INBRE-2 Currently Supported Research Projects
Research Themes : Cancer, Cardiovascular, Neurosciences
Research Theme - Cancer
Investigator: Dr. Deni Galileo, UD Biological Sciences
Mentor: Dr. Nicholas Petrelli, Christiana Care – Graham Cancer Center
Research Title: Autocrine Stimulation of Primary and Metastatic Brain Cancer Cells
Abstract: Primary brain tumors are insidious and can be lethal within weeks to months, even with current aggressive treatments. Unfortunately, the most common primary brain tumors in adults (glioblastomas) are ones with the worst prognosis. This is primarily because of their tendency and ability to spread within the brain along blood vessels and axon tracts, making their complete resection often impossible. Breast cancer metastases to brain also result in poor patient survival of only months. We have developed a new model in which to study these tumors and have uncovered a mechanism that these tumor cells use to be so aggressive. We are able to inject human and rat brain tumor cell lines into the early chicken embryo brain to produce aggressive brain tumors in less than 2 weeks. We have also injected human breast cancer cell lines into embryonic blood vessels to show that they metastasize to the brain in less than 2 weeks. We now use this system to study mechanisms that contribute to the aggressive behavior of these two cancer types. Our laboratory has also developed a sophisticated microscopy system that is capable of recording movies of the migratory behavior of live tumor cells in a dish, and that can precisely measure their minute velocities and directions over time. During the last few years, we have begun to elucidate a mechanism in these cancer cells whereby the neural recognition transmembrane protein L1 is aberrantly expressed and proteolytically cleaved to become “shed” so that it interacts with the cancer cell’s own cell surface receptors in an autocrine/paracrine manner to stimulate cell motility. We have shown that L1 is expressed by all surgical high-grade glioma samples analyzed to date and that high-grade glioma and metastatic breast cancer cell lines express and cleave L1 and express L1- binding receptors. Here, we will investigate 1) how L1 is produced and released by brain and breast cancer cells, 2) the mechanism of how L1 stimulates them to become more migratory in simple cell culture, 3) whether or not this mechanism controls their invasive and metastatic behavior in our chicken embryo model, 4) whether or not cancer cells from patient surgical samples use this stimulatory mechanism, and 5) whether or not the aberrant production and cleavage of L1 can transform normal adult human brain progenitors into a cancerous phenotype. This project involves collaborative efforts between the University of Delaware, the Helen F. Graham Cancer Center, and surgeons at Christiana Care Hospitals.
Investigator: Dr. Chandra Kambhamettu , UD – Computer Information Sciences
Mentor: Dr. Karl Steiner, UD – Electrical and Computer Engineering
Research Title: Interactive Computer-generated Diagnosis Tools for Ground-glass Opacity Lung Tumors
Abstract: High-resolution Computed Tomography (HRCT) is frequently used to detect tumors in patients, and to monitor tumor growth or shrinkage at different time intervals during treatment. The accurate classification of a tumor into benign or malignant categories is critical to determine the appropriate treatment and CTs are often used to assess the effectiveness of a selected treatment. Advances in CT imaging technology have assisted in acquiring the images at increasingly high resolution; however, current algorithms are limited to measuring volume changes of the tumor rather than providing an accurate measurement of tumor growth in three dimensions. Of particular interest for this study are Ground-Glass Opacity (GGO) tumors that pose a special challenge to conventional image analysis algorithms, which are traditionally tuned toward detection of high gradient changes and thus would frequently miss GGO tumors. Ground-glass opacity refers to the appearance of a hazy opacity during high-resolution computed tomography (HRCT) that does not obscure the associated pulmonary vessels [1]. This appearance results from parenchymal abnormalities that are below the spatial resolution of HRCT. In this proposed study, we will develop a novel three-dimensional (3D) method for interactive, automated and accurate segmentation and assessment of GGO tumors. The innovation of our method is the development of novel interactive 3D image analysis tool to extract GGO lung nodules, and perform analysis based on the resulting opacity map. To date, existing software algorithms are able to help detect and measure solid lung nodules based on available CT-image information; however, they are not capable of working on GGO tumors and estimating the overall GGO coverage of detected nodules in the lung. Current methods utilize manual expert analysis for this important task. We propose to measure quantitatively the opacity property of each pixel in a ground-glass opacity tumor from CT images. Our method results in an opacity map in which each pixel takes opacity value of [0-1?. Given a CT image, we propose to accomplish the estimation by constructing a graph Laplacian matrix and solving a linear equations system, with assistance from some manually drawn scribbles for which the opacity values are easy to determine manually. The development of an automated GGO lung tumor detection will greatly improve the efficiency of routine radiological and oncological analysis. Our innovative approach for an objective assessment of GGO tumors will allow the radiologist or thoracic surgeon to evaluate the threedimensional evolution of the tumor and the dimensional changes detected by CT scans taken at different time spans, including changes in growth pattern, maximum areas/orientation of growth, and opacity changes. This proposed study is the first step toward the development of a computerized assessment of GGO tumors and, if successful, will lead to further translational efforts to integrate these techniques into clinical practice. The team brought together to successfully work on this effort is comprised of a thoracic surgeon, who acts as a clinical subject matter expert, and experienced researchers in image enhancement, automated vision and biomedical imaging.
Investigator: Dr. Fengshan Liu, DSU – Mathematics
Mentor: Dr. Mitchell Schnail, University of Pennsylvania
Research Title: Volumetric Breast Density Estimation using Breast Surface Reconstructed from Optical Digitizer Images
Abstract: We propose to use breast surface reconstructions produced from optical digitizer images to improve the accuracy of volumetric breast density estimation. Breast density is used to estimate the lifetime risk of breast cancer based on the analysis of mammograms; it is indicative of changes in modifiable breast cancer risk factors. Estimation of volumetric breast density requires knowledge of the breast thickness at every point in a mammogram. The breast thickness is defined by the mammography acquisition geometry; this is determined by the distance between the compression plates, except near the breast edge where the breast is not fully compressed. Current methods for volumetric breast density (VBD) estimation address this issue by assuming a predefined breast shape. Based on our demonstrated high accuracy and precision in reconstruction of the breast surface, it is hypothesized that non-contact optical surface scanning can be used to more accurately determine the breast thickness at every point, and therefore improve VBD estimation
Investigator: Dr. Mary-Ann McLane, UD – Medical Technology
Mentor: Dr. Ulhas Naik, UD – Biological Sciences
Research Title: Direct Interaction of Eristostatin with Human Melanoma Cells
Abstract: Metastasis (i.e., tumor spread) is the major obstacle to cancer cure. The metastatic process consists of many steps, including those involving motility and adhesion. If the cascade of events is interrupted at any step, metastasis will not occur. Eristostatin, a member of the disintegrin family of viper venom proteins, can inhibit melanoma cell colonization in the lungs of mice injected with either murine or human melanoma cells. We have shown that the presence of eristostatin can cause changes in adhesion and motility in melanoma cells, but does not affect cell growth or survival. To date, the basis for eristostatin's anti-metastatic effect remains unknown, but these functional studies have opened the way to unlocking this natural protein's anticancer mechanism. The long term objective of this research is to identify mechanisms by which melanoma metastasis may be inhibited. The specific goals proposed here are to investigate the molecular mechanism used by eristostatin to affect melanoma cell function. We will do this by pursuing three specific aims: (i) Characterize the direct interaction of eristostatin with melanoma cell molecule(s). We will use atomic force microscopy, confocal microscopy and chemical crosslinking to identify the binding partner for eristostatin that is present on 6 different melanoma cell lines with varying degrees of metastatic potential. (ii) Compare the interaction differences between eristostatin and melanoma cells in a 2-dimensional versus 3-dimensional environment. Cellular responses can be very different in tissue culture (2-D) compared with what happens in the body (3-D). We will investigate eristostatin-melanoma cell interactions involving adhesion, proliferation and signaling in a 3-dimensional environment using matrices containing fibronectin and/or collagen. (iii) Identify intracellular signaling events associated with eristostatin’s interaction with melanoma cells. The clearest example of melanoma cell activity inhibition by eristostatin is with motility when placed on fibronectin. We will perform immunochemical assessment of the intracellular signaling occurring when melanoma cells are exposed to eristostatin, focusing on known pathways associated with motility. Taken together, these studies will provide insights into how one naturally occurring protein, eristostatin, possesses the "right fit" to bind melanoma cells and block their metastatic ability. The information will, in turn, lead to a rational design of therapeutic agents that will target these cells.
Investigator: Dr. Krishna Sarker, UD – Biological Sciences
Mentor: Dr. Nicholas Petrelli, Christiana Care – Graham Cancer Center
Research Title: Calcium- and Integrin-Binding Protein 1 (CIB1) in Cancer Cell Invasion
Abstract: Cancer is one of the leading causes of death for all mankind. Cancer cells not only display uncontrolled proliferation, but also develop the ability to migrate from their original site to other organs in the body. This event is known as metastasis, the hallmark of malignant cancers. During metastasis, cancer cells break numerous barriers to travel through the body’s circulatory system and invade other organs to form secondary tumors. Therefore, it is important to understand the underlying mechanism of cancer metastasis to find a cure for cancer. Integrins, membrane protein receptors for extracellular matrix proteins, have been implicated in cancer cell proliferation and metastasis. In addition, focal adhesion kinase (FAK) has been shown to be pivotal for cell adhesion and migration. However, the involvement of effector molecules which lie in the integrin and FAK mediated signaling pathway is largely unknown. Our lab recently discovered an ubiquitously expressed calcium- and integrin-binding protein 1 (CIB1) which interacts with a number of cellular proteins, including platelet specific integrin αIIbβ3. Further, CIB1 also interacts and co-localizes with FAK at the membraneous extensions and has been implicated in cell spreading and migration. The role of CIB1 in a pathophysiological condition such as cancer remains to be elucidated. Our preliminary results show that CIB1 expression is significantly increased in breast cancer tissue compared to normal breast tissue. Overexpression of CIB1 in T47D, a breast epithelial cell line, showed increased cell migration on collagen matrix as determined by a trans-well migration assay. When endogenous CIB1 was knocked down in T47D cells using siRNA, cell migration was significantly decreased. A decreased tyrosine phosphorylation of FAK was also observed in CIB1 knocked-down T47D cells compared to mock-transfected cells as determined by Western blot analysis, demonstrating that CIB1 may mediate cancer cell migration by enhancing phosphorylation of FAK. The goal of the present study is to have better insights of CIB1’s role in cancer cell invasion leading to metastasis. This will be achieved by determining the relationship of CIB1 expression and invasive behavior of the breast cancer cells in vitro and vivo and by elucidating the signaling pathways that CIB1 regulates in order to dictate the invasive behavior of breast cancer cells. We believe that our study will give a better understanding of the role of CIB1 in cancer cell invasion. It will also identify a novel cellular target for therapeutic intervention of breast cancer. Further, a clearer understanding of this process will provide a basis for developing effective therapies for this most lethal aspect of breast cancer.
Investigator: Dr. Cynthia van Golen, DSU – Biology
Mentor: Dr. Russell Taichman, University of Michigan
Research Title: CXCR4 and P-glycoprotein in Neuroblastoma Metastasis
Abstract: Advanced stage neuroblastoma is largely incurable using current treatment protocols. Children die of metastatic disease, with metastases occurring primarily within bone. Therefore, identifying factors contributing to the metastasis of neuroblastoma to bone may lead to new, more effective targeted treatment options. The expression and modification of cell surface proteins is critical for the regulation of the metastatic process. Gene expression studies in NBL suggest that several cell surface proteins, including the receptor tyrosine kinases A and B (trk A and trk B), CD44, CXCR4, and P-glycoprotein (Pgp), are highly expressed in late-stage, metastatic tumors. Trk A, Trk B, and CD44 have been extensively studied in neuroblastoma; however, CXCR4 and Pgp have not. Therefore, experiments within the current proposal will address the role of the remaining two cell surface proteins, CXCR4 and Pgp, in NBL bone metastasis. Our hypothesis is that highly tumorigenic, metastatic NBL cells will over express both CXCR4 and Pgp on their cell surface, contributing to migration and invasion into bone.
