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Curtis C. Harris, M.D.
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Our continuing research projects utilize an integrative biology and translational strategy that addresses facets of the NCI strategic objectives: (a) Understand the causes and mechanisms of cancer; (b) Improve early detection and diagnosis; (c) Understand the factors that influence cancer outcomes; and (d) Overcome cancer health disparities. (The NCI Strategic Objectives; the Nation's Investment in Cancer Research, FY2009) As described in the overview of LHC, our strategy and strength is to conduct laboratory-epidemiological investigations and to mentor young investigators.
Project 1: Biomarkers in Cancer Diagnosis, Prognosis, and Therapeutic Outcome Biologically relevant biomarkers may help guide therapeutic decisions for cancer patients. Chronic inflammation and infection are major causes of cancer. Key mediators of inflammation-induced cancer include nuclear factor kappa B, reactive oxygen and nitrogen species, inflammatory cytokines, prostaglandins and specific microRNAs (miRNAs). The collective activity of these mediators is largely responsible for either a pro-tumorigenic or anti-tumorigenic inflammatory response through changes in cell proliferation, cell death, cellular senescence, DNA mutation rates, DNA methylation and angiogenesis. These studies require multiple cohorts to conduct ethnic, racial or geographic analyses including biological factors of health disparity, e.g., Norway Lung Cancer Cohort (A. Haugen), Japanese Lung Cancer Cohort (J. Yokota), German Colon Cancer Cohort (M. Mohler), Japanese Colon Cancer Cohort (W. Yasui), Hong Kong Colon Cancer Cohort (S.Y. Leung), and prospective MD Anderson Colon Cancer Cohort (S. Kopetz). We are investigating connections between inflammation, miRNAs, metabolomics, microbiome, and cancer; highlighting how our improved understanding of these connections may provide novel preventive, diagnostic, prognostic, and therapeutic strategies to reduce the health burden of cancer. Thus our program strongly emphasizes molecular mechanisms of miRNAs and cytokines and their association with human cancer diagnosis, prognosis, and therapeutic outcomes.
A continuing aim of our research is to identify diagnostic, prognostic and predictive biomarkers that can provide actionable information to guide medical decisions for cancer patients. We and our collaborators have a strong publication history in the field of cancer biomarkers. We continue to build on this foundation and contribute to the international effort by both translational and clinical cancer researchers, (referenced in [1-8]). Of critical importance is the development of diagnostic biomarkers to identify individuals with early stage cancer or those at high risk of developing cancer. Prognostic biomarkers that can guide therapeutic decisions, especially in early stage patients, are equally important. Over the last four years, we have been successful at publishing several biomarker-related manuscripts in lung, colon and esophageal cancer. These studies use a variety of techniques to examine the profiles of miRNAs and inflammation genes as they relate to cancer diagnosis, prognosis and therapeutic outcome. In our studies, we routinely begin by using tissues from cancer patients recruited through the NCI-MD resource contract and we then validate relevant findings in independent cohorts from various regions of the world. Our strategy is aimed at finding associations that are generalizable to cancer populations globally and not limited to one study population. Our goals are in line with the research objectives of "Improving Early Detection and Diagnosis" and "Understanding the Mechanisms of Cancer" as laid out in the 2013 NCI Congressional Budget Justification. Over the next four years we continue to use next-generation omics-based approaches to identify molecular characteristics of early stage cancer that are responsible for aggressive disease. This includes using metabolomic strategies to determine if blood and urine-based metabolites are diagnostic and prognostic biomarkers for lung cancer and begin studies examining the microbiome and how it can affect prognosis and therapeutic outcomes of colon cancer.
Project 2: Integrative Molecular Epidemiology of Human Cancer
Gene-environment interaction is a seminal concept in the integrative molecular epidemiology of human cancer. Our ongoing case-control studies (using population-based controls) focus on lung cancer, a tobacco-related cancer, and colon cancer, a cancer type more associated with chronic inflammation. These studies require the integration of data from genome associated studies, analyses of carcinogen exposure, rapidly developing technologies, bioinformatics, social-ethical concerns, and epidemiological study-design methods. Moreover, they integrate the hypothesis, aims, and demographic characteristics of study subjects from multiple investigations. We also validate our results with independent cohorts, e.g., the prospective Southern Community Cohort Study and Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, and Mayo Clinic Never Smoker Lung Cancer Cohort. We have a long standing interest and record of accomplishments of health disparities studies including African American (AA) and European American (EA) cohorts. We are currently finishing the analysis of a Genome Wide Association Study (GWAS) of AA Lung Cancer Cases. Functional studies of these single nucleotide polymorphisms (SNPs) in coding and non-coding genes that are uniquely associated with AAs have been initiated.
We and our collaborators have been longtime contributors to the field of molecular epidemiology. Our continuing research projects complement the research objectives of "Improving Early Detection and Diagnosis" and "Understanding the Mechanisms of Cancer" as laid out in the 2013 NCI Congressional Budget Justification and NCI’s research priorities to improve early detection and prognosis and to understand the causes of cancer. We have focused on an integrative epidemiological approach to our studies. This has meant the inclusion of new high-throughput platforms for genotyping, such as SequenomTM and FluidigmTM (TaqMan), and omics platforms such as NanostringTM and methylation arrays. We have leveraged the expansive design of the case-control study resource to integrate molecular and biological data into our epidemiological studies. Moreover, with an appreciation for the power that large-scale collaborative studies can provide, we have contributed to several national and international consortia to create a genomic map of recombination in AA and explore the contribution of genetic mosaicism to cancer. We have participated with our colleagues in the International Lung Cancer Consortium in several pooled epidemiological analyses, including one to assess the contribution of family history to lung cancer. Recently, we conceived, and are leading, a multi-center study to explore the genetic and biological basis of racial health disparity through the first GWAS of lung cancer in AA. We are also incorporating Ancestry Informative Markers (AIM) to control for confounding by population admixture.
Project 3: p53, Aging and Cancer
The p53 network is an intrinsic monitoring and responsive pathway of telomeric attrition involved in cellular aging and senescence. Cellular senescence is a tumor suppressive mechanism that can be activated by p53 in cancer cells. We are currently studying the molecular mechanisms of cellular senescence in normal human cells and the role of the telometric multiprotein complex, shelterin, that includes TRF2 in aging and carcinogenesis; David Lane, Ettore Appella and Thomas Zheng are collaborators. Our research focuses on integrative p53 and miRNA networks in tumor suppression and the functional role of p53 isoforms, e.g., “dominant negative” delta133p53 and “co-transactivator” of p53, p53beta, both as natural regulators of cellular senescence and stem cell biology and their dysregulation in cancer.
p53 regulates cellular stress responses, including cellular senescence, which functions as a tumor suppressor mechanism in vivo and may contribute to organismal aging in humans. Natural p53 protein isoforms are produced via alternative splicing (e.g., p53beta isoform) or usage of alternative promoters (e.g., delta133p53 isoform) and may be degraded via an isoform-specific protein turnover mechanism. These p53 isoforms likely play physiological roles in p53-regulated cellular senescence in vivo during carcinogenesis and aging. The p53-mediated regulation of pluripotent stem cells, such as human embryonic stem cells (hESC) and induced pluripotent stem cells (iPSC), normal tissue stem cells and cancer stem cells may also be modulated by these p53 isoforms.
This page was last updated on 11/18/2013.