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Mouse Cancer Genetics Program

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Overview

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. Currently, the MCGP consists of 11 investigators. 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 the role of selenium in cancer prevention.

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.

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 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.

Molecular Biology of Selenium
The Molecular Biology of Selenium Section is headed by Dr. Dolph Hatfield, who joined MCGP in 2013. Before joining MCGP, Dr. Hatfield was part of the Laboratory of Cancer Prevention. The major aims of his laboratory 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. 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.

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.

Vascular Biology
The Vascular Biology Section is headed by Dr. P. Charles Lin who joined the MCGP in August, 2010. Vascular biology plays a vital role in the progression of many debilitating diseases including: cancer, diabetes, and heart disease. Vascular disease is the most common cause of death and disability in Western societies. Understanding the vascular system is critical in the war against these diseases. Research in Dr. Lin's laboratory centers on the mechanisms that govern blood vessel formation (angiogenesis) and vascular homeostasis in cancer. Vascular networks form to satisfy the metabolic demands of tissue growth during development. When we reach adulthood, the vascular endothelium becomes quiescent. However, under disease conditions, this delicate balance is disturbed and endothelium is reactivated. What distinguishes physiological angiogenesis during normal growth from pathological angiogenesis in diseases is an important question, which has major implications in therapeutic interventions. Dr. Lin's group believes the major difference is inflammation. Their working hypothesis is that tissue injury/insult leads to inflammation, which then triggers pathological angiogenesis. To this end, they are focusing on the interaction between inflammation and pathological angiogenesis, which offer the potential to preferentially target angiogenesis in disease conditions and spare normal blood vessels. Dr. Lin's group combines genetic and biochemical approaches, in vitro, three-dimensional organotypic culture and animal models as well as non-invasive imaging technology, to dissect the molecular mechanism in angiogenesis and vascular homeostasis in cancer. The current research focuses on three areas: 1). Role of myeloid suppresser cells in regulation of the tumor microenvironment with a focus on angiogenesis and lymphangiogenesis. 2). Vascular integrity and endothelial-to-mesenchymal transformation (EMT) in tumor progression. 3. Exploring the genetic differences in vasculature between human and other species.

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.

Genetic Modifiers of Tumorigenesis
The Genetic Modifiers of Tumorigenesis Section is headed by Dr. Karlyne Reilly, who joined the MCGP in March 2002. Neurofibromatosis type 1 (NF1) is one of the most common human genetic diseases affecting the nervous system and is characterized by clinical heterogeneity. Familial studies suggest that modifier genes affect the severity of the disease. NF1 patients are at increased risk for developing tumors and these tumors can be modeled in mice carrying mutations in Nf1 and p53 on the same chromosome. When the linked mutations are congenic on a C57BL/6J background, the most common tumor types are astrocytomas and malignant peripheral nerve sheath tumors. By crossing the mutations onto other inbred strain backgrounds, it has been possible to identify dominantly acting modifier genes that affect susceptibility to tumors. Members of Dr. Reilly's group are now using various genomic and molecular biological approaches to identify and characterize the genes implicated by the genetic studies. In addition, the Nf1 and p53 doubly mutant mice develop astrocytomas that recapitulate the stages of progression and diffuse infiltration seen in human patients. Thus, members of the section are using a combination of in vitro and in vivo approaches to study astrocytoma biology with the goal of identifying new molecular targets for rational drug design. Finally, they are also taking advantage of new initiatives in small animal imaging to develop in vivo imaging procedures that will allow for the detection of early-stage tumors for treatment studies.

Tumor Growth Factor
The Tumor Growth Factor Section is headed by Dr. David Salomon, who joined the MCGP in 2013. Before becoming part of MCGP Dr. Salomon was part of LCP. The Tumor Growth Factor Section 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. 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.

Tumor Angiogenesis
The Tumor Angiogenesis Section is headed by Dr. Brad St. Croix, who joined the MCGP in June 2002. Targeting tumor blood vessels is an anti-cancer strategy that has generated widespread excitement among biologists and clinicians and is based on the idea that the majority of solid tumors are angiogenesis dependent. Several years ago, in an attempt to identify novel molecular targets of the newly forming vasculature, serial analysis of gene expression (SAGE) was performed on endothelial cells that line vessels from either human normal colonic mucosa or colorectal cancer. Forty-six tumor endothelial markers, or TEMs, were identified. Now, members of the Tumor Angiogenesis Group are focusing on five TEMs that appear to be located on the cell surface and are thus potentially accessible to blood-borne pharmacological agents. One of the current goals is to determine the role of each TEM in angiogenesis. Studies include analyzing TEM protein expression in normal and tumor tissue using monoclonal antibodies, identifying ligands and downstream binding partners for cell surface TEMs, and generating conditional null mutations in each of the genes. SAGE analysis on various other models of angiogenesis is also ongoing in an effort to identify the most tumor-specific endothelial markers. The end goal is to use this new molecular information on tumor angiogenesis to develop clinically useful agents for improved diagnostics and therapeutics of cancer and other vascular diseases.

Cancer Pathways and Mechanisms
The Cancer Pathways and Mechanisms is headed by Dr. Terry Van Dyke, who joined the MCGP in September 2007. The central goal of the Van Dyke lab is to study and understand the mechanisms and pathways to cancer development at many levels, including genetic, molecular, cell and organ biology. Because cancer can develop in over 100 distinct mammalian cell types, and does so amidst complex cell-cell and cell-environment interactions, we have utilized genetically engineered mice (GEM) as the foundation for our analyses. We have established several preclinical cancer models that have facilitated analyses of the tumor suppressors, p53, pRb, and PTEN, among others, including their contribution to normal growth control and the consequences of their inactivation to multi-step tumorigenesis. This approach enables a detailed examination of the molecular and cellular events in developing tumors - studies that are not possible in humans. We couple in vivo approaches with in vitro primary cell culture approaches to refine our discoveries. Projects in the Van Dyke lab have elucidated mechanisms of aberrant proliferation, apoptosis and invasion of cancer cells of multiple lineages in vivo. Studies are underway to characterize the chromosomal and gene expression aberrations that characterize these events. Furthermore, mechanisms of angiogenesis and invasiveness are being explored. In the process of these mechanistic studies, we have developed highly penetrant preclinical models for cancers of breast, prostate, and choroid plexus epithelia, as well as high-grade astrocytoma. These models are also being used to develop live animal imaging approaches to both characterize the disease process and to monitor preclinical therapeutic testing. Thus, the Lab utilizes a tool box full of modern technologies to approach the complexities of this aggressive and devastating disease.


This page was last updated on 11/25/2013.