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| Dan Notterman Webpage | coming soon |
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| Lewis Thomas Lab-224 | Faculty Assistant: |
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| Lab Phone: 609-258-2531 | Phone: 609-258-1694 |
Tumor Biology; Gene-Environment Interactions in Children's Development
For several years my laboratory has studied molecular events that support the initiation and propagation of cancer. Most of the work of the lab is organized around the theme that cancer should be approached by correlating the global clinical, genetic, epigenetic and functional (mRNA expression) characteristics of the patient and his/her malignancy. We use colon cancer as a model system, because of the availability of tissue of varying stages and because of its public health importance. To this end, my collaborators and I have developed a comprehensive molecular profile across almost 400 colon samples in about 280 patients. In addition to developing new approaches to correlating different classes of data, the lab is also looking to understand the interaction of the cumulative mutational burden, polymorphisms in p53 pathway genes, and gender on response to therapy, ultimate outcome, and age of onset. In all, we have about 200 genetic and clinical fields of information for each of the 400 samples in our database. Lately we have developed computational models to integrate our extensive and unique colon cancer databases.
Starting from this colon cancer database, we have identified several important candidate genes for study. One example is informative: we observed that the alpha chemokine CXCL1, usually considered to be a player in mediating the acute immunological and wound-healing response, is hijacked by colon cancer cells to foster the growth and spread of the tumor. These experiments with CXCL1 are of direct importance to the human tumor because several experimental compounds known to block the interaction between CXCl1 (and CXCl3) and the receptor, CXCR2, offer the possibility of targeted chemotherapy. We are currently studying the effect of these compounds in cell culture on colon cancer and melanoma, where CXCL1 is also over-expressed. Initial experiments have been successful—the compounds inhibit growth. We are now planning to move this work from the cell culture to the whole animal model. Our long-range goal is to learn if these compounds can prevent or attenuate colon cancer development or melanoma progression in individual with a high-risk of developing the disease.
Gene-Environment Interactions in at Risk Woman and Children
Many complex human phenotypes result from interactions between functional polymorphisms in central nervous system pathways and specific environmental stressors. For example, children exposed to maltreatment or abuse often grow up to develop antisocial behaviors such as violence toward others. However, some children seem protected from this unhappy outcome. Why? One possibility is that these individuals have a functional polymorphism in the neurotransmitter degrading enzyme monoamine oxidase gene A (MAOA) that increases the enzymes activity. This increase in MAO activity seems to reduce the likelihood of developing violent or other anti-social behavior as an adult. This is an example of a gene-environment interaction (G x E), because both an adverse environment (maltreatment) and an adverse genotype (low MAOA expression) are needed to produce the “violent” phenotype (see, Caspi, A. et al, 2002. Role of genotype in the cycle of violence in maltreated children. Science 297:851–854). To learn more about G X E interactions and childhood development, my lab has recently partnered with the The Fragile Families and Child Well-being Study, a nationally representative, longitudinal study of approximately 4,900 new parents, followed from birth until the child is age nine. The program includes a large cohort of non-marital births, providing a large proportion of low-income families in the sample, a group that has heretofore been neglected in much of the literature on gene-environment interactions. The FFCWS, based at Princeton, contains detailed measures of key environmental variables including material hardship, neighborhood or social disorganization, and stressful family environments. In addition, at the 9-year wave of data collection, samples of DNA are being collected from mothers and children. My lab is serving as the Core DNA Resource, and is developing high-throughput genotyping techniques for evaluating polymorphic genes, such as 5-HTT, MAOA, and DRD2 and about 10 others, that may interact with a stressful environment to foster substance abuse, violence, anxiety, and depression. We are preparing to study how the stressful life of the single mother—often from a minority community with limited access to health care and other support systems—interacts with functional genetic polymorphisms to affect her ability to cope with a difficult and stressful environment. One study examines the effect of several gene polymorphisms on substance abuse in the mother; another will test the hypothesis that depression and anxiety syndromes are conditioned by interactions between specific maternal genotypes and the involvement of the father in support and parenting. The long-term goal is better understand how genetics and environment interact to produce specific types of personality and behavior.
Selected Publications
Bacolod MD, Schemmann GS, Wang S, Shattock R, Giardina SF, Zeng Z, Shia J, Stengel RF, Gerry N, Hoh J, Kirchhoff T, Gold B, Christman MF, Offit K, Gerald WL, Notterman DA, Ott J, Paty PB, Barany F. (2008) The signatures of autozygosity among patients with colorectal cancer. Cancer Res. [Epub ahead of print]
Gavert N, Sheffer M, Raveh S, Spaderna S, Shtutman M, Brabletz T, Barany F, Paty P, Notterman D, Domany E, Ben-Ze'ev A. (2007) Expression of L1-CAM and ADAM10 in human colon cancer cells induces metastasis. Cancer Res. 67: 7703-7702. PebMed
Hertzberg l, Betts R, Raimondi S, Schäfer B, Notterman D, Doman E, Izraeli S. (2007) Prediction of chromo-somal anueploidy from gene expression data. Genes Chromosomes Cancer. 46: 75-86. PubMed
Hanna N, Weinberger B, Notterman, D. (2006) The Cell. In A. Slonim & M. Pollack(Eds.), Pediatric Critical Care Medicine. Philadelphia: Lippincott Williams & Wilkins.
Stevens J, Notterman D. (2006) Personalizing medicine: The single nucleotide polymorphism and the treatment of status asthmaticus Pediatr Crit Care Med. 7: 87-89. PubMed
Cheng Y, Shawber C, Paty P, Notterman D, Barany F. (2006) Multiplexed profiling of candidate genes for CpG island methylation status using a flexible PCR/LDR/Universal Array assay. Genome Res. 16: 282-289. PubMed
Tsafrir D, Selvanayagam Z, Tsafrir I, Shia J, Zeng Z, Sheffer M, Liu H, Krier C, Stengel R, Barany F, Gerald W, Paty P, Domany E, Notterman DA. (2006) Relationship of gene expression and chromosomal abnormalities in colorectal cancer. Cancer Res. 66: 2129-2137. PubMed
Schaar D, Liu H, Sharma S, Krier C, Ciardella M, Osman M, Goodell L, Notterman DA, Strair R. (2005) TPA-induced phosphatase expression in AML cell survival. Leuk Res. 29: 1171-1179. PubMed
Tsafrir D, Tsafrir I, Ein-Dor L, Zuk O, Notterman DA, Domany E. (2005) Sorting points into neighborhoods (SPIN): Data analysis and visualization by ordering distance matrices. Bioinformatics 21: 2301-2308. PubMed
Getz G, Gal H, Kela I, Notterman, DA, Domany E. (2003) Coupled two-way clustering analysis of breast cancer and colon cancer gene expression data. Bioinformatics 19: 1079-1089.
Notterman DA, Alon U, Sierk AJ, Levine AJ. (2001) Transcriptional gene expression profiles of colorectal adenoma, adenocarcinoma, and normal tissue examined by oligonucleotide arrays. Cancer Res. 61: 3124-3130.