TRANSLATIONAL CANCER BIOLOGY TRAINING PROGRAM

FACULTY MEMBERS

Professors 


Eric H. Baehrecke, Ph.D. - Dr. Baehrecke is a Professor of Cancer Biology and he is a member of the executive committee of the cancer biology graduate program. Research in the Baehrecke laboratory focuses on fundamental cellular processes that influence tumor cell biology, including cell survival and death. Forward genetic screens and genomic approaches in the model organism Drosophila were used to identify genes that function in cell survival and death. Genes that function in the regulation of cell growth, autophagy, nutrient utilization and steroid signaling were identified, and current studies are focused on understanding how these processes are regulated and coordinated in the context of normal development, and in cancer models. Components of the genetic pathways that have been identified in these studies represent candidate targets for therapy, as well as biomarkers that may be diagnostic of response to treatment.

Roger J. Davis, Ph.D. - H. Arthur Smith Chair in Cancer Research.  Dr. Davis is a Howard Hughes Medical Institute Investigator and a Professor of Molecular Medicine. The goal of the Davis laboratory is to understand the role of the c-Jun NH2-terminal kinase (JNK) signaling pathway in the etiology of cancer development.  JNK is implicated in proliferation, cell migration, cell survival, apoptosis, and the response to DNA damage.  Drugs that target JNK may be therapeutically beneficial for the treatment of cancer.  Dr. Davis’ research is designed to identify molecular mechanisms of JNK signaling and to evaluate the potential relevance of JNK to cancer therapy.  The major approaches employed in the laboratory include the construction and molecular genetic analysis of mouse models of human cancer, molecular imaging, cell biology techniques, and biochemistry. 

Stephen J. Doxsey, Ph.D.  – Dr. Doxsey is a Professor of Molecular Medicine whose laboratory is interested in understanding how two hallmarks of cancer–aneuploidy and centrosome defects–develop in essentially all human carcinomas. Centrosomes are organelles that form the poles of mitotic spindles and contribute to the segregation of chromosomes and thus to the fidelity of genomic inheritance. His lab and one other were the first to show that centrosomes are defective in most human carcinomas, increase with cancer grade and occur together with aneuploidy. He is now studying how centrosome defects contribute to aneuploidy and tumor formation by depleting or elevating centrosome protein levels in cells and testing for chromosome missegregation and acquisition of tumor-like features using in vitro and in vivo tumor assays and models. He has found that many centrosome proteins promote genetic instability by cytokinesis failure and mitotic spindle dysfunction. Through protein interaction studies, he has learned that the oncogenic nature of many centrosome proteins lies in their ability to interact with known tumor associated molecules and to serve as templates for anchoring both oncogenes and tumor suppressors at various cellular sites. His lab is now studying how these protein interactions and distributions contribute to the development and progression of human cancers.

Michael R. Green, M.D., Ph.D. – Lambi and Sarah Adams Chair in Genetic Research.  Dr. Green is a Howard Hughes Medical Institute Investigator and a Professor of Molecular Medicine.  His is also Director of the Program in Gene Function and Expression.  His lab has a broad interest in the mechanisms that regulate gene expression in eukaryotes, and the role of gene expression in various human disease states, in particular cancer.  Transcriptional regulation plays an important role in several aspects of cancer initiation and progression, and his lab uses a variety of molecular biological, genetic and biochemical approaches to study these transcription-based processes, to delineate the relevant regulatory pathways, and to identify the components in these pathways.  Currently, they are performing a series of genome-wide RNA-interference screens to identify factors involved in oncogene-induced epigenetic silencing, oncogene-induced senescence, transcriptional regulation of tumor suppressor genes and the induction of apoptosis by chemotherapeutic agents.  They are also using genome-wide RNA-interference screens to identify new tumor suppressor genes and genes that regulate metastasis.  The pathways and components revealed by these screens provide potential new targets for therapeutic intervention.

Chung-Cheng Hsieh, Sc.D. – Dr. Hsieh is a Professor of Cancer Biology whose area of interest is cancer epidemiology. His current research focuses on (1) prenatal origin of cancer risk, with special interest in the association of stem cells and perinatal factors with breast cancer risk, (2) gestational characteristics and maternal risk for breast and ovarian cancer, and (3) breast cancer risk factors for women of different ethnic backgrounds. His laboratory has ongoing large population-based studies to examine in umbilical cord blood samples the relation between measurements of stem cell potential, such as endothelial progenitor and mammary stem cell pools, and perinatal factors, such as endocrine mediators and birth size, for breast cancer risk. Studies using experimental animal models are also newly-initiated to test the hypothesis that mammary gland density is determined in part by the number of breast stem/progenitor cells that arise during the in utero/prenatal period and that the breast stem cell pool is correlated with exposure to in utero mitogen, in particular IGF-1. Additionally, his laboratory employs proteomic technologies to identify candidate biomarkers of reduced breast cancer risk. Understanding the mechanisms involved in the sequence of events between early-life exposures and adult cancer is important in cancer prevention research.

Michelle A. Kelliher Ph.D. – Dr. Kelliher is a Professor of Cancer Biology and she is a member of the executive committee of the cancer biology graduate program. One focus of her laboratory is to understand the molecular basis of T cell acute lymphoblastic leukemic (T-ALL) using the mouse as a model system. They find that mutation of the Notch1 receptor occurs in 72% of mouse tal1 T cell tumors and these tumors remain dependent on Notch1 signals for their growth/survival. Notch1 contributes to leukemic growth by directly inducing the expression of c-myc and potentially other target genes. They are currently investigating the contribution of the Notch1-myc pathway to normal thymocyte development and to the development of other malignancies. A second area of interest is in NF-kB signaling, where they have identified Rip1 as a critical mediator of TNF-induced IKK activation. They have shown that the kinase activity of Rip1 is not required, but rather its stable modification by K63-linked polyubiquitin chains is critical for its ability to mediate IKK activation. Rip1 has also been implicated in NF-kB activation by Toll-like receptors and they are currently testing a role for polyubuiquitinated Rip1 in these pathways and in innate immune responses.

Arthur M. Mercurio, Ph.D. (Program Director) – Dr. Mercurio is the Interim Chairman of the Department of Cancer Biology and Director of the Graduate Program in Cancer Biology.  His research focuses on understanding the biology of aggressive carcinomas, especially their invasive behavior.  The epithelial to mesenchymal transition (EMT) has proven to be a useful paradigm for studying mechanisms that underlie invasive carcinoma, and the laboratory has established several model systems for probing the EMT of breast, colon and prostate carcinoma.   These models are being used to decipher how the tumor microenvironment affects the EMT, and to identify potential therapeutic targets for disseminated disease.   A major strength of the laboratory is the role of integrins, especially the a6b4 integrin, in promoting invasive growth.  Ongoing projects also involve the role of growth factor and nuclear hormone receptors in regulating the EMT and invasion.  The laboratory has also initiated studies on the involvement of microRNAs and epigenetics in these processes.

Peter E. Newburger, M.D. – Ali and John Pierce Chair in Pediatric Hematology/Oncology.  Dr. Newburger is a Professor of Pediatrics and Cancer Biology.  His laboratory currently investigates the molecular basis for neutrophil function and development. Neutrophils provide the first line of host defense against microbial invasion and play a major role in the protection of cancer patients from bacterial and fungal infections.  Previous studies of RNA expression in neutrophils have revealed a remarkably vigorous transcriptional response to activation by various stimuli, including changes in expression of a large number of transcription factors.  He is now pursuing a coordinated and comprehensive investigation of the transcribed regions, non-coding RNAs, and the regulators of transcriptional activity in developing and mature neutrophils. Studies include the identification of “novel” transcripts using massively parallel sequencing, investigation of transcription factors and their promoter sequence targets, testing the roles of chromatin structure and remodeling proteins in neutrophil activation and differentiation, and exploring changes in the sites of DNA methylation during myeloid differentiation. Identification of novel neutrophil-specific genes and regulatory networks could provide new targets for augmentation of host defense in cancer patients. His laboratory is also exploring a novel approach to gene therapy for chronic granulomatous disease, a hereditary disorder of neutrophil function.

Alonzo H. Ross, Ph.D. – Dr. Ross is a Professor of Biochemistry & Molecular Pharmacology. – The Ross lab studies the PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumor suppressor. PTEN was originally cloned as a tumor suppressor for brain tumors, but we now know that it is mutated or deleted in many human cancers and is probably the second most commonly mutated tumor suppressor. He currently has five projects in the lab. First, he is developing a mouse model for brain tumors that lack PTEN and have a hyperactivated epidermal growth factor receptor. Second, using the cells from the mouse model as well as human lines, he is examining the relative effects of chemotherapy on cancer stem cells. He hopes to learn how to target the cancer stem cells and, thereby, reduce the side effects of these treatments. Third, glioblastomas are unusual in that even low-grade tumors tend to be invasive. This invasiveness makes glioblastomas extremely difficult to treat and cure. He is examining PTEN-regulated proteins that may regulate invasiveness, seeking new targets for therapy. Fourth, he has proposed that certain non-substrate phosphatidylinositols can induce a PTEN conformational change and thereby activate the phosphatase domain. He is now analyzing this conformational change with biophysical techniques such as infrared spectroscopy and fluorescence to determine the mechanism by which PTEN is regulated. Fifth, PTEN mutations have also been detected in patients with autism. He is expressing and characterizing these mutant proteins as a first step to understanding how PTEN mutations contribute to this developmental disease. His lab is excited to study a protein such as PTEN that plays a role in so many normal and pathological processes. The potential for practical applications to human maladies is enormous.

Gary S. Stein, Ph.D. – Gerald L. Haidak, M.D., and Zelda S. Haidak Professor of Cell Biology.  Dr. Stein is also Chairman of the Department of Cell Biology and Deputy Director of the UMCC. His research program is defining the relationships between nuclear structure and function during cell proliferation, differentiation and tumorigenesis.   He is analyzing the organization, assembly and integration of regulatory machinery for gene expression in nuclear microenvironments, to mechanistically investigate control of transcription within the context of nuclear architecture. Projects include: 1) mechanisms by which the AML1 (Runx1) transcription factor promotes hematopoietic cell differentiation and how Runx1 is linked to the onset and progression of cancer; 2) modifications in intranuclear morphology and subnuclear organization of the combinatorial assembly of regulatory machinery within the nucleus which is paramount to the onset and progression of tumorigenesis; 3) temporal and spatial parameters of the mitotic partitioning and selective reorganization of tissue-specific transcription factors in progeny cells; 4) fidelity of intranuclear trafficking that is required for developmental control of gene expression by AML3/Runx2 as well as for expression of AML/Runx responsive genes that control the formation of osteolytic lesions in bone by metastatic breast cancer cells); 5) cell cycle control using the histone gene promoter as a paradigm for the G1/S phase transition.  He is actively pursuing the temporal and spatial parameters of cell cycle progression and maintenance of integrity of essential cell cycle surveillance mechanisms and check points; 6) cell cycle control in human embryonic stem cells as a component to our commitment to address stem cell involvement in the onset and progression of tumorigenesis; 7) the influence of AML/Runx transcription factors on metastatic cancer cells, and; 8) the intranuclear organization of regulatory domains in relation to tumor growth and metastasis to define in vivo the dynamic changes that are operative within the context of nuclear architecture during tumor progression. 


Associate Professors

Sharon B. Cantor, Ph.D. – Dr. Cantor is an Associate Professor of Cancer Biology and a member of the executive committee of the graduate program whose research focuses on hereditary cancer syndromes. Research is dedicated to understanding how inherited defects in DNA repair proteins, such as the hereditary breast cancer associated protein, BRCA1, and its direct binding partner, BACH1/FANCJ, lead to aberrant DNA repair and loss of tumor suppression. Thus far, research demonstrates that loss of function of BRCA1, BACH1/FANCJ, or the direct interaction between these proteins leads to defects in DNA double strand break repair and maintenance of chromosomal stability. What’s more, both proteins are linked to Fanconi anemia, a recessively inherited childhood disease plagued by a high rate of cancer, such as leukemia. Molecular genetic and biochemical approaches to dissect the function of these proteins in DNA repair has also lead to the finding that BACH1/FANCJ binds directly to mismatch repair protein,MLH1. MLH1 is linked to hereditary colon cancer, as well as to the development of chemoresistance of tumors following chemotherapy. The Cantor laboratory is pursuing how the link between these proteins and cancer syndromes may provide new strategies for combating chemoresistance.

Lucio H. Castilla Ph.D. – Dr. Castilla is an Associate Professor of Molecular Medicine and a member of the Program in Gene Function and Expression. His research focuses on the study of hematopoietic stem cell function and leukemia development. He uses genetic (mouse models and retroval insertional screens), cellular and molecular approaches to identify and characterize the pathways affected by the recurrent fusion oncogene Cbfb-MYH11 in hematopoietic progenitors and its cooperating mutations responsible for leukemic transformation.

JeanMarie Houghton, M.D., Ph.D. – Dr. Houghton is an Associate Professor of Medicine and Director of Cancer Stem Cell Affinity Group of the UMCC.  Her research focuses on two aspects of cancer. Helicobacter infection is the leading cause of gastric cancer worldwide.  How the bacterium cause disease is not clear, but it is clear the host immune response is crucial in this process.  Her laboratory has focused on the Fas Ag/FasL signaling cascade where Fas Ag is expressed on gastric mucosal cells and the Fas L is supplied by invading inflammatory cells.   Normally, the Fas signaling cascade triggers apoptosis through either direct caspase 8 activation (type 1 signaling) or through a mitochondrial amplification loop (type 2 signaling).  During the progression from metaplasia to dysplasia to gastric cancer, cells acquire resistance to Fas medicated apoptosis via upregulation of FLIP- an endogenous inhibitor or FLICE/procaspase 8. Interestingly, Fas signaling in these cells activates Erk1/2 resulting in apoptosis, thus converting an apoptotic pathway to a proliferative pathway.   Using both in vitro models of cancer and in vitro assays, her laboratory is continuing to define the proliferative pathway of Fas signaling and its role in gastric (and colon) cancer, and metastatic disease.

The second focus of her laboratory is to determine the role of bone marrow derived cells in the formation of cancer.  Using their mouse model of Helicobacter-induced gastric cancer, they have shown that bone marrow derived cells (BMDC) act in repair of inflamed and injured gastric mucosa, incorporate as gastric mucosal cells which then undergo metaplastic, dysplastic and neoplastic changes with continued exposure to the inflammatory milieu.  Using a combination of in vitro culture systems and bone marrow transplantation of marked, gender mismatched MSC, they are exploring the role of BMDC in other solid tumors, the contribution of these cells to the stroma and the role of fusion.

Stephen N. Jones, Ph.D. – Dr. Jones is an Associate Professor of Cell Biology, Director of the Transgenic Core Facility and a member of the executive committee of the graduate program. Research in the Jones lab involves the generation and analysis of genetically modified mice to investigate the regulatory pathways governing normal cell growth and development, and to examine how alteration of these pathways leads to tumorigenesis. Ongoing projects include the role of Mdm2 in p53-dependent and p53-independent regulation of cell growth, chromatin remodeling in tumor suppression, and the effects of non-canonical wnt signaling in development and cancer.

Timothy F. Kowalik Ph.D.  – Dr. Kowalik is an Associate Professor of Molecular Genetics & Microbiology. Research in the Kowalik laboratory is focused on the relationship between proliferation control and apoptosis signaling.  He has found that perturbation of retinoblastoma protein function by viral oncoproteins, including HPV-E7, or RNAi-mediated depletion activates an ATM-Chk2-p53 apoptosis program. Surprisingly, the initiator of this apoptotic response is an E2F1-mediated accumulation of DNA double strand breaks (DSBs). He is currently determining how E2F1 activity can lead to DSBs and, given that E2F1 is deregulated in all cancers, whether this damage contributes to the genomic instability observed during tumorigenesis. These studies are part of an ongoing collaboration with Stephen Jones. He is also collaborating with Dario Altieri on his novel findings that activated Chk2 can sometimes function as a oncogene. A newer area of research is directed at understanding the relationship between DNA tumor viruses and the RNAi pathway. Some viruses, such as Adenovirus and Kaposi sarcoma associated herpesvirus, encode miRNAs and presumably use RNAi as part of their replication program. His lab is determining how the host RNAi pathway influences virus replication using 3T3 cells derived from mice that are conditionally null for Dicer and how the viral miRNAs affect both the host environment and virus replication/latency.

Brian Lewis, Ph.D. – Dr. Lewis is an Associate Professor of Molecular Medicine and a member of the Program in Gene Function and Expression. His laboratory group is interested in understanding the mechanisms through which specific genetic alterations contribute to the phenotype of malignant tumors. His lab focuses on two tumor types – pancreatic cancer and hepatocellular carcinoma. Using novel mouse models that they have generated, they are exploring how specific events – activating k-ras gene mutations, activation of the hedgehog signaling pathway – affect the initiation and progression of pancreatic cancer. In particular, they are interested in understanding how other commonly occurring events, such as genomic instability and the loss of the Ink4a/Arf and p53 tumor suppressors, interact with these oncogenic changes to influence the disease process. In hepatocellular carcinoma, their current focus is on understanding the events that influence extra-hepatic spread of this malignancy, a common finding upon patient presentation that eliminates the possibility of surgery, which remains the only curative option for this disease.

Stephen Lyle, M.D., Ph.D. – Dr. Lyle is an Associate Professor of Cancer Biology and Pathology, and Director of the Tumor Bank of the UMCC. He is also Director of the graduate course on Histology and Tumor Pathology, and a member of the executive committee of the graduate program. The goal of the Lyle laboratory is to understand the molecular mechanisms involved in the transformation of adult stem cells into cancer and the characterize the signaling pathways that define the phenotype of "cancer stem cells". The Wnt/b-catenin/LEF/TCF signaling pathway is known to play an important role in normal adult stem cell fate determination, and alterations in this pathway have been found in several types of cancer. Dr. Lyle's research uses human skin as a model system to study the oncogenic effects of this pathway on skin stem cells. His lab has developed methods for extracting multi-potent stem cells, as well as lineage-restricted cells from human skin, and they are addressing these questions using genetic modification of stem and progenitor cells. More recent studies are designed to characterize genotypic and phenotypic differences between bulk cancer cells and the subpopulation of "cancer stem cells" present within tumors. Dr. Lyle's lab has established a novel sebaceous carcinoma cell line and normal sebaceous progenitor cell line to expand upon evidence from sebaceous tumor tissue and to develop an in vitro model for studying "cancer stem cells." More effective targeting of "cancer stem cells" may decrease cancer recurrences and lead to more effective treatments.

Leslie M. Shaw, Ph.D.  – Dr. Shaw is an Associate Professor of Cancer Biology and Co-Director of the Breast Cancer Program of the UMCC and a member of the executive committee of the graduate program. The research interests of the Shaw Lab are aimed at understanding the mechanisms involved in the progression of breast cancer to metastatic disease. A major interest of the lab is the contribution of Insulin Receptor Substrate (IRS)-dependent signaling pathways to breast cancer metastasis. The IRS proteins are adapter proteins that are recruited to surface receptors in response to ligand binding where they organize complexes that initiate intracellular signaling cascades.    With regard to breast cancer, the IRS proteins are the major downstream intermediates of a variety of surface receptors, including the IGF-1 receptor, which have been implicated in tumor progression.  Studies from her lab have demonstrated that IRS-1 and IRS-2 play divergent roles in mammary tumor metastasis.  Specifically, mammary tumors that lack IRS-2 are significantly diminished in their ability to metastasize and IRS-1 cannot substitute for this function.  In fact, tumors lacking IRS-1, and expressing only IRS-2, are more metastatic than their normal counterparts.  Ongoing studies in the lab are aimed at investigating the differences between IRS-1 and IRS-2 regulation and signaling and at elucidating the mechanism by which IRS-2 promotes and IRS-1 suppresses metastasis using both in vitro and in vivo approaches. 


Assistant Professors

Karl J. Simin, Ph.D. - Dr. Simin is an Assistant Professor in the Department of Cancer Biology. The goal of the Simin laboratory is to identify genetic alterations that cooperate in breast cancer progression. Using mouse mammary tumor models and human breast cancers, Dr. Simin’s research is designed to first identify molecular signatures that improve cancer prognosis, and then define the mechanism through which these changes contribute to cancer progression. The major approaches employed in the laboratory include the construction and molecular genetic analysis of mouse models of human breast cancer, microarray analysis of gene expression and chromosomal imbalances, bioinformatics, and cell biology techniques.

Merav Socolovsky, Ph.D., M.B.B.S. – Dr. Socolovsky is an Assistant Professor of Pediatrics and Cancer Biology whose research focuses on the molecular mechanisms of the erythropoietic stress response, a process whereby the rate of red cell formation is accelerated up to ten-fold the baseline rate. The erythropoietic stress response is essential for survival and recovery from therapeutic procedures such as chemotherapy and stem cell transplantation, both of which are used in the treatments of hematological malignancies and solid tumors. Further, deficits in erythropoiesis, the mechanisms of which are as yet unknown, are responsible for the frequent anemia that is associated with cancer of many etiologies. Erythropoietin (Epo) is the principal regulator of erythropoiesis; Epo therapy provides an important treatment for anemia and associated fatigue in cancer patients, with resultant improvement in quality of life. Therefore, a mechanistic understanding of the erythropoietic stress response and the role of Epo may suggest therapeutic ways to increase its efficacy.

Lan Xu, Ph.D. -  Dr. Xu is an Assistant Professor of Molecular Medicine whose research focuses on TGF-b signal transduction and its regulation of cell proliferation and differentiation, and cancer development.  They use genome wide RNA interference (RNAi) to identify factors that modulate TGF-b signal transduction and evaluate their functions in TGF-b-mediated control of cell proliferation and differentiation. His interest is to dissect the molecular network underlying the multifaceted impacts of TGF-b on both cancer cells and the stroma, and to understand how cancer cells evade the tumor suppression function of TGF-b at the onset of tumorigenesis and how at later stages certain aspects of TGF-b network is exploited by the cancer cells to facilitate local invasion and metastasis. The ultimate goal is to identify targets of intervention that will enable us to manipulate TGF-b signaling in order to combat cancer progression.