Cancer Biology Commons^™

Impact Of Targeting Glycosylated Ceramides On Tumorigenic Properties, And Characterization Of Sphingolipids In Head And Neck Tumors, Katherine E. Hylton

Theses and Dissertations

Sphingolipids play a crucial role in signaling, membrane structure, and migration, making them important molecules in cancer development, metastasis, and drug resistance. While some sphingolipids have been associated with pro-apoptotic or pro-survival behaviors, the role of many sphingolipids in cancer remains poorly defined. Chapter 1 of this study investigated the impact of three enzymes that compose most of the ceramide to Lc3 ceramide pathway – UGCG, GBA, and B3GNT5 – and how their alteration impacts chemoresistance and basal membrane invasion in vitro. It was found that the CΒE-induced inhibition of GBA, which converts glucosylceramide to ceramide, has no effects on …

Mechanisms By Which Mnte-2-Pyp Suppresses Prostate Cancer Cell Growth, Yuxiang Zhu

Theses & Dissertations

Prostate cancer patients are often treated with radiotherapy. MnTE-2-PyP, is a superoxide dismutase (SOD) mimic and a known radioprotector of normal tissues. Our recent work demonstrates that MnTE-2-PyP also inhibits prostate cancer progression with radiotherapy; however, the mechanisms remain unclear. In this thesis, we identified that MnTE-2-PyP-induced intracellular H2O2 levels are critical in inhibiting growth of prostate cancer cells. We found that MnTE-2-PyP induced protein oxidations in PC3 cells and one major group of oxidized protein targets were involved in energy metabolism. The oxidative phosphorylation rates were significantly enhanced in both PC3 and LNCaP cells with MnTE-2-PyP treatment, but mitochondrial …

Fibroblast Heterogeneity In Pancreatic Cancer Immunity, Josephine Darpolor

Dissertations and Theses (Open Access)

Fibroblasts are a unique cell type defined by their mesenchymal phenotype and exclusion from epithelial, immune, and endothelial cell subsets. Although well studied in wound healing, cancer associated fibroblasts (CAFs) are incredibly heterogeneous, leading to contradictions as to the roles CAFs play in the tumor microenvironment (TME). CAFs were thought to be a barrier to treatment of pancreatic ductal adenocarcinoma (PDAC). However, general stromal targeting strategies have largely failed in the clinic likely due to the heterogeneity of CAFs in the TME. Therefore, our groups and others have worked to unravel the heterogeneity of CAFs in PDAC. In the works …

Immunohistochemical Localization Of Prolactin Receptor (Prlr) To Hodgkin's And Reed-Sternberg Cells Of Hodgkin's Lymphoma, Rajendra Gharbaran, Onyekwere Onwumere, Naomi Codrington, Latchman Somenarian, Stephen Redenti

Publications and Research

Prolactin receptor (PRLR), a type-1 cytokine receptor, is overexpressed in a number of cancer types. It has attracted much attention for putative pro-oncogenic roles, which however, remains controversial in some malignancies. In this study, we reported the localization of PRLR to the Hodgkin's and Reed-Sternberg (HRS) cells of Hodgkin's lymphoma (HL), a neoplasm of predominantly B cell origin. Immunohistochemistry performed on 5-μm thick FFPE sections revealed expression of PRLR in HRS cells. Cellular immunofluorescence experiments showed that the HL-derived cell lines, Hs445, KMH2 and L428 overexpressed PRLR. The PRLR immunofluorescent signal was depleted after treating the cell lines with 10 …

Luteolin Induces Cytotoxicity In Mix Cellularity Classical Hodgkin's Lymphoma Via Caspase Activated-Cell Death, Rajendra Gharbaran, Enyuan Shang, Onyekwere Onwumere, Naomi Codrington, Evangelina Dankwa Sarpong, Stephen M. Redenti

Publications and Research

Background/aim: We investigated the effects of luteolin (LUT) on classical Hodgkin's lymphoma (cHL), since such studies in malignant lymphomas are lacking.

Materials and methods: Effect of LUT on cell growth was assessed with water-soluble tetrazolium 1 (WST-1) cell proliferation assay and automated hemocytometry on trypan blue-exclusion assay. Cell death was investigated with acridine orange/ethidium bromide live-dead assay, propidium iodide (PI) flow cytometry, and Annexin-V-PI microscopy. Caspase activation was studied using CellEvent Caspase-3/7 Green detection reagent. High resolution immunofluorescence microscopy was used to detect cleaved-PARP-1.

Results: LUT induced a dose-dependent decrease in the growth of KMH2 and L428 cells, cellular models …

Epithelial-Mesenchymal Status Predics Tumor Agressivenss, Chemoresistance And Invasiveness In High Grade Serous Ovarian Cancer, Linda Sanderman

Electronic Theses, Projects, and Dissertations

High Grade Serous Ovarian Cancer (HGSOC) is one of the deadliest gynecological diseases in the United States ranking fifth in cancer deaths among women. Approximately 22 thousand new cases are expected to occur in the year 2020, and unfortunately, it is estimated that 14 thousand women will succumb to the disease; the incidence to death ratio, 64%, remains high despite current research. Current treatment includes debulking surgery followed by combinatorial chemotherapeutics with platinum-based and taxol-based compounds. But despite aggressive surgery and standard-of-care chemotherapeutics, 80% of patients will experience a recurrence and only 15-30% of those with recurring disease will respond …

Microglia-Neuron Interactions In A Mouse Model Of Low Grade Neuroepithelial Tumors, Veolette Hanna

Honors Scholar Theses

Microglia are the macrophages of the brain and spinal cord, playing an important role in the immune response to disease states of the nervous system. This study conducts an investigation on the activity of microglia in response to low grade neuroepithelial tumors. Using mouse models and microglial markers, a qualitative and quantitative analysis of microglia activation, migration, and invasion within the brain cortex during early stages of tumor development was conducted. It was found that the presence of a low grade neuroepithelial tumor in the cortex of one hemisphere of the brain causes significant microglia activation in comparison to the …

Impact Of Epa And Dha Supplementation And 15-Lox-1 Expression On Colitis And Colitis-Associated Colorectal Cancer, Jonathan Jaoude

Dissertations and Theses (Open Access)

Inflammatory bowel disease (IBD) patients not only suffer from colitis but also from increased morbidity and mortality of colitis-associated colorectal cancer (CAC). The enzyme 15-lipoxygenase-1 (15-LOX-1) is crucial to converting omega-3 fatty acid derivatives eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to resolvins, potent anti-inflammatory products. 15-LOX-1 effects on the conversion of EPA and DHA to resolvins that subsequently exert anti-inflammatory and anti-tumorigenic effects have received little attention. To address this knowledge gap, we hypothesize that 15-LOX-1 expression in colonic epithelial cells is essential for resolvin biosynthesis from EPA and DHA to modulate immunophenotype, limit inflammation, promote resolution, and help …

365— Clobetasol-Induced Quiescence In The Vulvar Carcinoma Cell Line Umscv-4 Can Be Overcome By Repeated Removal And Re-Exposure To This Ultrapotent Corticosteroid, Nolberto Jaramillo Jr., Nina Mustico

GREAT Day Posters

Vulvar cancer is rare, mostly afflicting women aged 60 and older. The cancer is often preceded by a common vulvar rash, Lichen sclerosis, that is usually treated with the ultra-potent corticosteroid, clobetasol propionate. This treatment may, in turn, be associated with vulvar carcinogenesis. Quiescence, a common characteristic of stem cells, is a reversible state of growth arrest. Our results suggest that clobetasol is causing UMSCV-4 vulvar carcinoma cells to enter quiescence, and may allow them to evade the standard treatments that target rapidly proliferating populations. Furthermore, when these cells are removed from clobetasol and re-exposed, they proliferate at higher levels. …

147— The Effect Of A Histone Deacetylase Inhibitor On Pd-L1, Hla-Abc, Hla-E, And Hla-G On Human Breast Cancer Cell Lines, Nikhil Reddy, Alec Toufexis

GREAT Day Posters

Increased expression of human leukocyte antigen (HLA) allows tumor cells to be more easily detected by the immune system. In previous research, epigenetic modifiers including the histone deacetylase inhibitor 3 (HDAC3), RGFP966, has been shown to decrease PD-L1 expression. PD-L1 expression inhibits T cell cytotoxicity, and decreasing it can enhance the immune response. We hope to elucidate whether or not HLA-ABC expression similarly decreases upon exposure to the HDAC3 inhibitor which would be detrimental to immune detection. Two breast cancer cell lines that express HLA-ABC are MCF-7 and MDA-MB-231. Our initial results show that HLA-ABC is expressed on the MDA-MB-231 …

Functional And Transcriptomic Characterization Of Cisplatin-Resistant Ags And Mkn-28 Gastric Cancer Cell Lines, Barbara Mora-Lagos, Irene Cartas-Espinel, Ismael Riquelme, Alyssa C. Parker, Stephen R. Piccolo, Tamara Viscarra, Maria Elena Reyes, Louise Zanella, Kurt Buchegger, Carmen Ili, Priscilla Brebi

Faculty Publications

Gastric cancer (GC) is a significant cancer-related cause of death worldwide. The most used chemotherapeutic regimen in GC is based on platinum drugs such as cisplatin (CDDP). However, CDDP resistance reduces advanced GC survival. In vitro drug-resistant cell model would help in the understanding of molecular mechanisms underlying this drug-resistance phenomenon. The aim of this study was to characterize new models of CDDP-resistant GC cell lines (AGS R-CDDP and MKN-28 R-CDDP) obtained through a stepwise increasing drug doses method, in order to understand the molecular mechanisms underlying chemoresistance as well as identify new therapeutic targets for the treatment of GC. …

Ototoxicity Of Cisplatin, Pyriplatin, And Phenathriplatin In The Auditory Hybridoma Cell Line, Hei-Oc1, Alexandra Johnston

Mahurin Honors College Capstone Experience/Thesis Projects

Cisplatin is an anti-cancer drug which is effective against several cancers, but also causes harmful side-effects, including ototoxicity and hearing loss. While cisplatin is a bifunctional compound that forms coordinate covalent bonds with both strands of DNA, recently investigated monofunctional platinum(II) compounds bind to only one DNA strand, and may activate different cell-death mechanisms. As several monofunctional platinum(II) compounds have anti-cancer properties, but could target different cell-death pathways, they could potentially have different and reduced side-effects. In this study, the HEI-OC1 auditory hybridoma cell line was used to investigate the ototoxicity of cisplatin and two monofunctional platinum(II) compounds, phenanthriplatin and …

Identification Of Imiquimod As A Potential Combination For Anti-Cd47 Antibodies In Cancer Therapy, Nicole Brittaney Pang

Scripps Senior Theses

The avenues of targeted immunotherapy offers a promise of less toxic treatment options for those battling different forms of cancer. Specifically, the process of hijacking a patient’s own immune system to fight cancer from within versus using external treatments like chemotherapy which is extremely damaging to the patient. One such avenue includes the usage of monoclonal antibodies as an effective modality for immunotherapy. Cluster of Differentiation 47 (CD47), also known as the ‘don’t eat me signal’, aids in cell proliferation and evasion of phagocytosis and has been found to be a target for stopping tumorigenesis. Previous research has been successful …

Sphingolipids In Cancer Health Disparities And As Prospective Targets For Cancer Therapy, April E. Boyd

Theses and Dissertations

Lung cancer is the deadliest cancer both in the United States and worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. However, lung cancer disparities are not shared equally across racial groups, with large differences between African American and Caucasian populations. Advances in research have revealed roles of lipid mediators in cancer biology and disease progression, but sphingolipid alterations in tissues should be explored further. To address this, using mass spectrometry (MS), extensive sphingolipidomic characterization of NSCLC tumors and adjacent uninvolved tissues from African American and Caucasian patients were performed. This study revealed that NSCLC …

Investigating The Relationship Between Hormone Receptors Dax-1 And Estrogen Receptor Within Prostate Cancer Cell Lines, Meghana G. Vijayraghavan

Master's Theses

Prostate cancer (PCa) is estimated to be the second leading cause of cancer-related deaths among men in the United States in 2019. While most prostate tumors rely on androgens for growth signaling, there are subsets of tumors that become androgen-resistant, therefore resisting conventional androgen-depravation therapy. Consequently, research has focused on targeting different hormone receptors for novel therapeutics. One such receptor is Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX-1). DAX-1 is known to interact with other hormone receptors, such as androgen receptor (AR) and estrogen receptors (ERs) to suppress the proliferative effects …

Uncovering The Zeb1 Interactome To Identify Novel Regulators Of Metastatic Non-Small Cell Lung Cancer, Roxsan Manshouri

Dissertations and Theses (Open Access)

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the United States, due in part to the robust affinity of lung cancer cells to metastasize. Understanding the processes that contribute to metastasis provides promise for the discovery of novel therapeutic targets. Epithelial-tomesenchymal transition (EMT) is a proposed model for the initiation of metastasis. During EMT cell adhesion and polarity is reduced, allowing epithelial cancer cells to dissociate from the primary tumor and invade distant organs. The transcription factor zinc finger E-box-binding homeobox 1 (ZEB1) has been reported to uniquely correlate with NSCLC disease progression and to …

Discovery Of An Egfr Inhibitor For The Treatment Of Lung And Other Cancers, Jodie Meng '20

Student Publications & Research

The Epidermal Growth Factor Receptor (EGFR), a transmembrane protein involved in the regulation of signaling pathways, is frequently overexpressed in epithelial tumors. First generation EGFR TKIs, such as erlotinib and gefitinib, traditionally improved outcomes for non-small-cell lung carcinoma and pancreatic cancer patients by attaching competitively and reversibly to the ATP binding domain of EGFR. Second-generation EGFR TKIs have been developed to combat resistance among patients, despite demonstrating toxic side effects. In the present study, 1400 selective inhibitors were designed based on the molecular scaffolds of first and second generation EGFR TKIs. Results were refined by parameters outlined in Lipinski’s rule. …

Cul3 Regulates Cyclin E1 Protein Abundance Via A Degron Located Within The N-Terminal Region Of Cyclin E, Brittney Marie Davidge, Katia De Oliveira Rebola, Larry N. Agbor, Curt D. Sigmund, Jeffrey D. Singer

Biology Faculty Publications and Presentations

mammalian cells. Increased levels of cyclin E are found in some cancers. Additionally, proteolytic removal of the cyclin E N-terminus occurs in some cancers and is associated with increased cyclin E–Cdk2 activity and poor clinical prognosis. Cyclin E levels are tightly regulated and controlled in part through ubiquitin-mediated degradation initiated by one of two E3 ligases, Cul1 and Cul3. Cul1 ubiquitylates phosphorylated cyclin E, but the mechanism through which Cul3 ubiquitylates cyclin E is poorly understood. In experiments to ascertain how Cul3 mediates cyclin E destruction, we identified a degron on cyclin E that Cul3 targets for ubiquitylation. Recognition of …

Comparison Of Nickel And Cobalt Induced Hypoxic Cell Models Using Cell Proliferation Assay, Melissa Delcasale

Seton Hall University Dissertations and Theses (ETDs)

Hypoxia is an imbalance in oxygen delivery and oxygen consumption, ultimately affecting cell survival. Low levels of oxygen diminish adenosine triphosphate synthesis resulting from a decline in oxidative phosphorylation in the mitochondria, therefore inducing apoptosis and cell death. To create a hypoxia mimicked environment, we used hypoxia mimetic compounds cobalt and nickel to treat human neuroblastoma (NMB) cells. Using hypoxic mimic human neuronal cell models, we examined and compared the effects of compound-induced hypoxia on NMB cell proliferation. The cells were treated with 100mM and 300mM concentrations of each compound at 24- and 48-hour intervals. To investigate cell proliferation, the …

Med12 Mutations Promote Castration-Resistant Prostate Cancer Through Hyperactivated Gli3/Shh Signalling, Soundharrya Muthukumar

Theses & Dissertations

When cells of the prostate gland start growing uncontrollably, it results in cancer due to genetic aberrations. The development and progression of prostate cancer depend on androgenic stimulation. Although prostate cancer is temporarily treated by depriving a tumor of androgen, the patient relapses getting a castration-resistant form of the disease called castration-resistant prostate cancer (CRPC). CRPC can specifically develop through crosstalk of androgen receptor signalling pathways. One such pathway that is of specific interest in this paper is the MED12 regulated SHH signalling pathway. The mediator is a signal processor that helps in the transduction of gene-specific transcription factors to …

Embryonic Lethality Of Cranial Neural Crest Deletion Of Cdc73, Lilia Shen

Honors Scholar Theses

Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is a disease characterized by parathyroid tumors, renal cysts or tumors, uterine tumors, and ossifying jaw fibromas. The cause of this syndrome is linked to a tumor suppressor gene called Cdc73, which encodes the protein product parafibromin. The loss of proper expression of Cdc73/parafibromin is implicated in the development of the tumors typical of HPT-JT, although the exact mechanisms of tumorigenesis are unclear. In particular, not much is understood about the development of ossifying fibromas (OF) of the jaw in this syndrome. OF is a benign bone neoplasm that can affect the mandible and …

The Role And Regulation Of Alternative Polyadenylation In The Dna Damage Response, Michael R. Murphy

Dissertations, Theses, and Capstone Projects

Cellular homeostasis is achieved by the dynamic flux in gene expression. Post-transcriptional regulation of coding and non-coding RNA offers a fast method of adapting to a changing cellular environment, including deadenylation, microRNA (miRNA) pathway, and alternative polyadenylation (APA). In this dissertation, I explored some of the mechanisms involved in the post-transcriptional regulation of gene expression. The main hypothesis in these studies is that a single APA event after DNA damage is governed by specific conditions and factors outside of current known regulators of APA, and that the resultant transcript has a role in the DNA damage response (DDR). My aims …

Context Dependent Roles Of Mdmx (Mdm4) And Mdm2 In Breast Cancer Proliferation And Circulating Tumor Cells, Chong Gao

Dissertations, Theses, and Capstone Projects

Many human breast cancers overexpress the E3 ubiquitin ligase MDM2 and its homolog MDMX. Expression of MDM2 and MDMX occurs in both estrogen receptor α positive (ER+) and triple negative breast cancer (TNBC). We and others have reported that estrogen activated MDM2 strongly promotes proliferation in ER+ T47D breast cancer cells in a p53-independent manner. Whether MDM2 elicits in vivo p53-independent proliferative functions in T47D breast cancer cells has not been determined. Furthermore it has been shown that ectopic expression of MDM2 targets E-Cadherin for degradation thus leading to increased cell migration and invasion. Therefore we assessed the in vivo …

The Molecular Mechanisms Underlying The Cancer Killing Effect Of Interleukin-24, Leah Eshanie Persaud

Dissertations, Theses, and Capstone Projects

Interleukin-24 (IL-24) is an immunomodulatory cytokine that also displays specific anti-tumor effects across many cancer cell types. The tumor suppressor activities of IL-24 include inhibition of angiogenesis, metastasis, toxic autophagy, cancer-specific apoptosis, and sensitization to traditional cancer treatments like chemotherapy and radiation. Overexpression of IL-24 can selectively induce apoptosis in various cancer cells while having no adverse effects on normal cells. Due to this favorable killing effect, IL-24 is currently in phase II clinical trials. There is accumulating evidence that IL-24’s anti-cancer activity is primarily through the endoplasmic reticulum (ER) stress pathway but other pathways leading to cell death are …

Cross-Presentation Is A Source Of Tumor Antigens For Multiple Myeloma Immunotherapy, Alexander A. Perakis

Dissertations and Theses (Open Access)

Cross-presentation is an essential bridge between the innate and adaptive arms of the immune system where antigen presenting cells (APCs) prime cytotoxic T cell responses. We have recently identified cross-presentation as a mechanism by which solid tumors present exogenous antigens. We therefore hypothesized that multiple myeloma would be capable of cross-presentation as these cells are derived from B cells, known APCs. We explored the capacity of multiple myeloma to cross-present PR1, a human leukocyte antigen (HLA)-A2 nonameric peptide that is derived from neutrophil elastase (NE) and proteinase 3 (P3), and the ability to treat multiple myeloma using PR1-targeting immunotherapies. Here …

Cellular Localization Of Rad51d Mutant Proteins And The Application Of Art To Increase Scientific Literacy In America, Claire L. Chabot

Senior Theses

Ovarian cancers are the leading cause of death from cancer of the female reproductive system. Approximately 50% of ovarian cancers have defects in the homologous recombination (HR) DNA repair pathway that is required for the repair of DNA double-stranded breaks. The status of HR genes, such as BRCA1, BRCA2, and the RAD51 family, contributes to ovarian cancer development as well as treatment decisions regarding chemotherapy, radiation, and immunotherapy. The overarching goal of this project is to identify new insights into HR that can integrate with Precision Medicine Initiatives and align with the goals of the Cancer Moonshot 2020 Program. I …

Mechanisms Of Oriented Cell Division And Their Roles In Tissue Development, Evan Blake Dewey

Biology ETDs

Properly executed cell division is crucial to development, maintenance, and longevity of multicellular organisms. Defects in both symmetric and asymmetric divisions can lead to improper developmental patterning, as well as genomic instability, disruption of tissue homeostasis, and cancer. Our research focuses on how regulators orchestrate proper cell divisions. Mushroom Body Defect (Mud) is one such regulator, and here we describe how Mud is regulated via the Hippo signaling pathway kinase Warts (Wts), showing Wts phosphorylates Mud to enhance interaction with the polarity protein Partner of Inscuteable, promoting spindle orientation activity. We next focus on another regulator, Shortstop (Shot), describing a …

Functional And Transcriptomic Characterization Of Carboplatin-Resistant A2780 Ovarian Cancer Cell Line, Tamara Viscarra, Kurt Buchegger, Ignacio Jofre, Ismael Riquelme, Louise Zanella, Michel Abanto, Alyssa C. Parker, Stephen R. Piccolo, Juan Carlos Roa, Carmen Ili, Priscilla Brebi

Faculty Publications

Background

Ovarian cancer is a significant cancer-related cause of death in women worldwide. The most used chemotherapeutic regimen is based on carboplatin (CBDCA). However, CBDCA resistance is the main obstacle to a better prognosis. An in vitro drug-resistant cell model would help in the understanding of molecular mechanisms underlying this drug-resistance phenomenon. The aim of this study was to characterize cellular and molecular changes of induced CBDCA-resistant ovarian cancer cell line A2780.

Methods

The cell selection strategy used in this study was a dose-per-pulse method using a concentration of 100 μM for 2 h. Once 20 cycles of exposure to …

Unified Methods For Feature Selection In Large-Scale Genomic Studies With Censored Survival Outcomes, Lauren Spirko-Burns, Karthik Devarajan

COBRA Preprint Series

One of the major goals in large-scale genomic studies is to identify genes with a prognostic impact on time-to-event outcomes which provide insight into the disease's process. With rapid developments in high-throughput genomic technologies in the past two decades, the scientific community is able to monitor the expression levels of tens of thousands of genes and proteins resulting in enormous data sets where the number of genomic features is far greater than the number of subjects. Methods based on univariate Cox regression are often used to select genomic features related to survival outcome; however, the Cox model assumes proportional hazards …

Supervised Dimension Reduction For Large-Scale "Omics" Data With Censored Survival Outcomes Under Possible Non-Proportional Hazards, Lauren Spirko-Burns, Karthik Devarajan

COBRA Preprint Series

The past two decades have witnessed significant advances in high-throughput ``omics" technologies such as genomics, proteomics, metabolomics, transcriptomics and radiomics. These technologies have enabled simultaneous measurement of the expression levels of tens of thousands of features from individual patient samples and have generated enormous amounts of data that require analysis and interpretation. One specific area of interest has been in studying the relationship between these features and patient outcomes, such as overall and recurrence-free survival, with the goal of developing a predictive ``omics" profile. Large-scale studies often suffer from the presence of a large fraction of censored observations and potential …