. Implications of salivary proteomics in drug discovery and development: a focus on cancer drug discovery. Drug Discov Today. 2007 Nov; 12(21-22):911-6. view on PubMed

Hu S, Wong DT. Oral cancer proteomics. Curr Opin Mol Ther. 2007 Oct; 9(5):467-76. view on PubMed

Zimmermann BG, Park NJ, Wong DT. Genomic targets in saliva. Ann N Y Acad Sci. 2007 Mar; 1098:184-91. view on PubMed

Hu S, Loo JA, Wong DT. Human saliva proteome analysis. Ann N Y Acad Sci. 2007 Mar; 1098:323-9. view on PubMed

Zhou X, Temam S, Oh M, Pungpravat N, Huang BL, Mao L, Wong DT. Global expression-based classification of lymph node metastasis and extracapsular spread of oral tongue squamous cell carcinoma. Neoplasia. 2006 Nov; 8(11):925-32. view on PubMed

Park NJ, Li Y, Yu T, Brinkman BM, Wong DT. Characterization of RNA in saliva. Clin Chem. 2006 Jun; 52(6):988-94. view on PubMed

Gu F, Lux R, Du-Thumm L, Stokes I, Kreth J, Anderson MH, Wong DT, Wolinsky L, Sullivan R, Shi W. In situ and non-invasive detection of specific bacterial species in oral biofilms using fluorescently labeled monoclonal antibodies. J Microbiol Methods. 2005 Aug; 62(2):145-60. view on PubMed

Zhou X, Rao NP, Cole SW, Mok SC, Chen Z, Wong DT. Progress in concurrent analysis of loss of heterozygosity and comparative genomic hybridization utilizing high density single nucleotide polymorphism arrays. Cancer Genet Cytogenet. 2005 May; 159(1):53-7. view on PubMed

Kim Y, Ohyama H, Patel V, Figueiredo M, Wong DT. Mutation of Cys105 inhibits dimerization of p12CDK2-AP1 and its growth suppressor effect. J Biol Chem. 2005 Jun 17; 280(24):23273-9. view on PubMed

Hu S, Denny P, Denny P, Xie Y, Loo JA, Wolinsky LE, Li Y, McBride J, Ogorzalek Loo RR, Navazesh M, Wong DT. Differentially expressed protein markers in human submandibular and sublingual secretions. Int J Oncol. 2004 Nov; 25(5):1423-30. view on PubMed

Zhou X, Mok SC, Chen Z, Li Y, Wong DT. Concurrent analysis of loss of heterozygosity (LOH) and copy number abnormality (CNA) for oral premalignancy progression using the Affymetrix 10K SNP mapping array. Hum Genet. 2004 Sep; 115(4):327-30. view on PubMed

St John MA, Li Y, Zhou X, Denny P, Ho CM, Montemagno C, Shi W, Qi F, Wu B, Sinha U, Jordan R, Wolinsky L, Park NH, Liu H, Abemayor E, Wong DT. Interleukin 6 and interleukin 8 as potential biomarkers for oral cavity and oropharyngeal squamous cell carcinoma. Arch Otolaryngol Head Neck Surg. 2004 Aug; 130(8):929-35. view on PubMed

Zhou X, Cole SW, Hu S, Wong DT. Detection of DNA copy number abnormality by microarray expression analysis. Hum Genet. 2004 Apr; 114(5):464-7. view on PubMed