Cancer Biology

It is well established that the processes of endocytosis and signaling are functionally linked.  For example, abnormalities in the process of endocytosis are associated to malignant transformation due to deficient downregulation of signaling receptors. However, endocytosis is also implicated in signaling activation.  For instance, internalization is required for routing ligand-receptor complexes to endosomal compartments (‘signaling endosomes’) where they can initiate specific signaling events.  Further, our laboratory established that endocytic proteins can directly activate signaling pathways involved in cell polarity and cytoskeleton remodeling. Currently, our research is focused on the role played by the endocytic machinery in the activation of signaling pathways related to cancer cell invasion.  We are particularly interested in the mechanisms linking endocytosis with epithelial-mesenchymal transition in fibrosarcoma and bladder carcinomas. In order to pursue our research goals, we use genetic, biochemical and cell biological techniques in yeast and mammalian cells.  We study protein-protein interactions by using biophysical, biochemical and genetic tools.  We also investigate the physiological relevance of these interactions in live cells by combining siRNA-mediated knock-down, functional assays (e.g., cell migration and invasion), time-lapse microscopy and Fluorescence Resonance Energy Transfer.

Obesity is associated with breast cancer incidence, tumor invasiveness and higher cancer morbidity rates.  Our work focuses on understanding the mechanistic links between obesity and cancer progression.  Towards this, the goals of our research are to 1) define the relationship between diet, early onset obesity and breast cancer aggressiveness, 2) identify mechanisms of the adipocyte hormones leptin and adiponectin on breast cancer progression 3) determine the impact of obesity on mammary tissue and tumor microenvironment. We have developed a rat model of early obesity and used multiphoton multimodal imaging to simultaneously evaluate tumor cells and multiple stromal components in mammary tumors.  We have also used proteomic and genomic methods to identify actions of the adipocytokine leptin on tumor cell growth.  Furthermore, a unique co-culture system is used to study molecular cross-talk between adipocytes and cancer cells.  This work is revealing new insights in the role of obesity on breast cancer and lays a foundation for development of novel cancer treatment and prevention strategies.

Mutations in the highly conserved Notch receptor have been shown to cause T-cell leukemia in human.  It is now known that the activation of the Notch pathway requires the internalization of the ligand, but the precise mechanism is not well understood.  Using Drosophila, we have shown that auxilin, a critical regulator of the clathrin-mediated endocytosis, participates in the Notch signaling pathway.  Furthermore, we have shown that this function of auxilin in Notch is conserved in vertebrate systems.  We are combining molecular genetics and cell biological approaches to improve our understanding of how ligand endocytosis facilitates Notch activation..

Fekete, Donna

Our research program investigates many aspects of vertebrate inner ear development, at least two of which have relevance to cancer research.  The first involves asking how the Wnt signaling pathway controls proliferation and the progression of cell differentiation.  The Wnt pathway has been linked to development and disease, including cancer, in other organ systems.  Using the avian inner ear as a model system, we have found that uncontrolled Wnt signaling blocks chondrogenesis in the mesenchyme, generates an over-abundance of sensory cells in the ectoderm, and affects the choice of sensory cells fates (favoring vestibular over auditory).  A second line of investigation asks what role microRNAs play in regulating the transition from a cycling progenitor cell, or stem cell, to the differentiated state.  A survey of the expression and function of individual microRNAs in the zebra fish inner ear is underway.  In limited cases, we are testing the potential use of microRNAs as a therapeutic tool for regenerating sensory hair cells using the mouse as a model system.

Kirshner, Julia

Strong evidence in support of the cancer stem cell theory has been steadily accumulating over the last decade.  In addition to tumor generating potential, a cancer stem cell possesses characteristics of normal stem cells including proliferative quiescence and self-renewal potential.  Patients suffering from both hematological malignancies and solid tumors often see their disease relapse due to the inability of the currently used therapies to target cancer stem cells, which are inherently drug-resistant.  My laboratory studies properties of the cancer stem cells using two model systems: multiple myeloma, a cancer of the bone marrow, and breast cancer, representing hematological and solid malignancies respectively.  The long-term research objective of my laboratory is to investigate the role of microenvironment in maintaining the balance between self-renewal and differentiation of cancer stem cells.  We hypothesize that cancer stem cells are localized to a specialized microenvironment niche, which keeps these cells in a non-proliferative state.  Upon receiving proliferation signal(s) from the microenvironment, a cancer stem cell switches its program from self-renewal to differentiation initiating tumor growth and/or metastatic spread.  To study the basic biology of cancer stem cells and to explore their therapeutic vulnerabilities, we utilize both in vitro and in vivo approaches.  We have developed a three-dimensional tissue culture model recapitulating the microenvironment and architecture of the human bone marrow and a xenograft, humanized mouse model faithfully reproducing human bone disease.  In addition to these model systems, we employ state of the art techniques such as microscopy, flow cytometry, mass spectrometry, and microarray-based technologies.

Konieczny, Stephen

Our laboratory is interested in defining the molecular mechanisms by which normal pancreatic cells become genetically altered on their way to producing pancreatic ductal adenocarcinoma (PDA).  The processes involved in this transition are complex and include mutation of the Kras protooncogene, which leads to cellular dedifferentiation and activation of downstream signaling pathways and transcriptional networks.  To understand the very earliest events responsible for generating PDA, we utilize genetically engineered mouse models that can be induced to develop pancreatic cancer in a highly reproducible fashion.  A multipronged approach involving mouse genetics, molecular biology, gene arrays, and cell and organ imaging are used extensively to characterize the transcriptional and signaling pathways that underlie this disease.  Our long-term goals are to define the initiation events so that appropriate therapeutic strategies can be exploited to successfully treat patients with PDA.

Leung, Yuk Fai

We are working to establish zebra fish as a cancer research model.  In collaboration with Dr. Joe Ogas, Department of Biochemistry, we are studying the effect of a chromatin remodeler, CHD5, in growth regulation and neural development.  We use microinjection to deliver biomolecules that perturb CHD5 function in developing zebra fish embryos and follow the resulting effects using various histological techniques.

Mattoo, Seema

(Biochemistry, Signal Transduction, and Microbiology) Investigation of Fic domain containing proteins in Cellular Signaling.

Suter, Daniel

Cell movements play a critical role during development, adult life and in various diseases.  Important examples include the growing tip of an axon, the neuronal growth cone, and the invasive behavior of cancer cells.  Our laboratory is currently focusing on the mechanisms of growth cone motility and guidance.  Using the very large growth cones of cultured Aplysia neurons as a model system, we investigate how the growth cone integrates its sensor, signaling and motility functions to achieve directional movements towards target cells.  We use a combination of advanced live cell imaging, cell biological and molecular techniques to investigate the dynamics and function of adhesion, signaling, and cytoskeletal proteins involved in cell migration.  We focus on the role of Src tyrosine kinases and one of its substrates, cortactin, in adhesion-mediated growth cone steering.   Both Src and cortactin have been implicated in cancer metastasis.  Thus, we hope that our growth cone studies will provide important insights into how Src and cortactin regulate cell migration, including in cancer cells.

Taparowsky, BJ

Our laboratory is interested in proteins that regulate cell growth.  We study how alterations in the expression of these proteins influence mammalian development and contribute to the aberrant growth characteristics of cancer cells.  Our current focus is on the Batf family of basic leucine zipper transcription factors (Batf, Batf2 and Batf3) which function as inhibitors of cell growth.  Two of these proteins (Batf and Batf3) are normally expressed in the cells of the immune system and we are exploring how overexpression of these inhibitors, or loss-of-function of these inhibitors, impacts the development of B and T lymphocytes.  While we can investigate some of these effects using isolated subsets of immune system cells grown in culture, we also are using genetically engineered mice to test how these inhibitors impact the global regulation of the immune system in vivo.  Our goal is to provide the basic observations necessary to assess the feasibility of using the Batf family proteins to design molecular strategies to control disease states such as cancer. 

Waddell, Peter (member of Molecular Biosciences Cluster)

My research focuses on the TP53 gene and how it has evolved and functions.  TP53 is the most frequently modified gene in cancers and a critical aspect of their suppression and potential treatment.  As you may be aware, the gene directly upstream and head-to-head with TP53 is the WRAP53 gene.  It now seems to be equally important as TP53, since it appears to be essential for the activity of telomerase.  Critically, a minor transcription/splice variant of WRAP53 which overlaps the short first non-translated exon of TP53 is required for TP53 expression.  The mechanism of this is highly novel and involves non-stoichometric RNA-transcript stabilization.  Thus, a critical part of the TP53 story is no WRAP53 expression = no telomerase = no TP53 expression.  This appears to be a logical mechanism for preventing TP53 induced apoptosis, unless telomerase is active.  Surprisingly, this gene to gene association seems a relatively recent innovation apparently restricted to mammals alone (the WRAP53 gene moved into its current position immediately upstream of TP53 along with a few other genes).  To explore the lowest levels of transcriptional regulation we are looking in detail at chromatin structure near TP53.  This includes nucleosome affinity mapping in vitro and FAIRE mapping in vivo.  Both procedures require mass sequencing technologies.  To aid us in our studies we have accumulated and maintain a wide collection of wild-type fibroblasts for a wide range of mammals.  Thus, studying the activities of dangerous (from an aging perspective) genes like TP53 in long lived animals is rather easier than it might sound given human, elephant, whale and horse cell lines.  My lab also has specialization in bioinformatics, so we develop better methods for mapping gene expression data.  Beyond that, we have interests in the classification and identification of sub-classes of cancers using data mining techniques.  We are currently redeveloping the basic hierarchical clustering tools for grouping cancers based on their gene expression profiles and comparing them to MDS based representations.  One of our hopes is to sequence and assemble the complete the genome of that very popular but understudied mammal, the aardvark.  One of its appeals, apart from being the most popular mammal (based on phone book listings), is that its genome apparently experienced a huge burst of LINE insertion activity in the past 20 million years (as evidenced by FISH analysis). It will be interesting to investigate which of its cancer genes may have been disrupted by this activity.  Curiously, the common regulatory region of TP53 and WRAP53 experienced just such a LINE insertion in the common ancestor of mammals, in the same general period that WRAP53 and TP53 seemed to first "join forces" so to speak.  This supports the remarkable aspects of cancer regulation that can be illuminated by comparative genomics.