Focusing diagnostics and therapeutics on those most likely to benefit is a key to successful intervention at both the public health and clinical levels. The translational goal of the Spivack laboratory is to identify individuals at particularly high risk for lung malignancy, and selected non-malignant lung diseases, upon whom to focus smoking/toxin exposure cessation (primary prevention), chemoprevention (secondary prevention), and early disease detection efforts (disease screening, tertiary prevention).
The laboratory is currently exploring individual Gene x Environment signatures as susceptibility markers by exploring quantitative gene (mRNA) expression phenotypes, and the DNA sequence, methylation, microRNA, and other epigenetic features potentially underlying these expression phenotypes, in vitro and in human populations. This is performed in the setting of defined tobacco, diet, and other exposures. There are both mechanistic and translational components to the studies.
Mechanistically, the role of epigenetic variation in promoter regions in the 5' and 3' regulatory regions of carcinogenesis and oxidant pathway genes is being explored in vitro, using human genomic DNA reporter constructs, and native gene regulation models. High resolution technologies include the realtime quantitation of native mRNA and microRNA by the laboratory's RNA-specific strategy (patented); the tagged-bisulfite genomic sequencing strategy to determine single base resolution CpG methylation status (tBGS, patented); an experimental strategy for assaying microRNA binding to mRNA, for determining the role of miRNA in candidate gene regulation (patented); and evaluation of functional consequences of DNA methylation detail, using a novel patch reporter construct (patented). A new method to engineer methyl-cytosines into the epigenome has recently been developed.
Whole (epi)genome approaches to identify molecular events unique to lung cancer are being completed, which will represent one of the initial cross-platform 'omics level discovery examinations of lung tissues. The execution of each individual discovery platform involves expert local collaborators and cores in (epi)genetics and genomics, and the "integromics" is critically reliant on Einstein strengths in informatics and biostatistical analyses.
Translationally, human lung carcinogenesis biomarkers are being established by pairing laser capture microdissected lung with several unique, non-invasively collected surrogate specimens developed in the laboratory. These include mRNA expression signatures from brush-exfoliated buccal mucosa cells, and microRNAs detected in exhaled breath condensate, representing first reports for a new exhaled airway biomarker class. These airway-derived specimens continue to accrue from a sampling (currently n>1000) of a population assembled in a lung cancer case-control context. The specimens are being studied with a view toward non-invasive assays in populations.
The overall aim is to develop informative non-invasive risk profiling, preventive, and early disease detection strategies for the lung in human populations.
Work is funded by ongoing NIH, DoD, and Foundation support.
Selected Publications/Manuscripts, as of January, 2016:
Mullapudi N, Ye B, Suzuki M, Wang T, Fazarri M, Han W, Shi M, Marquardt G, Lin J, Wang T, Keller S, Zhu C, Locker J, Spivack SD. Genome-wide methylome alterations in lung cancer PLoS ONE, Dec. 2015.
Lin J, Marquardt G, Mullapudi N, Wang, T, Han W, Shi W, Zhu C, Keller S, Zhu C, Locker J, Spivack SD. Lung cancer transcriptomes refined with laser capture microdissection. Am J Pathology 06.028. 2014 .
Han W, Shi M, Spivack SD. Site-specific methylated reporter constructs for functional analysis of DNA methylation. Epigenetics 4; 8(11), 2013.
Shi M, Han W, Spivack SD. A quantitative method to identify miRNAs targeting an mRNA using a 3'UTR RNA affinity technique. Analytic Biochem 1;443(1):1-12, 2013.
Alberg AJ, Brock MV, Ford JG, Samet JM, Spivack, SD. Epidemiology of lung cancer. In Evidence-based Practice Guidelines. Diagnosis and Management of Lung Cancer (ACCP position statement). CHEST. May 2013;143(5 Suppl):e1S-e29S. doi: 10.1378/chest.12-2345. PMID: 23649439.
Tan XT, Marquardt G, Shi M, Han W, Spivack SD. High throughput library screening identifies phytochemical inducers of phase II mutagen/oxidant metabolism enzymes GSTP1 and NQO1 in human lung cells. Am J Resp Cell Molec Biol, 46(3): 365-71, 2012.
Brock GJ, Moschos S, Spivack SD, Hurteau GJ. The 3' prime paradigm of the miR-200 family and other microRNAs. Epigenetics (6:3, 1-5), 2011.
Tan XT, Shi M, Minna JD, Han W, Spivack SD. Candidate phytopreventive agent modulation of phase II metabolism enzymes GSTP1 and NQO1 in human bronchial cells. J Nutrition, 140(8): 1404-10, 2010.
Tan, XT, Wang T, Xiong S, Kumar SV, Han W, Spivack SD. Smoking-related gene expression in laser capture microdissected human lung. Clin Cancer Res, 15(24): 7562-70, 2009.
Han W, Tang T, Reilly AA, Keller S, Spivack SD. Gene promoter methylation analyses from exhaled breath, with differences in smokers and lung cancer cases. Resp Res, 10:86 epubl, 2009.
Tan X-L, Moslehi R, Han W, Spivack SD. Haplotype tagging single nucleotide polymorphisms in the glutathione S-transferase P1 gene promoter and susceptibility to lung cancer. Cancer Detection Prev,32:403-415, 2009.
Tan X-L, Spivack SD. Dietary chemoprevention strategies for induction of phase II metabolism: a review. Lung Cancer,65(2):129-37, 2009.
Hurteau GJ, Carlson AJ, Spivack, SD, Brock GJ. Restoration of E-Cadherin expression by over-expression of the microRNA hsa-miR-200c via reduced expression of the transcription factor TCF8. Cancer Res. 67:7972-76, 2007.
Hurteau, GJ, Spivack SD, Brock G. Parallel identification of miRNA and target mRNA by combined informatics and qRT-PCR approaches: application to has-miR-200c. Cell Cycle 5(17):1951-56, 2006.
Han W, Cauchi S, Herman JG, Spivack SD. Methylation mapping of DNA by tag-modified bisulfite genomic DNA sequencing. Analytic Biochem. 355: 50-61, 2006.
Cauchi S, Han W, Kumar SV, Spivack SD. Haplotype-environment interactions regulating the human GSTP1 promoter Cancer Res. 66(12): 6439-6448, 2006.
Kumar SV, Hurteau GJ, Spivack SD. Validity of mRNA expression analyses of human saliva. Clin. Cancer Res. 12: 5033-39, 2006.
Spivack SD, Hurteau GJ, Jain R, Kumar SV, Aldous KM, Gierthy JF, Kaminsky LS. Gene-environment interaction signatures by quantitative mRNA profiling in exfoliated buccal mucosal cells. Cancer Res, 64:6805-6813, 2004.
Spivack SD, Hurteau GJ, Fasco MJ, Kaminsky LS. Phase I and II carcinogen metabolism gene expression in human lung tissue and tumors. Clinical Cancer Research, 9:6002-6011, 2003.
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