Students & Research

Years shown as of Sept 2011.

Functional Role of Met in the Nucleus.

Year: 6
PI: Rimm

The Met receptor is a transmembrane receptor tyrosine kinase that when activated signals through a number of pathways essential for cell spreading, cell-cell dissociation, and increased motility. Previous work in our lab has shown that like a number of other membrane-bound RTKs, Met can localize to the nucleus. We have also demonstrated that high levels of nuclear Met are associated with poor survival. The aim of my research is to determine the function of nuclear Met and how it is contributing to cancer progression.

Signaling by the NRG1 ICD.

Year: 6
PI: Stern

NRG1 is a ligand for the ErbB receptor family and is essential for development due to its involvement in the cardiac and nervous systems. NRG1 is also involved in signaling in the mammary gland that occurs during pregnancy and lactation. NRG1 is expressed on the cell surface as a transmembrane protein. The extracellular domain is released by cleavage and acts as the ligand for the receptors ErbB3 and ErbB4. Interestingly, the NRG1 intracellular domain is extremely large compared to other ErbB ligands and is evolutionarily conserved. My project investigates potential functions of this conserved intracellular region.

Thrombospondin 2 in wound healing.

Year: 6
PI: Kyriakides

Thrombospondin 2 (TSP2) is an anti-angiogenic extracellular matrix protein, known to modulate cell-ECM interactions. TSP2 knockout mice have altered collagen fibrillogenesis and enhanced wound healing in ischemia and angiogenesis models. Improved healing is associated with enhanced angiogeneisis, through mechanisms including altered ECM assembly, MMP expression and altered receptor mediated signaling. The goals of this project aim to understand the significance of these components to vascular remodeling, particularly in the context of wound healing.

Mechanism of the Nuclear Localization of c-Met.

Year: 6
PI: Rimm

The Met receptor tyrosine kinase for the hepatocyte growth factor (HGF) plays a critical role in cancer cell proliferation, motility, invasion and metastasis. Our lab has found tthat high expression of Met in the nucleus is associated with shorter survival in breast cancer. Furthermore, we have found a 60 kD fragment that localizes to the nucleus. My project aims to identify the proteins and pathways involved in this process with the underlying hypothesis that Met in the nucleus is playing an important role in cancer. Since several pharmaceutical companies are actively investigating Met inhibitor based therapies for cancer, a more complete understanding of the mechanism and function of Met in the nucleus is essential.

Defining the interaction between the Fanconi anemia pathway and the transcriptional machinery/RNA.

Year: 6
PI: Kupfer

Fanconi anemia(FA) is an autosomal and X-linked recessive disorder caused bybiallelic mutation of one of the 13 genes which make up the FA pathway. Cells from patients with FA exhibit hypersensitivity to DNA crosslinking agents and gross chromosomal abnormalities such as radial chromosomes and translocations. As the result of these characteristics, FA has been categorized as a disease of genomic instability and the FA pathway has been hypothesized to function in DNA repair.  While the interaction of several FA proteins with proteins known to participate in the homologous recombination and translesion synthesis methods of DNA repair has lent credibility to this hypothesis, there are several lines of evidence which link the FA pathway to RNA metabolism and the transcriptional machinery as well.  As aberrant processing of nascent RNA transcripts produced by the transcriptional machinery can result in genomic instability, a role for the FA protein FANCD2 in sensing DNA damage encountered by transcribing polymerases and in signaling for transcription termination fits well with the hypothesized function of the pathway.  My project involves defining the interaction of the FA pathway and more specifically FANCD2 with the transcriptional machinery and RNA.

Multiplexed Assessment of HER2 pathway proteins to predict response to Trastuzumab.

Year: 5
PI: Rimm

My project aim is to quantify the level of expression and subcellular localization of HER2 pathway proteins and use the information to predict response and resistance of Trastuzumab. Through this project, I intend 1) to classify HER2 positive breast cancer into more detailed sub-types; 2) to find clinical implication of complicated Trastuzumab resistance; 3) to find a model that will assist the determination of Trastuzumab administration.

Exploring Receptor Tyrosine Kinase Activation in Melanoma.

Year: 5
PI: Stern

Receptor tyrosine kinases (RTKs) are proteins located at the cell surface which control cell differentiation, proliferation, and survival. RTKs are frequently dysregulated in cancer, which makes them viable targets for therapeutic intervention. Development of RTK-directed therapies has, however, been limited by a lack of information about which RTKs are active in specific cancer subtypes, how these activations are occurring, and how the signaling of one RTK may compensate for the signaling of another RTK. My project explores the activation of RTKs in melanoma and whether these activations occur in specific patterns. The project’s goal is to determine which RTKs have the greatest influence on melanoma pathogenesis and how these RTKs should be targeted to modulate disease progression.

Thrombospondin-2 in vascular pathology.

Year: 4
PI: Kyrikides

Thrombospondin 2 (TSP2) is a matricellular protein that modulates cell-matrix interactions and is a potent inhibitor of angiogenesis during tissue repair. Previous studies in TSP2-null mice showed enhanced wound healing, increased angiogenesis, and altered collagen fibrillogenesis suggesting that TSP2 regulates several cellular processes during repair. In addition, preliminary evidence suggests of a potential negative feedback mechanism between TSP2 and nitric oxide (NO). Moreover, there seems to be a correlation between the negative outcome of tissue repair in the presence of low NO levels and the presence of increased TSP2. Interestingly, patients with Diabetes Mellitus type I and II are unable to heal wounds efficiently and this pathology is associated with reduced angiogenesis, altered extracellular matrix (ECM) deposition and remodeling, and a decrease in the levels of NO. The main goal of this project is to investigate the hypothesis that increased TSP2 expression in diabetic wounds, due to low NO levels, contributes to vascular pathology leading to compromised healing.

The Potential Role of E-cadherin during Megakaryocyte and Erythroid Differentiation

Year: 4
PI: Krause

E-cadherin is an adhesion molecule with crucial roles in epithelial cell organization, development, and tumorigenesis. However, aside from studies dating back several years that suggest a potential role of E-cadherin in erythropoiesis, its role in hematopoiesis has not been extensively investigated. Given current research supporting non-adhesion functions of E-cadherin as a signaling molecule, and its potential role in promoting actin polymerization, the objective of my thesis project is to elucidate the role of E-cadherin in megakaryopoiesis and erythropoiesis.

Characterization of the Histone Demethylase PLU-1.

Year: 4
PI: Yan

Recent studies have shown the importance of histone methylation in the regulation of target gene expression. My project involves characterizing roles of the histone demethylase PLU-1 in the human breast cancer. Another focus of the study is to determine whether PLU-1 would act as a mechanism for Herceptin resistance observed in breast cancer cells.

Development of Potential Novel Combinatorial Therapies in Malignant Melanoma.

Year: 3
PI: Stern

Malignant melanoma is a rapidly increasing public health problem in the United States and in the world, with an increasing incidence of cases as well as decreasing average age of diagnosis. Currently, few treatment options are available for malignant melanoma patients, but, recently, new potential therapeutics have been developed, such as the mutant BRAF inhibitor PLX4032, that target proteins that are specifically oncogenic. For my project, I will explore the effects that some of these targeted agents have on important signaling pathways that are often constitutively activated in melanomas using patient-derived melanoma cell lines. Also, I plan to further elucidate the underlying mechanisms of action behind the therapeutic effects seen with these targeted drugs. Furthermore, my project includes determining potential combinations of drugs that may show some synergistic mechanisms of effect in these melanoma cells.

Significance of Progesterone Receptor Isoforms Alpha and Beta in Breast Cancer.

Year: 3
PI: Rimm

Levels of progesterone and estrogen receptors are routinely assessed in breast cancer patients to aid in diagnosis and prediction of response to endocrine therapy. There are two isoforms of progesterone receptor, alpha and beta. Little is known about the significance of the relative levels of the receptor isoforms so the current aim of my research is to quantify levels of progesterone receptor isoforms in large breast cancer cohorts to assess their value as prognostic and/or predictive factors for breast cancer.

Title

Year: 2
PI: Rimm

Cancer stem cells are cancer cells that can both self-replicate and differentiate. They have also the ability to generate tumors in nude mice from as few as one hundred cells, whereas other cancer cells do not have this capability. Previously, the lab has investigated CD44 and ALDH1 as biomarkers for cancer stem cells. My project investigates the prognostic and/or predictive value of other potential biomarkers for breast cancer stem cells, including factors involved in epithelial-mesenchymal transition and developmental signaling pathways. I also intend to develop a new cohort of patients treated with neoadjuvant chemotherapy to study the capability of breast cancer stem cells to confer resistance to conventional cancer therapies. 

Title

Year: 2
PI: Robeck

Hepatitis B virus (HBV) infection, which can lead to chronic hepatitis and hepatocellular carcinoma, is responsible for millions of deaths each year and therefore, is a crucial worldwide public health problem. Although a prophylactic vaccine exists and protects individuals without prior contact with HBV, current therapies are frequently limited in effectiveness by severe side effects and development of viral resistance. Individuals that progress from an acute to chronic HBV infection have a decreased T cell response. While many factors may contribute to this immunological tolerance, it is likely that regulatory T cells (Tregs), a subpopulation of T cells that negatively regulate the immune system, and PD-1/PD-L1 interactions, which regulate the activation, proliferation, and cytokine production of T cells, both play a role. Thus, my project aims to further explore the role of Tregs and PD-1/PD-L1 interactions and to apply this knowledge to the development of a therapeutic vaccination for chronic HBV infection that in overcoming immunological tolerance will stimulate a potent immune response against HBV.

ErbB4 isoform signaling in tumorigenesis 

Year: 2
PI: Stern

EGFR/ErbB receptor tyrosine kinases are signaling nodes critical in cell growth and development that transduce extracellular signals into a directed cellular response. Members of this receptor family, namely EGFR and ErbB2/HER2/neu, have been shown to be important therapeutic targets in non-small cell lung carcinoma (NSCLC) and breast cancer respectively. Recent data shows ErbB4 mutations are present in certain cancers (e.g., lung, breast, melanoma) but the role of this receptor and its various cleavable isoforms in tumorigenesis is still uncertain. My project will investigate signaling of the four spliced ErbB4 isoforms in cancer and determine if/how particular mutations contribute to tumorigenesis.

Title

Year: 2
PI: Bosenberg

The Role of Macrophages in Melanoma Formation and Progression Melanoma, the most deadly form of skin cancer, is characterized by early metastasis and resistance to medical interventions.  While much work has focused on the role of recurrent genetic alterations in melanoma biology, the tumor microenvironment may also be instrumental in disease progression. In particular, tumor associated macrophages  (TAMs) are thought to support tumor growth and even enhance metastasis.  Using novel genetically engineered mouse models of melanoma, my project focuses on deciphering specific mechanisms by which TAMs promote these processes. Additionally, I have begun to identify and characterize TAM sub-populations that may be essential for tumor growth.

Title

Year: 2
PI: Nguyen

Lung adenocarcinoma (ADC) is the most common subtype of lung cancer, and even when diagnosed at early stages, metastases can occur to distant organs. This propensity to metastasize suggests that a subpopulation of malignant cells with high metastatic potential may emerge in a subset of primary tumors. Cancer stem cells have been identified in the lung, but these cell populations are heterogeneous, and although they are all capable of propagating tumors, they display varying degrees of metastatic potential. Previous computational analysis from our lab has shown that genes associated with alveolar differentiation can stratify a cohort of primary lung ADCs into two distinct classes, a differentiated alveolar-like and a stem-cell like class. This stem-like signature classifies patients with poor survival, which indicates it may mark a dedifferentiated cell type that has enhanced metastatic capabilities. My project will focus on identifying biomarkers that are differentially expressed in both the stem-like signature and in our experimental models to identify the origin of metastasis propagating cells in lung ADCs and determine their fate upon disseminating from the primary tumor. I will also determine the putative role of these biomarkers in mediating functional interactions between subpopulations of metastatic cancer stem cells and their microenvironment.