Our Science – LCP Website

Laboratory of Cancer Prevention

Research

(For current overviews of our research from our 2009 Site Visit report - see the "Links" page.)

The Laboratory of Cancer Prevention (LCP) investigates the molecular basis of cellular processes that, when perturbed, can lead to cancer induction and progression. Discovery and characterization of molecular targets for cancer prevention and intervention is a common area of interest among the seven principal investigators in the LCP.

Members of the LCP are active in the NCI/CCR Cancer Prevention Faculty as well as in the Molecular Targets and the Cell Molecular Developmental Biology faculties. Collaborations with members of the Cancer Prevention Faculty aim to generate preclinical prevention outcomes that inform human clinical prevention trials.

The Gene Regulation Section (Nancy Colburn, Ph.D.) investigates gene regulation events that drive carcinogenesis and can be exploited for cancer prevention. Of particular interest is the activation of oncogenic transcription factors AP-1 and NFkB and of the novel tumor suppressing translation inhibitor Pdcd4. Mice genetically engineered for resistance to carcinogenesis are used to validate known targets and to discover new targets. Human cancer cell models are used to test applicability of molecular targeting for intervention in human disease.

In collaboration with both NCI scientists and our colleagues in universities, the GRS continues its work on identification of biomarkers for response to chemoprevention of colon cancer. Dietary interventions are being used to prevent colon carcinogenesis in genetically obese and non-obese mice and to discover response biomarkers. An ongoing study is identifying early biomarkers of response to bean diet interventions in humans under conditions in which the risk of adenoma recurrence is reduced.

The The Cancer Stem Cell Section (William L. Farrar, Ph.D.) studies genomic and epigenomic regulation in normal and cancer stem cell differentiation. Current focus is on understanding the role of inflammation in breast and prostate cancer stem cell development and in targeting these inflammatory processes for cancer prevention and intervention.

The Molecular Biology of Selenium Section (Dolph Hatfield, Ph.D.) Our major aims are to understand the molecular mechanisms by which selenium and selenium-containing proteins (selenoproteins) provide essential roles in development, cancer prevention and human health and the means by which selenium is incorporated into protein as selenocysteine, the 21st amino acid in the genetic code. Our conditional knockout mouse models provide a means of assessing the biological roles of selenoproteins in diseases and in development. By modifying specific RNAi technology methods, we developed unique vectors for 1) simultaneously knocking down multiple proteins and their individual reintroduction as mutant or wild type proteins, 2) specifically knocking down and reintroducing mutant selenoproteins to study their function in preventing and promoting malignancy and 3) elucidating how selenium is inserted into protein.

The Eukaryotic Transcriptional Regulation Section (Peter F. Johnson, Ph.D.) studies transcriptional mechanisms that regulate cell proliferation, tumorigenesis, and tumor suppression. Research involves a combination of biochemistry, cell biology, and mouse genetics to investigate the regulation and function of C/EBP transcription factors, focusing on their roles in Ras-induced oncogenic transformation and senescence.

The Hematopoiesis and Stem Cell Biology Section (Jonathan R. Keller, Ph.D) studies the transcriptional regulation of stem cell quiescence, survival, self-renewal, and differentiation. We seek to understand how commitment to specific lineages is programmed and cell specific patterns of gene expression are established. Current studies are focused on defining the role of transcriptional regulators in myeloid cell development and their potential role in leukemogenesis.

The Epigenetics Group (Kathrin Muegge, M.D.) investigates heritable chromatin modifications that are crucial for normal embryogenesis. Using a mouse model that shows defects in genomic methylation and histone tail modifications they study the effects of perturbed chromatin structure on gene silencing, imprinting, mitosis and tumorigenesis. Understanding molecular pathways of chromatin modifications should lead to better targeting of epigenetic dysregulations occurring in cancer development.

The Retroviral Pathogenesis Section (Sandra Ruscetti, Ph.D.) understanding the molecular basis for the pathogenesis of retrovirus-induced diseases. We have been studying retroviruses that cause leukemia or neurological disease in rodents to obtain basic information on how molecular changes in normal cells result in pathological consequences. By providing important information about the cause of disease, these animal models are invaluable for designing studies to understand the biological effects of related human retroviruses and for identifying and validating molecular targets relevant to human diseases for their prevention and treatment.

The Tumor Growth Factor Section (David Salomon, Ph,D) is devoted to understanding the role of embryonic genes and signaling pathways controlled by these genes in rodent and human mammary stem cells and in the maintenance and self-renewal of breast cancer stem cells. Of particular interest is the function of Cripto-1/TDGF-1 in regulating stem cell functions. In vitro cell models and in vivo mouse transgenic and knockout models are being employed to delineate the mechanism(s) by which Cripto-1 might regulate stem cell identity and cancer progression in the mammary gland. We have already identified Cripto-1 as a therapeutic target in breast, colon and lung cancer and are currently attempting to screen for other drugs or small molecules that might attenuate other stem cell-related signaling pathways such as Wnt and Notch and that might potentially synergize with anti-Cripto-1 agents in eradicating tumor cell growth, progression and cancer stem cell populations.

Adjunct Investigators:

Dr. Yinling Hu heads the Inflammation and Tumorigenesis Section of the Laboratory of Experimental Immunlogy, CCR. Dr. Hu's laboratory studies the mechanisms of skin and lung tumorigenesis, the effect of inflammatory microenvironments on skin and lung tumorigenesis in the absence of inhibitor of NF kappa B kinase-alpha (IKKalpha), and the role of IKKalpha in the development of lymph cells and organs.

Dr. P. Charles Lin heads the Vascular Biology Section of the Mouse Cancer Genetics Program, CCR. Dr. Lin's laboratory studies the mechanisms that govern angiogenesis and vascular homeostasis in cancer with a focus on the interaction between inflammation and pathological angiogenesis. Current research comprises three areas: 1) Role of myeloid suppresser cells in regulation of the tumor microenvironment, 2) Vascular integrity and endothelial-to-mesenchymal transformation (EMT) in tumor progression and 3) The genetic differences in vasculature between human and other species.

Dr. James M. Phang heads the Metabolism and Cancer Susceptibility Section of the Laboratory of Comparative Carcinogenesis, CCR, focusing on the role of proline in metabolic signaling. These studies are based on the special properties of proline; its abundance in collagen, and on the localization and redox mechanisms of the enzymes of this metabolic pathway. Specific components of this regulatory axis are modulated by p53, PPARgamma, c-Myc, and AMPK. Depending on context, the proline metabolic system plays an important role in reprogramming the cell in apoptosis, autophagy, energy metabolism, and epigenetic regulation.

This page was last updated on 10/5/2012.