OHSU Knight Cancer Institute Research Groups:Members

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Primary Faculty

Eric Barklis,PhD

Professor

OHSU faculty page
Research in the Barklis lab focuses on the assembly and replication of viruses, such as retroviruses, flaviviruses, and hantaviruses, using molecular genetic, biochemical, and biophysical techniques. Molecular genetic and biochemical are employed to investigate viral protein interactions, RNA recognition and encapsidation, and cellular factors involved in virus replication and assembly. To analyze virus particles, proteins, and macromolecular complexes, a variety of biophysical methods are utilized, including sedimentation, crosslinking, fluorescence microscopy, fluorescence anisotropy, transmission electron microscopy (EM), and atomic force microscopy (AFM). One set of recent investigations concentrates on the identification and analysis of small molecule inhibitors of virus replication. A second avenue of inquiry concerns the mechanisms that govern how HIV structural proteins assemble conical, cylindrical and spherical cores. Our third major area of research focuses on protein-protein and protein-lipid interactions of retrovirus membrane-binding proteins. Ultimately, we believe our studies will lead to the development of new antivirals, and a better understanding of the basic principles controlling macromolecular assembly.

Michael Deininger, MD,PhD

Associate Professor

OHSU Faculty Page
Joining OHSU in 2002, Dr. Deininger`s clinical interests concentrate on bone marrow transplantation and leukemia. His research focuses on the molecular basis of resistance to imatinib mesylate in patients with chronic myelogenous leukemia.
Our work in the Hematology and Medical Oncology Division is dedicated to the study and treatment of cancer and disorders of the blood in adults. Research in the diagnosis and treatment of various anemias, lymphomas, leukemias and pre-leukemia, cancer of the lung, prostate, breast, colon, head and neck, testicular cancer, thrombosis and coagulation disorders, aging, supportive care and bone marrow failure are integral elements of our clinical practice. Our laboratory research is conducted in the interest of coagulation, hematopoiesis, tumor immunology, transplantation immunology, DNA repair, leukemogenesis, HIV biology, cell cycle control, retroviral mediated gene transfer, cancer chemotherapeutics, and gene therapy

Brian Druker, MD

Professor

OHSU Faculty Page
Dr. Druker's current research projects are aimed at learning why each year some 4% of newly diagnosed patients with CML develop resistance to Gleevec and why most patients on the drug have minute levels of cancer that linger even after treatment ends. Resistance to Gleevec most commonly results from mutations in the BCR-ABL kinase that reactivates its signaling mechanism. He recently identified a class of compounds that can inhibit most of these mutants, and similar compounds are now in clinical trials. A more pressing problem, Druker believes, are the traces of leukemia that remain in patients' bodies, a phenomenon called molecular persistence. He is working in the laboratory to purify leukemia cells from patients to determine why these cells aren't being killed so that a strategy can be developed to eradicate the cancer.

William Fleming,PhD

Professor
OHSU faculty page
Over the past several years, my laboratory has been interested in functional relationship between hematopoiesis and blood vessel formation. Recently, we have found that adult vascular endothelial cells are an important component of the hematopoietic microenvironment. Specifically, endothelial cells can produce signals that protect hematopoietic stem cells (HSCs) from radiation induced cell death. Classical studies in embryology demonstrated the existence of the hemangioblast, a stem cell that can give rise to both hematopoiesis and blood vessels. To address the question of whether bone marrow derived cells with hemangioblast activity exist in the adult, the vascular compartment of bone marrow transplanted mice and humans was carefully evaluated for the presence of donor derived cells. A similar frequency of bone marrow derived endothelial cells was detected in both mouse and human transplant recipients. A single HSC can give rise to both hematopoietic and endothelial cells in vivo providing direct evidence for the existence of an adult hemangioblast. Additional studies demonstrate that endothelial cells can arise from hematopoietic progenitors cells committed to the myelomonocytic cell lineages. These functional interactions between HSCs and blood vessels represent a new area of investigation that has important implications for our understanding of both normal and malignant hematopoiesis.

Markus Grompe, MD

Professor

OHSU Faculty Page
Single gene disorders, although individually rare, cumulatively represent a significant medical burden, particularly in the pediatric age group. Current treatment options are very limited and outcomes remain poor in many cases. Gene transfer and cell therapy (including stem cell transplantation) are hopeful strategies for future therapies. It is our long-term goal to develop these into clinically useful procedures. Our particular focus is metabolic liver diseases and the DNA repair disease Fanconi Anemia.

Michael Heinrich, MD

Professor

OHSU Faculty Page
Michael Heinrich M.D. earned his medical degree in 1984 from Johns Hopkins School of Medicine in Baltimore and completed both his residency training and Hematology and Medical Oncology fellowship at OHSU. His primary research interest is in the development of novel tyrosine kinase inhibitors for treatment of human cancers. Dr. Heinrich's research includes both pre-clinical identification of novel molecular targets and testing of new agents in the laboratory and the clinic. Dr. Heinrich has extensive national and international collaborations for his research into the molecular biology of sarcomas and hematologic malignacies.

Ann Hill, PhD

Professor

OHSU Faculty Page
My lab is interested in the immunobiology of cytomegalovirus (CMV). CMV is a beta herpesvirus; like most herpes viruses it establishes lifelong asymptomatic infection. The immune system, however, becomes uniquely obsessed with CMV, devoting an increasing proportion of the T cell response to CMV over an individual’s lifetime. In old age this response can become truly enormous. Our main focus is understanding how this lifelong “détente” between virus and host is maintained. What does the virus do to prevent the immune system from eradicating it? How does the immune system keep the virus under control, and why is it so “obsessed”? How active is the guerilla war that host and virus wage? What are the implications for human health? We work mostly in the mouse model, and have performed a detailed characterization of the CD8 T cell response to murine (M)CMV in C57BL/6 mice, and have investigated the mechanism and impact of MHCI immune evasion in this model.

Maureen Hoatlin, PhD

Associate Professor

OHSU Faculty Page
We are interested in understanding how cells maintain genomic stability. One of the mechanisms that regulates this critical process is defective in Fanconi anemia (FA), a genetic model for human host susceptibility to cancer. FA is a rare but devastating multi-gene disease thought to have an underlying defect in DNA interstrand crosslink repair.

Our Labpioneered the use of cell-free assays for FA proteins in extracts from Xenopus eggs. These extracts allow analysis of FA protein function and post-translational modifications in a context that is permissive for naturally regulated DNA synthesis. The recruitment of Fanconi proteins with chromatin in S-phase is providing us with a biochemical platform for elucidating the molecular function of the Fanconi proteins during the DNA damage response.

Molly Kulesz-Martin, PhD

Professor

OHSU Faculty Page
Tripartate Motif Protein 32 (Trim32) is a novel E-3 ligase and scaffold protein with specificity for substrate proteins that regulate apoptosis, potentially explaining its role in disorders of cellular failure to die, such as psoriasis and neoplasia, when activated and in muscular dystrophy type 2H when inactivated. We are studying two aspects of Trim32 function: its role in human keratinocyte survival disorders and its regulation of activity of PIASgamma/y and other substrates by targeting them for proteolysis. We have identified substrates of Trim32, in particular the SUMOligase Piasy, by yeast two hybrid and interaction and functional domains by targeted mutagenesis approaches. We are using targeted knock down or expression by lentiviral or adenoviral systems in cell culture and in mice to dissect the role of Trim32/its substrates in initiation and malignant conversion.

Map kinase phosphatases (MKP) have dual roles in activation or inhibition of cellular differentiation or apoptosis through ERK1/2, jun kinase (JNK) or p38 kinase. We discovered downregulation of an MKP associated with rapid progression to malignancy and metastasis in a microarray/metagene analysis of skin carcinogenesis. We are using targeted/inducible gene expression and knock down strategies in cell culture and in mice to study the MKP role in regulation of MAPK functions in balancing cell proliferation, differentiation and apoptosis and cellular transformation and malignant progression.

The p53 family proteins as critical regulators of cellular response to DNA damage and stress signals and provide the context for the roles of putative initiators such as Trim32 and MKP4 in malignant conversion. We have detected p53 and p63 loss of function and dramatic downregulation of p73 during multistage carcinogenesis. As in at least half of human tumors, these losses occur without p53 family gene mutations. Using novel DNA binding assays to determine isoform specificity of action of this complex family, we are tracing the differential interactions of endogenous p53 family proteins with regulatory proteins partners and with DNA. Understanding p53 family protein ability to orchestrate the cell cycle, apoptosis and differentiation response to ionizing and ultraviolet radiation and other stresses may open new approaches to treat human disease.

Mike Liskay, PhD

Professor

OHSU Faculty Page
We use yeast and mice to study DNA mismatch repair (MMR),which corrects mismatches and senses DNA damage. MMR gene mutations increase spontaneous mutation and predispose to hereditary and sporadic cancer. Using gene targeting strategies, we derive and study knockout mice for four MutL homologs, Mlh1, Pms1 or Pms2, and Mlh3. We have observed increased mutation and cancer risk in these animals although the severity varies between the different knockouts. In a related project, we have developed an assay using the site-specific recombinase Cre to stochastically inactivate tumor suppressor genes or activate oncogenes in the mouse. The system also uses a color marker (b-galactosidase) which is activated by the recombinase thus marking those celllineages experiencing inactivation (or activation) of the "loxp"-tagged tumor suppressors/oncogenes. One question being addressed is "What is the minimum number of gene alterations necessary to promote intestinal tumor formation and progression in the mouse?" Our studies in yeast are centered on a better understanding of mechanism and the gene products involved in DNA mismatch repair.

Stephen Lloyd, PhD

Professor

OHSU Faculty Page
DNA repair processes and high fidelity DNA replication represent the major mechanisms to maintain genomic stability. Our laboratory uses multi-disciplinary approaches to focus on: strategies to prevent sunlight-induced skin cancer via the topical introduction of repair enzymes into human cells; the mechanisms by which the loss of a DNA repair enzyme can lead to the clinical manifestations of Metabolic Syndrome - a constellation of diseases (obesity, fatty liver disease, insulin resistance and hypertension) that affect >45 million Americans; the molecular mechanisms by which environmental toxicants create mutations in DNA; and; the cellular response mechanisms for the repair of DNA-protein crosslinks. See our Lab webpage.

Charlie Lopez, MD,PhD

Associate Professor

OHSU Faculty Page
My major research interest is the laboratory investigation into the basic cellular and molecular mechanisms underlying tumor formation and response to therapy. By studying these complex mechanisms, I ultimately hope to identify molecular targets for novel cancer t herapies. My clinical focus is in the area of gastrointestinal oncology and I am actively involved in clinical trials for a variety of GI malignancies.

Bruce Magun, PhD

Professor

OHSU Faculty Page
My major fields of interest involve cellular mechanisms of inflammatory signaling cascades that control the responses to environmental toxic agents.In some studies, the laboratory investigates how proinflammatory signals (cytokines, toxins, and other stressors) interact with surface receptors to activate the stress-activated protein kinases and NF-kappaB and how activation of these pathways leads to transcriptional regulation of genes. Some projects involve the effects of ricin, a potential bioterrorist agent, on activating proinflammatory pathways in vitro and in mouse models.In other studies we are investigating the mechanisms that control the responses keratinocytes to environmental agents such as ultraviolet radiation and xenobiotic toxic agents.

Amanda McCullough, PhD

Associate Professor

OHSU Faculty Page, CROET Page
Research interests in the McCullough laboratory are focused on the biochemical mechanisms of DNA base excision repair systems and the regulation and roles of DNA repair in cellular responses to environmental stress. Ultimately, we are interested in correlating alterations in these systems with human cancers, aging, and other disease states. Currently our research is focused primarily on two distinct DNA repair processes: 1) mechanisms and regulation of human oxidative DNA damage-specific repair and 2) biochemical mechanisms and therapeutic applications of ultraviolet (UV) light-induced DNA damage-specific glycosylases. In the area of oxidative DNA damage and repair, we primarily focus on the human MutY (hMYH) enzyme that functions as an adenine-specific DNA glycosylase. This enzyme is crucial in mutation avoidance following replication of DNAs containing 8-oxoguanine, where polymerases tend to incorporate adenine opposite the oxidized guanine. Failure to remove the adenine results in GC to TA transversion mutations. See our Lab Page.

Peter Rotwein, MD

Professor

OHSU Faculty Page
Peptide growth factors regulate cell division, intermediary metabolism, and differentiation by binding to and activating specific cell-surface receptors, and play essential roles in the growth and development of organisms as diverse as flies, worms, frogs, mice, and humans. Our laboratory studies regulation and actions of the insulin-like growth factors (IGFs), peptides critical for normal embryonic and post-natal growth in mammals and other species, and important for controlling aging and senescence. One major research direction focuses on the developmental biology of the IGFs by analyzing the signal transduction pathways and effectors of IGF-mediated muscle and bone differentiation. These studies make use of genetic complementation of cell lines engineered to lack different components of the IGF system, and our ability to knockdown and replace key signaling intermediates. Goals are to define the target genes and signaling mechanisms critical to stimulation of differentiation, which distinguish the actions of the IGFs from those of other peptide growth factors. Our other major research area focuses on control of IGF gene expression. Growth hormone, another key regulator of somatic growth, promotes IGF-I gene transcription via the Jak - Stat pathway. We have established that Stat5b is the key transcriptional intermediate in this process, but the biochemical mechanisms have not been defined. Goals are to use a combination of bio-informatic and molecular genetic approaches to dissect this pathway. As growth hormone and IGF-I have been used both therapeutically and illicitly to build body mass, our observations will have both scientific and biomedical implications.

Rosalie Sears, PhD

Associate Professor

OHSU Faculty Page
We are studying cellular signaling pathways involved in the generation of human cancer. In general, disruption of these pathways alters the ability of a cell to control its proliferation as well as the initiation of programmed cell death (apoptosis). We are focusing on three key signaling pathways that regulate both cellular proliferation and apoptosis: the Myc transcription factor, the Ras signaling protein, and the G1 cyclin dependent kinase (Cdk)/retinoblastoma(Rb)/E2F pathway. While each of these pathways has been extensively studied over the past decade, the nature of their interrelations remains elusive. Since these pathways are deregulated in the majority of all human tumors, we want to understand how they network and synergize to precisely control cellular proliferation versus cell death. This information will contribute to our understanding of the complex nature of cancer progression, and facilitate the generation of meaningful therapies

Jeffrey Singer, PhD

Assistant Professor

Faculty Page
One of the major protein degradation pathways found in eukaryotic cells is the ubiquitin degradation system. Ubiquitin mediated protein degradation utilizes a sequential cascade of enzymes, called E1 through E3, that result in the addition of ubiquitin to the substrate that is targeted for degradation. E3s, or ubiquitin ligases, are proteins that are responsible for recognition of the substrates targeted for degradation. One important class of E3s are the cullins that function as parts of multi-subunit complexes that are assembled in a modular fashion. Cullins have been shown to be involved in a large variety of biological processes, including cell cycle control, removal of N-glycosylation containing proteins, transcriptional control, hormonal regulation, differentiation, development, and prevention of neurological disorders. Our laboratory is interested in understanding how E3 ligases, the substrate recognition activity, function in mammalian cells. Our initial work has identified an E3 ligase that contains a cullin called Cul3 as a regulator of cyclin E. A targeted knockout of the Cul3 gene in mice resulted in early embryonic lethality with some cells exhibiting elevated levels of cyclin E compared to controls. Since not all cells exhibited this phenotype and elevated levels of cyclin E have not been shown to cause embryonic lethality, we hypothesized that Cul3 was involved in other important cellular processes. In order to determine what these processes are, we constructed a conditional knock out of the Cul3 gene, a floxed allele, which allows us to reduce Cul3 levels in a selective manner.

Phil Stork, MD

Senior Scientist

OHSU Faculty Page
Two fundamental cellular responses are proliferation and differentiation. Researchers in the laboratory have been studying this question using a signaling molecule called mitogen-activated protein kinase (MAP kinase) or ERK (extracellular signal-related kinase) as a model system to examine signals governing proliferation and differentiation. The Stork laboratory discovered a novel pathway for MAP kinase activation involving the small G protein Rap1 and the protein kinase B-Raf. The laboratory has continued to study the function of this pathway as a critical regulator of MAP kinase signaling in neuronal differentiation, gene expression, and cell growth. Current efforts are directed toward determining the requirement of this novel signaling cascade in developmental paradigms and pathophysiological models of disease.

One area of current interest is the notion of strength of MAP kinase signaling being able to dictate distinct responses. To this end the laboratory has examined mouse models that show intermediate level of signaling through the MAP kinase cascade. One target is the MAP kinase kinase kinase B-Raf. These studies have confirmed the idea that B-Raf expression is a developmental switch that selectively activates signals through the MAP kinase cascade. The laboratory is currently examining B-Raf’s role in T cell development using conditional ablation of B-Raf.

Mathew Thayer, PhD

Professor

OHSU Faculty Page
We found that four different translocation chromosomes display a delay in mitotic chromosome condensation (DMC) that is associated with a delay in the mitosis-specific phosphorylation of histone H3. Furthermore, this DMC phenotype is preceded by a delay in chromosome replication timing (DRT) that is characterized by a delay in the initiation as well as the completion of DNA synthesis. In addition, chromosomes with this phenotype participate in numerous secondary translocations and rearrangements, indicating that these chromosomes display chromosomal instability. Chromosomes with this phenotype are common in tumor cell lines and primary tumor samples. Furthermore, chromosomes with DMC/DRT can be generated by ionizing radiation. Our findings suggest that certain chromosomal alterations cause a significant delay in replication timing of the entire chromosome that subsequently results in delayed mitotic chromosome condensation and ultimately in chromosomal instability.

In addition, we recently found that exposing cells to radiation can also result in this abnormal chromosome duplication problem. Chromosome duplication is central to cell division and is tightly regulated when cells divide. Our work indicates that these chromosomes that duplicate at the wrong time are prone to break during cell division, and as a result become extensively rearranged. The consequence to the cell of having one of these chromosomes is that new chromosome alterations occur quite frequently; thereby resulting in the generation of many new mutations. Therefore, our work has identified a process that occurs in both cancer cells and in cells exposed to radiation, and therefore can explain the genetic instability that occurs in both cancer cells and in cells exposed to radiation. On our most recent work, we have developed a “chromosome engineering” system that allows us to create chromosomes with this duplication problem in a controlled manner.

Mitchell Turker, PhD

Senior Scientist

OHSU Faculty Page
I am interested in the mechanisms of abnormal gene inactivation and the relevance of these events to cancer and aging. Cancer and aging are linked because the incidence of cancer increases as we get older, but the reasons for this link are not understood. One possible mechanism that can explain this link is aberrant gene inactivation, because it is known that gene inactivation plays a critical role in cancer, and it is believed that the frequency of gene inactivation increases as a function of age. Abnormal gene inactivation results from two distinct types of events. The first is DNA mutation, which represents a change in the structure of DNA that alters expression of a given gene. The second type of event is DNA methylation, which causes silencing of a gene without affecting the gene sequence. My laboratory is using the autosomal mouse Aprt gene to study both mutational and DNA methylation events. With regard to mutational events, we are interested in both endogenous and exogenous genotoxins that can affect the frequency and types of mutations that occur within the animal. Our work with DNA methylation focuses on how methylation patterns are formed and on how perturbations of these patterns can lead to silencing of genes

Marcel Wehrli, PhD

Assistant Professor

OHSU Faculty Page
One of the most important pathways in development is the Wnt pathway. First identified in the fly, the Wnt pathway is important not only during development of flies, worms, mice and humans, but in the etiology of a number of human cancers. Wnts are glycoproteins that are secreted from cells and can function as long- or short-range signals. On a responding cell, the Wnt signal is received at the membrane by receptors of the Frizzled family, a class of seven-pass transmembrane proteins. Activation of an intracellular signaling cascade culminates in the accumulation of beta-catenin/Armadillo, which translocates to the nucleus and, together with members of the Lef/Tcf-family of DNA-binding proteins, results in a transcriptional response in signaled cells. However, our understanding how precisely Wnt is received at the cell membrane and signaling initiated on the cytoplasmic side remains unclear. We have a unique handle on this question.

Using fly genetics, we identified a novel component acting in the Wnt pathway, a single-pass transmembrane protein called Arrow. This is a candidate co-receptor for the Wnt ligand (together with Frizzleds) and its identification and cloning now allows us to investigate how a signaling complex is assembled. For instance, we recently found that the cytoplasmic tail of Arrow interacts with the scaffolding protein Axin. Axin is thought to function by binding beta-catenin/Armadillo, thereby preventing it from activating transcription in the nucleus. Our model now is that Arrow may release Armadillo from the Axin complex, thereby eliciting a signal. We can now address this and other key questions concerning the Wnt signaling pathway. For example, we generated an Arrow construct that in vivo greatly potentiates signaling. This construct still depends on signaling. Another construct activates the intracellular signaling cascade in vivo independent of ligand. Thus it contains all the elements necessary to assemble the signaling complex, and thereby functions as an activated receptor. A molecular dissection of this activated receptor will shed light on the signaling mechanism.

Missy Wong, PhD

Associate Professor

OHSU Faculty Page
Stem cells hold the promise of a therapeutic approach for treating disease. In the intestine, however, little is known about what regulates the stem cell or how stem cells in the developing intestine differ from those in the adult intestine. During intestinal development multiple stem cells populate the proliferative zone but only one stem cell is selected to populate each adult crypt. Previous studies perturbing beta-catenin signaling in the developing intestinal stem cell niche provide a snapshot of the dynamic process of stem cell selection. However, a temporal analysis of this process is lacking. Using an inducible Cre recombinase system to ablate (or to stimulate) beta-catenin signaling in the stem cell niche during intestinal morphogenesis and in the adult stem cell niche, we are poised to determine the mechanistic differences that drive intestinal stem cell selection during development and maintain the steady state population of the adult epithelium.

Interestingly, stimulation of beta-catenin signaling in the adult epithelium results in adenomatous polyps and colorectal cancer. Because the early molecular response to beta-catenin signaling remains elusive, we are currently identifying the molecular and cellular response in our induced beta-catenin adult mice. Upregulated genes have potential to be used for non-invasive diagnosis of polyp formation or as drug targets for colorectal cancer therapeutics

Wayne Zundel, PhD

Assistant Professor

OHSU faculty page
ZundelLab Website
Knight Cancer Institute Faculty Page

The Zundel Lab studies the mechanism & consequences of acute hypoxia (periods of hypoxia/reperfusion (H/I) of variable duration occurring frequently during tumor growth) in cancer progression. Tumor hypoxia & ischemia is a physiologic stress that induces increased genomic instability & mutation rate & has been shown to select for gain of oncogenes & loss of tumor suppressors resulting in more aggressive, invasive & metastatic tumors that are radiation & chemo-resistant. To comprehensively understand how normal tissues respond to hypoxia/ischemia & how these processes & functions are altered or co-opted during tumorigenesis, we use a combination of functional genetics, genomics, HT-Y2H, proteomics & bioinformatics to examine both the normal & oncogenic molecular architecture underlying oxygen-sensing and response mechanisms. Such a systemic approach is serendipitously uncovering novel aspects of basic cellular functions, such as energy metabolism, novel consequences of O2-related protein post-translational processes (Pro, His, Arg-hydroxylation, neddylation, ubiquitylation & proteolysis), translational arrest, IRES-mediated translational initiation, mRNA stability, & stem cell biology to name but a few. Our goal in comprehensively defining the molecular responses to hypoxia & how these processes go awry during cancer progression is to identify essential pathway nodes that cannot be by-passed & therapeutically target these nodes & regulatory pathways with high specificity. We feel that this approach will ultimately lead to the development of novel therapies as well as the identification of stage-specific diagnostic and prognostic markers. We also feel that as we define O2-mediated responses in normal tissues, other hypoxic/ischemic pathophysiologies such as pulmonary disorders (i.e. COPD), cardiac and vascular disorders (i.e. myocardial infarction & stroke), diabetes, infection, obesity, other certain aging-related disorders, etc. could be similarly defined & therapeutically targeted. Specific Projects are listed under “Research” on my KCI Faculty Page.

Grompe Lab MMG

Mike Heinrich-Chris Corless Labs

Hoatlin Lab Biochemistry and Molecular Biology (BMB)

Kurre Lab Pediatrics

Liskay Lab Molecular and Medical Genetics (MMG)

Lloyd Lab Center for Research on Occupational and Environmental Toxicology (CROET)

Lopez Lab Hem Onc

McCullough Lab CROET & MMG

Sears Lab

Thayer Lab BMB

Turker Lab CROET

Wong Lab

Affiliate Labs

Singer Lab Portland State University, Biology Dept.

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