Our Laboratories

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Paul Ahlquist

We are studying the novel, RNA-based pathways and virus-host interactions underlying replication, gene expression and evolution by positive-strand RNA viruses, the largest class of viruses. Positive strand RNA viruses include many important human pathogens such as hepatitis C virus, which chronically infects nearly 3% of the world population, causing progressive liver damage and liver cancer, and the new SARS coronavirus. We are also studying selected replication processes of a reverse-transcribing virus, hepatitis B virus, which is also a major human tumor virus. Our studies integrate molecular genetics, genomics, biochemistry and cell biology to address fundamental questions in virus replication and virus-cell interactions.

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Elaine Alarid

The focus of our research is on understanding the molecular mechanisms governing the activity of estrogen receptor (ER), a member of the nuclear receptor transcription factor family that is critical in normal reproduction and is implicated in the pathogenesis of breast cancer.

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Caroline Alexander

We are studying aspects of mammary gland biology and neoplasia using transgenic mouse models. Particularly, we have found that Wnt signaling dysregulates mammary stem cells, and that this precedes the formation of differentiated, bilineal tumors. Wnt signaling is highly oncogenic to mammalian epithelia, and indeed comprises one of the main sources of human tumor initiation identified to date. Our hypothesis is that the transforming potential of Wnt signaling is unique to stem/progenitor cells.

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Lisa Arendt

Obesity is a world-wide problem, and two-thirds of the population in the United States is currently considered to be either overweight or obese. Obesity increases the risk for multiple different types of cancer. In particular, obesity significantly increases the risk for postmenopausal breast cancer. Obesity also enhances other risk factors, such as in women with a family history of breast cancer. Postmenopausal women are most commonly diagnosed with breast tumors that have a marker called estrogen receptor alpha (ERa). However in women with a higher body mass index, these ERa positive tumors are larger at the time of diagnosis and are more clinically aggressive. Both pre- and postmenopausal women who develop breast cancer also have an increased incidence of triple negative breast tumors. These tumors, which lack the markers ERa, progesterone receptor, and Her-2, are more difficult to treat clinically. Obese women also have an increased risk for the development of metastases and a shorter time before tumors may recur.

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Jon Audhya

Dysregulated cell proliferation underlies all forms of oncogenesis. In particular, chromosomal aberrations sometimes enable a subpopulation of cells to grow in an uncontrolled fashion, leading to tumor formation. Such defects are often associated with changes in cellular signal transduction pathways, such as the Ras-Raf-MEK-ERK kinase cascade, which promotes cell survival and growth. Notably, upregulated ERK activity has been implicated in numerous malignancies, including papillary thyroid carcinoma, pancreatic cancer, colorectal cancer, melanoma, and lung cancer. During the course of their studies, members of the Audhya laboratory demonstrated that two oncogenic fusion proteins, TFG-NTRK1 and TFG-ALK, created by distinct chromosomal translocation events, localize to subdomains of the endoplasmic reticulum (sites of COPII vesicle formation) and dramatically upregulate ERK activity. Using phosphoproteomic approaches, they are mapping downstream effectors of TFG-NTRK1 and TFG-ALK that simultaneously drive cell transformation and regulate vesicle secretion. By altering membrane transport in the early secretory pathway, TFG fusion proteins may modulate cargo export, potentially enhancing the secretion of growth factors that help to sustain a rich tumor microenvironment.

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David Beebe

Dr. Beebe continues to lead a large research effort consisting of 30-40 researchers. His research spans many fields including microfluidics, cell biology, cancer biology, global health, and diagnostics. While originally trained in engineering, he completed a 5 year “re-training” in cell biology via an NIH K25 award which transitioned his lab to more biology and medically focused work. Additionally, his retraining was cancer focused, and he now co-leads the Tumor Microenvironment Program within the University of Wisconsin Carbone Cancer Center (UWCCC). The Beebe laboratory is now focused on an integrated research process that works to match unmet biological and clinical needs with appropriate technology development and adaptation. Via multiple collaborations they are developing and applying micro-scale technologies to study and diagnose a range of cancers (e.g., prostate, lung, kidney, multiple myeloma). The laboratory’s emphasis is increasingly on clinical diagnosis through the analysis of patient samples (e.g., blood, tissue).

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Christopher Bradfield

Our laboratory is interested in a family of transcriptional regulators known as PAS proteins. Members of this emerging family of proteins control a number of processes, including xenobiotic metabolism (Ah-receptor and Arnt), circadian rhythms (Per), angiogenesis (HIF1a and Arnt), and neurogenesis (Sim). The model system that is currently emphasized is the signal transduction pathway mediated by Ah-receptor/Arnt heterodimeric complex. These helix-loop-helix-PAS proteins regulate the induction of a number of xenobiotic metabolizing enzymes that occur in response to exposure to a variety of polycyclic aromatic environmental pollutants. In addition, the Ah-receptor mediates a second battery of genes responsible for a number of “toxic effects” of dioxins, such as epithelial hyperplasia, immunosuppression, teratogenesis, and tumor promotion.

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Emery Bresnick

We use multidisciplinary approaches to understand stem/progenitor cell function, blood cell development, and vascular biology. Such approaches include genomics, proteomics, chemical genetics, embryonic stem cell differentiation, computational analysis, and traditional methodologies.

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Mark Burkard

Dr. Burkard is a chemical biologist and medical oncologist who specializes the treatment of breast cancer. His research laboratory is focused on using chemical biology to identify and validate mitotic protein kinases as breast cancer drug targets. The laboratory seeks to advance cancer therapy by two approaches-candidate evaluation (“bottom-up”) and therapeutic strategy (“top-down”). In the first approach, function of specific kinases is interrogated to determine how these control human cell division and evaluate the potential worth as a cancer drug target. Chemical genetics allows the group to dispense with the arduous task of up-front drug discovery and simply mutate the target kinase to prepare for chemical interrogation of function. In contrast, the top-down approach seeks to selectively target a unique characteristic of cancer cells that sensitize them to specific drugs. For example, the group seeks to develop compounds that specifically block proliferation of cells which harbor excess number of chromosomes; such polyploid cells are commonly found in cancer. The ultimate goal is to identify new drug targets or allow improved selection of patients likely to benefit from existing treatments.

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Jason Cantor

Our laboratory has broad interests in modeling, understanding, and exploiting the influence of environmental factors on human cell metabolism, with a particular focus on hematological cancers and normal lymphocytes. We apply a highly interdisciplinary approach that combines principles of biochemistry, engineering, and molecular biology with methods in metabolomics, genome editing, and chemical genetics. Within this framework, we will integrate and develop novel tools and reagents, including a physiologic cell culture medium, a diverse collection of over 50 human blood cancer cell lines that we have also engineered to contain unique DNA barcodes, and a chemostat bioreactor system that we have optimized to permit steady state mammalian cell culture.

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Christian Capitini

Dr. Capitini leads an NIH-supported laboratory focusing on development of cell-based therapies, including NK cells and CAR T cells, for the treatment of childhood cancers like neuroblastoma and osteosarcoma. The laboratory also manufactures alternatively activated macrophages for complications of hematopoietic stem cell transplant, like graft-versus-host-disease and acute radiation syndrome. In the clinic, Dr. Capitini was a site Principal Investigator for the first multi-center CAR T cell trial, which led to FDA approval of tisagenlecleucel (Kymriah) for the treatment of recurrent/refractory B cell leukemia in children. He remains a site PI for trials testing Kymriah as upfront therapy for high risk B cell leukemias and for treatment of relapsed non-Hodgkin lymphoma.

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Jane Churpek

The Churpek lab is focused on defining the contribution of rare genetic variation to risk of blood disorders and cancer and how environmental factors interact with inherited genetic variation to contribute to penetrance and/or progression from the at risk state to overt disease. Specific projects include defining new rare genetic variants that cause inherited bone marrow failure and inherited blood cancer syndromes in families clustering these disorders; comparing acquired tumor genomic signatures across subjects with and without inherited mutations to identify differences in pathogenesis; and testing functional consequences of specific inherited variants in both in vitro and in vivo model systems to determine mechanism.

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Vincent Cryns

The Cryns lab focuses on understanding how tumors adapt to and survive metabolic stress caused by their rapid growth. They are particularly interested in translating these insights into improved biomarkers and therapies. The Cryns laboratory group is widely recognized for identifying the molecular chaperone aB-crystallin as a novel anti-apoptotic protein that inhibits caspase-3 activation and for linking aB-crystallin to triple-negative breast cancer (TNBC). They have also developed unique mouse models of metastatic TNBC and demonstrated that aB-crystallin plays a key role in brain metastasis, a devastating complication with few treatment options.

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Dustin Deming

My laboratory is investigating kinase modulation of cellular signaling pathways driven by oncogenic mutant proteins.  To screen combinations of targeted agents in the setting of specific genetic alterations, novel mouse models of colorectal cancer including tumors driven by a constitutively active PI3K [Cancer Research, 2012; PLoSOne, 2013; Oncogene, 2013].  In addition to my laboratory research, I have also been active in early phase clinical trials. I have developed the concepts and chaired NCI/CTEP sponsored phase I clinical trials including AZD6244 in combination with cetuximab for KRAS mutant colorectal cancer [ASCO Annual Meeting, 2012] and ABT-888 in combination with capecitabine and oxaliplatin for BRCA mutant tumors and gastrointestinal cancers.

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David Evans

Dr. Evan’s research program is directed toward understanding host-pathogen interactions for human and simian immunodeficiency viruses. Current areas of investigation include mechanisms of lentiviral resistance to tetherin/BST-2, the role of killer-cell immunoglobulin-like receptor (KIR) and MHC class I interactions in regulating natural killer (NK) cell responses, and antibody-dependent cell-mediated cytotoxicity (ADCC) as a mechanism of protective immunity. Recent studies from the Evan’s lab have contributed to understanding the role of antibody-dependent cell-mediated cytotoxicity (ADCC) in immunodeficiency virus infection. Together the lab has developed an assay for measuring the ability of antibodies to direct the killing of HIV-1- and SIV-infected cells expressing native conformations of the viral envelope glycoprotein (Alpert et al. J. Virol. 2012).

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Andrea Friedl

My research focuses on the role of heparan sulfate proteoglycans (HSPGs) in tumorigenesis and cancer progression. HSPGs are hybrid molecules, which consist of core proteins and heparin-like polysaccharide domains. HSPGs are found in abundance on cell surfaces and in the extracellular matrix. One project focuses on the role of the HSPG syndecan-1 in stromal fibroblasts of breast carcinomas. The goal is to decipher the mechanisms by which stromal syndecan-1 stimulates breast carcinoma growth and invasion. A separate project aims at identifying the mechanisms by which the HSPG glypican-1 regulates cell cycle progression in brain tumor cells.

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Paul Friesen

Anne Griep

We are interested in understanding the role of cellular tumor suppressor genes in normal development and cancer. To this end we have focused on determining the molecular pathways that regulate a cell’s switch from proliferation to differentiation in various epithelial tissues of the mouse eye. Through our studies, we have contributed towards the understanding that the retinoblastoma susceptibility protein (pRB), which when mutated leads to retinoblastoma and other cancers, and its family members along with multiple growth factor signaling pathways are coordinately involved in regulating the developmental processes in the eye. Proper cell adhesion and polarity also are believed to be vital to the growth and differentiation of epithelial tissues and to maintaining their long-term integrity. In Drosophila melanogaster and Caenorhabditis elegans members of the PDZ (PSD95/Dlg/ZO-1) family regulate cell adhesion, polarity and proliferation. A major emphasis in the lab is to understand if, and how, the mouse homologs of dlg and scrib contribute to mammalian development. Finally, due to one approach used in the lab, we also are learning new properties that certain oncoproteins from human papillomaviruses (HPV) possess in vivo and how these novel activities may contribute to HPV-associated cancer. We use a variety of genetic, molecular, cell biological and embryological techniques and transgenic and knockout mice.

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Rich Halberg

Colorectal cancer is the second leading cause of cancer death in the United States. These cancers, like most cancers, are often heterogeneous with abnormal cells within a single tumor varying in several distinguishable properties including differentiation state, proliferation rate, and metastatic potential. Dr. Halberg’s research focuses on identifying sources of intratumoral heterogeneity and determining how such heterogeneity impacts prevention and treatment in the clinic.

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Paul Harari

The overall theme of my clinical and laboratory research is to improve treatment outcome for patients with head and neck cancer (HNC). Areas of particular research emphasis include the interaction of molecular growth inhibitors combined with radiation and the use of conformal radiation treatment techniques to limit normal tissue toxicity. I serve as PI for a recently funded SPORE Grant in HNC at the University of Wisconsin and direct one scientific project as well as the Administrative Core within the SPORE Grant. I have served as PI for NIH R29 and R01 laboratory research grants investigating HNC response and resistance mechanisms in combination with radiation. I have been an active RTOG HNC Committee member for more than 20 years (now NRG) and serve as PI or co-PI for a series of national and international HNC clinical trials.

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Anna Huttenlocher

Dr. Huttenlocher studies the basic molecular mechanisms that regulate cell migration and is interested in the implications of these mechanisms to human disease. Her laboratory has pioneered approaches to visualize and manipulate cell motility and innate immunity in zebrafish. Her work centers on understanding mechanisms that regulate the invasiveness of cancer cells using both human cell lines in vitro and cancer models in zebrafish. Her laboratory is also probing the role of the innate immune system in cancer progression using zebrafish models of melanoma and hepatocellular carcinoma

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David Jarrard

David Frazier Jarrard, MD, is a tenured Professor of Urology and an Associate Director at the UW Carbone Cancer Center. He trained at the University of Chicago and Johns Hopkins.  His laboratory studies clinically relevant epigenetic factors underlying cancer development and progression is part of the campus-wide Epigenetics consortium.   They were the first to identify that altered genomic imprinting with aging occurs and this increases the risk of prostate cancer development.  Alterations in CTCF, an insulator protein, underlies these epigenetic alterations and links diet and oxidative stress to cancer progression.  This epigenetic field effect arises in the histologically normal prostate tissue of men with prostate cancer and serves as a clinical diagnostic marker for the presence of prostate cancer.

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Eric Johannsen

Our research focuses on the molecular biology of Epstein-Barr virus (EBV) nuclear proteins, their role in the virus lifecycle and the pathogenesis of EBV associated malignancies. Herpesviruses infect their hosts for life and EBV precisely manipulates growth and survival signaling pathways of B lymphocytes, resulting in their immortalization. Understanding the mechanisms that EBV has evolved to exploit infected cells is an important basis for therapy of EBV associated diseases and offers a unique vantage from which to view and understand complex cellular pathways.

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Rob Kalejta

Our lab focuses on determining the mechanisms of human cytomegalovirus (HCMV) replication and pathogenesis, and also uses the virus as a tool to probe the pathways that lead to cell cycle progression and oncogenesis. We are interested in HCMV because it is a ubiquitous and medically relevant virus that causes severe disease in immunocompromised patients, is the leading viral cause of birth defects, and impacts upon the etiology and/or progression of cardiovascular disease and cancer. As an obligate intracellular parasite, HCMV relies upon its host cell for its replication. Thus, to promote its own survival, HCMV has evolved ways to commandeer cellular pathways such as cell cycle progression, transcriptional silencing, and protein degradation.

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Shannon Kenney

Dr. Kenney’s research effort has been focused upon understanding the molecular regulation and pathogenesis of the human herpesvirus, Epstein-Barr virus (EBV). Her work in EBV spans a broad range of topics, including viral gene regulation, the effects of the virus on the host immune response, and the development of novel, EBV-targeted therapies for EBV-positive tumors. She has extensively studied the mechanisms by which both EBV immediate-early proteins, BZLF1 and BRLF1, activate the lytic form of viral infection. Her group discovered that BZLF1 preferentially binds to, and transcriptionally activates, the methylated form of its downstream target promoter, suggesting a unique and unexpected mechanism by which EBV overcomes the inhibitory effect of viral genome methylation. Her group has also shown how the two EBV immediate-early proteins alter the host cell environment in multiple different ways, including usurping control of the host cell cycle, activating a variety of signal transduction pathways, inhibiting p53 function, dispersing PML nuclear bodies, and attenuating the host innate immune response. Dr. Kenney is now translating the results of these basic molecular studies into the development of new, EBV-targeted therapies for EBV-positive tumors. Her group is also developing a new small animal model to study EBV pathogenesis in vivo.

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Randy Kimple

My research laboratory is focused on understanding why cancers don’t always respond to treatment. We use patient-derived xenografts—patient tumor samples grown in animals—to test radiation, chemotherapy and combinations of therapies to understand which characteristics of a patient’s tumor may predict response to treatment. The goal of this work is to enable more personalized treatment and to find ways to combine different treatment methods to decrease treatment side effects without reducing cure rates.

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Pamela Kreeger

The Kreeger lab utilizes systems biology and tissue engineering to analyze cellular behavior in a variety of biological contexts. We utilize an iterative approach, where we develop model culture systems that allow us to study a disease in a controlled environment, use high-throughput experimental methods to gather information about the cellular signaling network and cellular responses, and employ computational models to interpret the data. Ultimately, our models will be utilized to identify new drug targets, match patients to the most effective drugs, and identify methods to direct cellular behavior.

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Paul Lambert

Our lab’s research is focused on understanding the role of human papillomavirus (HPV) in cancer. HPVs cause 5% of all human cancers. These include cervical cancer, other anogenital cancers and a growing proportion of head and neck cancers. Through the use of genetically engineered mice (GEM) we have developed models for HPV-associated cervical, anal and head/neck carcinogenesis, defined the individual roles of viral oncogenes in carcinogenesis in these organs, identified the mechanisms of action by which these oncogenes contribute to carcinogenesis, defined their temporal role in carcinogenesis, and defined the roles of estrogen and its receptor in cervical carcinogenesis and the utility of estrogen receptor antagonists in treating and preventing cervical cancer. Major current directions in the lab that make continued use of the GEM models include understanding the interplay between viral oncogenes and cellular signaling and DNA damage response pathways in causing cancer, and the influences of viral genes on epigenetic regulation and epithelial stem cell biology.

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Jessica Lang

My scientific mission is to leverage genomics and epigenetics in ovarian cancer (OvCa) models to produce translational and impactful science building on my research in somatic mutations in chromatin remodeling factors and epigenetic dysfunction through the following research goals: 1) Understand dynamics of epigenetic features following chemotherapy treatment and resistance; 2) Identify potential therapies for treatment that exploit epigenomic features; 3) Integrate epigenomic features with somatic cancer mutations towards a more comprehensive OvCa picture. I will approach these research goals using human cell lines and tumor tissue to identify shared and necessary OvCa enhancers, validated by innovative functional epigenomics approaches and preclinical models. I will also continue my history of scientific collaborations and clinical partnerships to support my research and ensure clinical translation of findings.

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Joshua Lang

The Lang laboratory has two focus areas with the overarching goal of improving clinical outcomes of prostate cancer: translational biomarkers and epigenetic mechanisms of immune evasion. Dr. Lang’s early studies identified mechanisms by which epigenetic modifying agents could improve immune recognition of tumor cells (3, 7, 10). His laboratory discovered a panel of neoantigens, known as Cancer-Testis Antigens that can be induced in a broad range of prostate cancer cell lines. To evaluate the translational relevance of these findings, they developed an ex vivo drug culture model to treat primary human prostate cancer biopsies with different epigenetic drugs followed by molecular analysis of mechanisms of response and resistance. These agents can also improve antigen presentation on tumor cells that may target one of the primary mechanisms of resistance to immune-based therapies.

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Peter Lewis

My research program is rooted in the idea that chromatin, the physiologically relevant form of eukaryotic genomes, contains an indexing system, sometimes referred to as a “histone or epigenetic code”, that represents a fundamental regulatory mechanism that operates outside of the DNA sequence itself. Covalent modifications to DNA and histones – the proteins that package our genome – are implicated in the epigenetic regulation of gene expression and the stable maintenance of cell type-specific gene expression patterns and cellular identity.

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Dan Loeb

Hepatitis B viruses (HBV) are a family of DNA viruses that can persistently infect the liver of a variety of animal hosts including humans. There is a close association between chronic HBV infection and hepatocellular carcinoma, though the mechanism of oncogenesis is not understood. Although they have a DNA genome, hepadnaviruses replicate via reverse transcription of an RNA intermediate (RNA pregenome) resulting in a relaxed circular DNA genome. The major project in our laboratory is understanding the mechanism of HBV reverse transcription. We are studying the mechanisms of RNA encapsidation, initiation and synthesis of minus-strand DNA, initiation and synthesis of plus-strand DNA, and genome circularization during plus-strand DNA synthesis. To understand the mechanism of these processes during reverse transcription we are (1) defining the cis-acting sequences involved in each step of the process, (2) determining the role of the viral trans-acting factors in each step of the process, and (3) determining the nature of the interactions between the trans-acting factors and the cis-acting elements during the process of reverse transcription.

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Kinjal Majumder

Parvovirinae are small DNA viruses that are pathogenic in most animals, made up of small linear single-stranded DNA genome, and rely extensively on host nuclear factors, particularly the DNA Damage Response (DDR) machinery that usually protects us from cancer. Upon infection, the parvovirus minute virus of mice (MVM) localizes to cellular sites of DDR to jumpstart its replication in host cells. As it replicates in the host cell nucleus, it continues to induce additional DNA damage through various means, which also serve as sites of viral replication, thereby enabling the virus to amplify in the host nuclear environment. We seek to elucidate the molecular mechanisms by which MVM localizes to cellular DDR sites, induce additional DNA damage and generate chromosomal aberrations. We have developed systems to study where viral genomes localize using genomics and single-cell imaging, inducible DNA damage systems to investigate the cause-effect relationship between the virus and cellular DDR, and have optimized methods to study how viral infection causes chromosomal aberrations. The findings from our work are applicable to understand the biology of small DNA viruses such as HPV and HBV, which are oncogenic, and for gene therapy applications which use modified AAV parvoviruses.   

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Paul Marker

Research in the Marker laboratory is focused on understanding the biology of the prostate gland at the molecular level.  Interest in understanding the biology of the prostate is driven both by the fascinating nature of the developmental processes that function during organogenesis of the prostate and by the high incidence in humans of prostatic diseases including prostatic adenocarcinoma and benign prostatic hyperplasia. The Marker lab is particularly interested in the role of intercellular communication between epithelial and mesenchymal/stromal cells during the progression of prostate cancer. Current projects in this area include a series of studies to investigate PDE4D and cAMP signaling in prostate cancer. This project is based on a genetic screen for novel prostate cancer genes.

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Douglas McNeel

Dr. McNeel is a genitourinary medical oncologist with a laboratory and clinical research program focused on prostate cancer immunology.  The goal of these efforts is to develop effective anti-tumor vaccines as treatments for prostate cancer, and Dr. McNeel has been focused on this area for nearly 20 years.  His initial studies sought to identify immunologically recognized antigens as potential targets for vaccines using blood from patients with prostate cancer, prostatitis, or patients treated with various immune-modulating agents.  More recent efforts have focused on three specific antigens (prostatic acid phosphatase (PAP), the ligand-binding domain of the androgen receptor (AR LBD), and synovial sarcoma X breakpoint 2 (SSX2)), characterizing these as tumor antigens, evaluating anti-tumor genetic vaccines targeting these antigens in appropriate rodent models, and translating these findings to early phase human clinical trials.  Dr. McNeel and his laboratory have specifically focused on plasmid DNA genetic vaccines as a means of antigen delivery, methods to increase the immunogenicity of DNA vaccines, and understanding the mechanisms of tumor resistance to anti-tumor immunization.  This research is translational in nature, taking results from the laboratory to clinical testing, and back again to the laboratory, and has been continuously supported by federal funding from NIH and/or DOD.  In the context of this research, Dr. McNeel has trained over 40 post-doctoral fellows, graduate students, and undergraduate students in laboratory research.  To date, they have conducted (or are conducting) six separate clinical trials using DNA vaccines developed in the McNeel laboratory.  Dr. McNeel has also been principal investigator for over 20 investigator-initiated clinical trials, primarily focused on immune-based treatment approaches.  As a physician-scientist with research experience in the laboratory and clinic, and focused on the development and evaluation of new cancer therapies, Dr. McNeel previously served as co-leader of the Experimental Therapeutics Program of the UW Carbone Cancer Center (UWCCC) from 2007 to 2015, and currently serves as UWCCC Director of Solid Tumor Immunology Research.

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Janet Mertz

Our group’s primary interest involves regulation of gene expression and mechanisms of oncogenesis by DNA tumor viruses implicated in a variety of human cancers. We have identified the cellular transcription factors ZEB-1 and Ikaros as key players in maintaining the human herpesvirus Epstein-Barr virus (EBV) in a latent state while Blimp-1α and HIF-1α are major physiological players in reactivating this virus into lytic replication during epithelial and B-cell differentiation and hypoxic conditions, respectively. In collaboration with the Kenney laboratory, we are identifying and testing both in vitro and in a mouse model system a variety of drugs and drug combinations that might prove useful as new therapeutic agents for treating patients with EBV-associated cancers.

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Shigeki Miyamoto

Over the last two decades, the Miyamoto lab has pursued a variety of research interests centered around cell signaling and asked “what happens when cells are no longer able to communicate effectively?” Most of the current research is focused on understanding the NF-κB signaling pathway as a model. Our lab, and others, have shown that NF-κB is key in promoting cell survival (anti-apoptotic), normal immune system development, stress response, early embryonic development, cell adhesion, and tumor metastasis.

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Zachary Morris

In the Morris Lab, we are focused on using preclinical and translational research approaches to study the mechanisms whereby radiation may impact the anti-tumor response to immunotherapies. Our primary objective is to determine whether and how radiation may optimally be employed to simultaneously modulate the tumor immune microenvironment and to increase the susceptibility of tumor cells to immune response. We seek to test these approaches in early phase clinical studies where they may be further refined with the ultimate aim of improving survival and achieving cures in patients with metastatic cancers.

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Deane Mosher

My laboratory has been a leader in characterization of structure and function of molecules of blood plasma, platelets, and extracellular matrix. We are best known for studies of fibronectin, thrombospondins, and vitronectin and participate in collaborative studies that utilize the reagents and expertise that we have developed over the years.

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Xuan Pan

It is of critical importance that the rates of hematopoietic stem cell (HSC) differentiation and self-renewal are carefully regulated and kept in balance, because severe disease states arise when this balance is disrupted. Unfortunately, the mechanisms that maintain this balance are poorly understood, and this lack of understanding represents a major roadblock to research progress, while also severely restricting the clinical potential of HSC-based therapeutic interventions. Our group identified PcG protein YY1 as an essential regulator of HSC self-renewal and differentiation in mice. Hematopoietic Stem Cell (HSC) quiescence is regulated by both intrinsic and extrinsic signals. Cell-cycle regulators, transcription factors, as well as epigenetic modifications, have been identified as intrinsic regulators of HSC cell-cycle progression. However, correlations of epigenetic signatures are often not highly instructive, and the mechanistic implication of epigenetic signatures in HSC self-renewal is incompletely understood. We have generated a conditional mouse knockout of YY1 in HSCs and showed that YY1 knockout decreases HSC long-term repopulating activity and ectopic YY1 expression expands HSCs. YY1-deficiency deregulates the genetic network that regulates HSC proliferation and impaired stem cell factor/c-Kit signaling, and interferes with establishment of quiescence in HSCs. These results reveal how a ubiquitously-expressed epigenetic repressor regulates lineage-specific functions and plays a critical role during hematopoiesis in adult mice.  Our group currently is focusing on assessing the structure-function relationships in YY1 and dissecting the underlying mechanisms that control chromosome structural change at the Kit locus.

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Alan Rapraeger

The Rapraeger laboratory focuses on the syndecan family of cell surface receptors.  Recent discoveries in the laboratory have shown that syndecans contain docking sites in their extracellular domains that act as“signaling organizers” by providing docking sites for other plasma membrane receptors, especially integrins and receptor tyrosine kinases with well-known roles in cancer (e.g., IGF-1R, EGFR, HER2 and VEGFR2).  They have found that tumor cells, and often vascular endothelial cells participating in tumor-induced angiogenesis, rely upon these receptor complexes to drive proliferation, suppress apoptosis and invade.  Furthermore, the signaling from the receptor tyrosine kinases that supports tumors demands that the kinases be assembled with the syndecan.  The Rapraeger lab also showed that highly specific peptide mimetics of the docking sites in the syndecans (called “synstatins” or “SSTNs”) compete for assembly of the receptor complexes, prevent tumor-specific signaling and block tumorigenesis.  The peptides are remarkably stable, with half-lives of over a day, show no toxicity because of their high specificity and their lack of effect on normal cells, and are thus promising new cancer therapeutics.  They are currently examining the role of these receptor complexes, and their inhibitory SSTNs, in head and neck cancer, breast cancer and multiple myeloma. Dr. Rapraeger is an experiences trainer ans was the founding Director of the Office of Postdoctoral Studies at the University of Wisconsin.

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Will Ricke

Dr. Ricke’s laboratory focuses on the tumor microenviroment as related to hormone action and stromal-epithelial interactions in prostate diseases including prostate cancer.  He discovered that steroid hormone action is critical in the stroma rather than epithelia for malignant transformation and metastasis in prostate cancer, and, that targeting stromal receptors with therapies are the primary mode of therapy.  Currently, the Ricke lab is investigating the role of hormones on collagen changes/metrics in gene expression, collagen fiber density and alignment.  Changes in collagens appear to be correlated with aggressive of prostate disease.

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Lixin Rui

The major research interest in Dr. Rui’s laboratory is the mechanisms of the JAK-STAT signaling pathway in lymphomagenesis. The goal of his research is to discover effective molecular targets in this pathway for therapeutic, diagnostic and prognostic development of human lymphoma. His research team employs a multidisciplinary approach, using biochemistry, RNA interference, next-generation sequencing (including ChIP-seq and RNA-seq), and systems biology methods, to identify JAK1 target genes in this lymphoma and to investigate crosstalk between JAK1 and other signaling pathways, such as NF-kB. Dr. Rui has collaborated with Dr. Shigeki Miyamoto in this area for the past four years, yielding three co-authored publications in Experimental Cell Research, Oncogene, and Molecular Cancer Research.

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Linda Schuler

Prolactin exposure has been epidemiologically linked to elevated risk for aggressive ERα+ breast cancer.  Anti-estrogen resistant metastatic ERα+ cancers account for the majority of breast cancer deaths.  The Schuler laboratory uses preclinical models to examine the role of prolactin in the developing pathology of metastatic ERα+ breast cancer, and its crosstalk with estrogen, growth factors, and properties of the extracellular matrix in tumor behavior and therapeutic responsiveness.  Using the NRL-PRL transgenic mouse, which elevates prolactin locally in the mammary gland, they have shown that prolactin can powerfully influence the epithelial hierarchy and transcriptional regulatory programs in the absence of estrogen and progesterone, resulting in increased progenitor/stem cell populations.  Prolactin can also temper the actions of ovarian steroids, opposing steroid-driven luminal maturation.   Together, these actions begin to explain its role in development of breast cancer.   The ERα+ cancers that develop in the NRL-PRL mouse can be serially transplanted to syngeneic recipients, providing a model to examine cancer stem cells and responses to anti-estrogens and other adjuvant therapies.  Recent investigations have revealed that anti-estrogens can raise cancer stem cell activity in the absence of effects on growth, and that primary tumors and lung metastases display activation of different signaling pathways and responses to therapies.  These studies are illuminating the biology of luminal B cancers, and will facilitate development of prevention and treatment strategies.

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Nathan Sherer

Retroviruses cause a variety of cancers and immunodeficiencies throughout the animal kingdom. Our group is interested in the cell biology underlying the assembly and spread of the human immunodeficiency virus type 1 (HIV-1), the etiological agent causing the acquired immunodeficiency syndrome (AIDS), as well as oncoretroviruses such as the murine leukaemia virus (MLV). Like all viruses, retroviruses have evolved to hijack specific features of their cellular hosts in ways that favor efficient viral replication. Understanding virus-host interactions can inform the development of novel antiviral strategies, and, in general, retroviruses provide great tools for probing questions of cellular function and immunity.

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Jim Shull

Estrogens are inextricably implicated in the etiology of breast cancer.  The primary goals of our research group are to utilize the ACI rat model of 17β-estradiol (E2)-induced mammary cancer to identify novel genetic determinants of breast cancer susceptibility and to define the molecular mechanisms through which estrogens contribute to development of breast cancer. Whereas ACI rats are highly and uniquely susceptible to E2-induced mammary cancer, the Copenhagen (COP) and Brown Norway (BN) rat strains are resistant to mammary cancer development when treated with E2.  In genetic crosses between ACI and COP or BN rats, we have mapped several genetic determinants of mammary cancer susceptibility within the rat genome, designated Emca1 through Emca9. Research currently underway is focused on high resolution mapping and identification of the mammary cancer susceptibility genes that reside within these Emca loci.  We hope to then determine how these genes influence mammary cancer development and to evaluate the impact of these same genes on breast cancer risk in human populations.  Knowledge regarding the identities of these genes should reveal novel insight into the mechanisms through which estrogens contribute to breast cancer development.

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Bill Sugden

We work with Epstein-Barr Virus (EBV) because it causes several different cancers in people. EBV is a herpesvirus that causes the common, benign infectious mononucleosis, as well as lymphomas such as Burkitt’s Lymphoma, most B-cell lymphomas in immunocompromised hosts, and carcinomas such as nasopharyngeal carcinoma. We study EBV both to understand its contributions to these diseases molecularly and to develop rational means to treat them.

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Ausie Suzuki

Our lab focuses on discovering the molecular mechanisms underlying force production, mitotic checkpoint control, and error correction in accurate cell division, with a focus on the role of the highly conserved Ndc80 complex and the kinetochore structural integirty. We recently developed a FRET (fluorescent resonance energy transfer)-based Ndc80 tension biosensor, which allows us to measure cellular tension using light microscopy. Using this tension biosensor, we will elucidate the mechanisms of how kinetochores generate and transmit force for accurate chromosome segregation. Tension at kinetochores may be important for the kinetochore deformation, which is thought to be critical for mitotic checkpoint control. We will investigate the kinetochore structural changes by super-resolution microscopy, electron microscopy, and ExM (expansion microscopy). In addition, we are committed to understanding how the loss of centromere/kinetochore integrity causes carcinogenesis and cancer progression. We recently found that the CENP-H/I complex, which is a member of core-kinetochore proteins, is overexpressed in primary colon cancer and its expression levels inversely depends on the stage of cancer progression. We are investigating the functions of CENP-H/I complex in cancer. In order to reveal centromere/kinetochore functions, our lab uses advanced light and electron microscopy techniques. They include quantitative confocal microscopy to measure cellular protein copy number, light-sheet microscopy for high spatial/temporal live cell imaging, various super-resolution microscopy (SIM/STORM/STED) for nm-scale analysis, FRET-based tension biosensor, FRAP/TIRF system for cellular protein dynamics, and immuno-electron microscopy.

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Randall Tibbetts

Current work in our lab is aimed at understanding how diverse growth-inhibitory signals, including DNA damage, cell-cell contact and growth factor depletion down regulate gene expression through the CREB pathway and how defects in this regulation contribute to tumorigenesis. A second related project is deciphering how alternative splicing influences DNA damage repair and tumor suppression using cellular and in vivo (mouse) models. Finally, our laboratory has developed several Drosophila melanogaster (fruit fly) models for the motor neuron disease amyotrophic lateral sclerosis. We are using these models to probe genetic mechanisms of neurodegeneration. We actively collaborate with both basic science and clinical colleagues within and outside the UW campus on each of these projects. I also teach material related to cell growth and DNA damage repair for several on-campus graduate programs, serve on both NINDS and NCI grant review panels and have served as editor and ad hoc reviewer for the Journal of Biological Chemistry, Nature, the EMBO Journal and other journals.

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Beth Weaver

The goal of Dr. Weaver’s research is to determine the consequences of mitotic defects on tumor initiation, progression and response to chemotherapy. Defects during mitosis result in the production of daughter cells with an abnormal number of chromosomes, a condition known as aneuploidy. Aneuploidy is a hallmark of tumor cells, which has led to the hypothesis that aneuploidy promotes tumors. The Weaver laboratory has found in animal models and cell culture that aneuploidy can both promote and suppress tumors, depending on the rate of chromosome missegregation. Low rates of chromosome missegregation are weakly tumor promoting, while high rates of chromosome missegregation lead to cell death and tumor suppression due to the loss of one or more essential chromosomes. Recently, they have also shown that high rates of chromosome missegregation suppress tumor growth and progression, rather than tumor initiation. These results suggested the hypothesis that inducing high rates of chromosome missegregation could be a useful strategy for tumor therapy. Indeed, the Weaver laboratory has recently shown that paclitaxel (TaxolTM), a cornerstone of chemotherapy for the last 30 years, causes chromosome missegregation on multipolar spindles in breast cancers. Future experiments will utilize cell culture, mouse models and clinical studies to leverage our fundamental knowledge of mitosis to improve treatment outcomes for cancer patients.

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Deric Wheeler

My laboratory is focused on understanding mechanisms of resistance to molecular targeting agents directed against receptor tyrosine kinases. Specifically, we center our work on cancers of the head and neck and breast. We use molecular biology, proteomics, mouse modeling, including patient derived xenografts, and human tissues to understand how tumors that are initially responsive to therapy become resistant over time. The overall goal of this research is to identify these mechanisms of resistance and to target specific pathways to increase the efficacy of molecular targeting agents. Ultimately, our goal is to take basic science discoveries in the lab and translate them to the clinic.

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Yongna Xing

My lab is interested in elucidation of signaling pathways related to cancer using multi-disciplinary biophysics and biochemical approaches, including structural biology and proteomics, in combination with cell biology. We focus on signaling pathways that affect cancer cell metabolism and cancer cell genome integrity.

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Wei Xu

My laboratory is focused on the transcriptional regulation of estrogen receptor (ER) signaling pathways by nuclear receptor co-factors. We identified a natural plant product that significantly decreased ERa but increased ERb stability. Via distinct mechanism from the existing agents for endocrine therapy, this compound also significantly promoted degradation of mutant ERa that is found in ~25% of patients with metastatic ERa-positive breast cancers. Biological functions of these estrogenic compounds have been investigated in cell-based and breast cancer mouse models. The bioactive derivatives may be developed as novel agents for treating metastatic, endocrine-resistant breast cancers caused by ERa mutations. Furthermore, we investigated the crosstalk between ERa pathways and other growth factors (e.g., HER2) and kinase networks, as these mechanisms account for the intrinsic or acquired endocrine resistance.

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Jing Zhang

My laboratory focuses on studying the mechanisms underlying the normal as well as oncogenic self-renewal of stem cells using the hematopoietic compartment as a model system. The hematopoietic system is one of the best tissues to study normal stem cells and prospective cancer stem cells; the developmental hierarchy of normal blood formation is well defined, hematopoietic stem cells (HSCs) can be highly purified based on their characteristic immunophenotypes, HSCs can be cultured in vitro, exogenous genes and shRNAs can be readily introduced into HSCs, and stem cell activities can be assayed by in vivo repopulation experiments in mouse. HSCs constantly make a choice between self-renewal and lineage differentiation, and the lineage-committed progenitors make a decision to proliferate, differentiate, or undergo apoptosis. This balance is critical because, once the balance is tilted towards “indefinite” self-renewal at the expense of normal terminal lineage differentiation, normal hematopoiesis evolves into hematopoietic malignancies.

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Shuang George Zhao

In the Zhao Lab, we focus on developing novel clinical biomarkers that predict response and resistance to specific therapies in prostate cancer and other malignancies. These biomarkers can be used to better select which patients derive a benefit from treatment, which patients do not and can be spared potential toxicity, as well as monitor for emergence of resistance. We seek to use advanced sequencing and computational technologies to better personalize the care of cancer patients.

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