The Mouse Cancer Genetics Program (MCGP) was established by Dr. Neal Copeland in 1999 and is currently directed by Dr. Lino Tessarollo. Dr. Shyam Sharan is Deputy Director. Members of the MCGP use molecular mouse genetics as a primary tool to better understand the fundamental processes underlying mammalian development and disease. Major areas of focus include developmental mechanisms and pathways usurped in cancer, stem cell and cancer-propagating cell function, genome integrity control, tumor suppressor function, transcriptional and epigenetic regulation, hematopoiesis, neurotrophin-activated signaling pathways, angiogenesis and proteomic instability in cancer. In addition, the MCGP runs world-class transgenic (headed by Mrs. Debbie Swing) and knockout (headed by Dr. Tessarollo) mouse cores, used by many investigators in the CCR as well as the wider NCI research community.
Recombineering Technology. The MCGP provides training and guidance not only to CCR investigators but also to scientists worldwide in the use of the recombineering technology (originally developed by Dr. Donald Court and Drs. Neal Copeland and Nancy Jenkins). This technology allows cloned DNA to be manipulated in E. coli by homologous recombination rather than by restriction enzymes and DNA ligases. This technology, which is continually being improved, is being used by hundreds of laboratories throughout the world and makes it possible to perform functional genomic studies on a scale that was difficult if not nearly impossible in the past.
Tumor Angiogenesis Unit. Tumors depend on neovasculature for expansive growth and metastasis. Anti-angiogenic therapies that block the VEGF/VEGFR pathway have become a common component of cancer treatment strategies, but are limited by the existence of VEGF-independent angiogenesis mechanisms. The goal of the Tumor Angiogenesis Unit is to better understand and exploit these VEGF-independent angiogenesis mechanisms. Dr. St Croix’s group pioneered the development of methods to uncover molecules expressed on tumor vasculature. This new molecular information on tumor angiogenesis is being used to develop clinically useful agents for improved diagnostics and therapeutics of cancer. The Tumor Angiogenesis Unit is lead by Drs. Tessarollo and St. Croix.
Neural Development. The Neural Development Section is headed by Dr. Lino Tessarollo, who joined the MCGP in 1999. His laboratory studies neurotrophins and their receptors in development and disease. These genes are critical players in the development of the nervous system of vertebrates and have attracted great interest as potential therapeutic targets for the management of neurodenerative disorders. Trk receptors are also frequently overexpressed in human cancers, particularly those with aggressive behavior and poor prognosis. Thus, while suppression of Trk-activated pathways may contribute to tumor management, strategies aimed at improving neurotrophin-mediated activities may also be beneficial to the control of neurodegenerative diseases. Dr. Tessarollo's laboratory focuses on the identification of specific neurotrophin-activated pathways that affect cell survival but do not affect cell proliferation. This information is then used to generate animal models in which the effects of these mutations on normal development and function of the nervous system can be studied. The aim of Dr. Tessarollo's research is to generate in vivo data that may lead to a better pharmacological use of neurotrophins to control cell proliferation and differentiation.
Genetics of Cancer Susceptibility. The Genetics of Cancer Susceptibility Section is headed by Dr. Shyam K. Sharan, who joined the MCGP in 1999. Mutations in the BRCA1 and BRCA2 genes play an important role in the development of early-onset familial breast cancer. The goal of this section is to carry out functional dissection of these genes using a mouse model system. Since there was no good functional assay for studying the in vivo effects of the large documented collection of human BRCA1 or BRCA2 mutations, they generated bacterial artificial chromosome (BAC) transgenic mice carrying the wild-type human BRCA1 and BRCA2 genes. These transgenes were then introduced into mice that lacked the endogenous Brca1 or Brca2 genes. In each case, the human genes rescued the lethality normally associated with the loss of both copies of the mouse Brca genes. Transgenic humanized mice now provide a valuable model system for understanding the functional significance of disease-associated mutations identified in human BRCA1 and BRCA2 patients. That is, specific mutations are introduced into the respective BAC and the BACs are then introduced into the germ line of mice lacking the endogenous Brca gene. The mice are then assessed for viability and characterized in many ways, including determining whether tumors develop. Although the humanized mice are excellent in vivo models for understanding the functional significance of the human mutations, they are not ideally suited for characterizing a large number of mutations. Therefore, members of the section are developing a new embryonic stem (ES) cell-based functional assay that should make it possible to rapidly screen large numbers of mutations. The long-term objective of this research is to comprehensively delineate the biological function of BRCA1 and BRCA2. In doing so, they hope to understand how the mutations that are scattered throughout the length of these genes lead to cancer.
Dr. Sharan is also Director of the Center for Advanced Preclinical Research (CAPR).
Eukaryotic Transcriptional Regulation. The Eukaryotic Transcriptional Regulation Section is headed by Dr. Peter F. Johnson, who joined MCGP in 2013. Dr. Johnson was part of LCP before joining MCGP. His laboratory 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.
Hematopoiesis and Stem Cell Biology. The Hematopoiesis and Stem Cell Biology Section is headed by Dr. Jonathan R. Keller. In 2013, Dr. Keller joined MCGP and prior to becoming part of MCGP he was with LCP. His laboratory studies the transcriptional regulation of stem cell quiescence, survival, self-renewal, and differentiation. The goal is 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.
Epigenetics. The Epigenetics Section is headed by Dr. Kathrin Muegge. In 2013, Dr. Muegge joined MCGP and prior to that she was part of LCP. The group 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.
Proteomic Instability of Cancer. The Proteomic Instability of Cancer Section is headed by Dr. Chengkai Dai who joined MCGP in 2016 as a Stadtman Investigator. Dr. Dai's laboratory is a pioneer in the field of proteomic instability of cancer. The recent findings from his laboratory have revealed the intimate interactions between the proteotoxic stress response and RAS/MAPK-MEK signaling, cell cycle regulation, protein translation, as well as tumor-suppressive amyloidogenesis. His ongoing research focuses on the molecular mechanisms through which proteomic instability may affect genomic stability, cell invasion, and autophagy, areas which hold promise to unveil new molecular pathways that could be targeted in cancer therapy.
Molecular Biology of Selenium. Dr. Dolph Hatfied is currently a Scientist Emeritus with the Mouse Cancer Genetics Program. Dr. Hatfield was head of the Molecular Biology of Selenium Section. The major aims of his laboratory were 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. The laboratory's 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, they 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.
Tumor Growth Factor. Dr. David Salomon is currently a Scientist Emeritus with the Mouse Cancer Genetics Program. Dr. Salomon was head of the Tumor Growth Factor Section. The major aims of his laboratory was 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. His laboratory has already identified Cripto-1 as a therapeutic target in breast, colon and lung cancer and they 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.
Metabolism and Cancer Susceptibility. Dr. James Phang is currently a Scientist Emeritus with the Mouse Cancer Genetics Program. Dr. Phang was head of the Metabolism and Cancer Susceptibility Section. Dr. Phang’s laboratory has pioneered studies of the regulatory functions of the amino acid, proline. His discoveries provided seminal insights into tumor reprogramming and metabolic epigenetics and introduced novel strategies for cancer therapy.
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Dr. Sharan is also Director of the Center for Advanced Preclinical Research (CAPR).