Cancer Biology Commons^™

Cd56-Specific T Cells: Using Genetically Engineered T Cells To Redirect Specificity To A T Cell Expressed Antigen, Denise L. Crossland

Dissertations and Theses (Open Access)

The CD56 antigen is expressed on several deadly malignancies currently lacking long-term efficacious therapies. Chimeric antigen receptor (CAR) based immunotherapies have shown both safety and efficacy and even a curative ability in clinical trials, laying the foundation for applying CARs to new targets. Using T cells to target a T cell expressed antigen, such as CD56, seems counterintuitive in that the T cells would be susceptible to self-targeting a.k.a. fratricide. However, we expand CD56-specific CAR⁺ T cells that co-express the CD56 antigen. Since other CARs targeting T cell expressed antigens are hypothesized to be undergoing fratricide, such as the …

Tyrosine 370 Phosphorylation Of Atm Positively Regulates Dna Damage Response, Hong-Jen Lee

Dissertations and Theses (Open Access)

Ataxia telangiectasia-mutated (ATM) mediates DNA damage response by controlling irradiation (IR)-induced foci formation, cell cycle checkpoint, and apoptosis. However, how upstream signaling regulates ATM is not completely understood. Here, we show that upon IR stimulation, ATM associates with and is phosphorylated by epidermal growth factor receptor (EGFR) at Y370 at the site of double-strand breaks. Depletion of endogenous EGFR impairs ATM-mediated foci formation, homologous recombination, and DNA repair. Moreover, ATM Y370F mutant or pretreatment with an EGFR kinase inhibitor gefitinib blocks EGFR and ATM association, hinders CHK2 activation and subsequent foci formation, and increases radio-sensitivity. Thus, we reveal a critical …

Egfr Modulates Microrna Maturation In Response To Hypoxia Through Phosphorylation Of Argonaute2, Jia Shen

Dissertations and Theses (Open Access)

MicroRNAs (miRNAs) are generated by two-step processing to yield small RNAs that negatively regulate target gene expression at posttranscriptional level. Deregulation of miRNAs has been linked to diverse pathological processes, including cancer. Recent studies have also implicated miRNAs in regulatory roles to cope with a spectrum of stresses, such as hypoxia, which is frequently encountered in the poorly angiogenic core of a solid tumor. However, the upstream regulators of miRNA biogenesis machineries remain obscure, raising the question of how tumor cells efficiently coordinate and impose specificity on miRNA expression and function in response to stresses. Here, we show that EGFR, …

Brit1/Mcph1 Mediates The Dna Damage Response By Inducing P53 Stability And Promoting Atr Signaling, Edward Wang

Dissertations and Theses (Open Access)

The BRCT-repeat inhibitor of hTERT (BRIT1)/MCPH1 protein promotes the process of homologous recombination (HR) to repair DNA double strand breaks (DSBs). In response to DSBs, BRIT1 foci form at damaged sites, and recruits downstream repair proteins including 53BP1, MDC1, NBS1, and the SWI/SNF complex to the DSB region to promote DNA repair. BRIT1 copy number deficiency correlates with increased genomic instability in ovarian cancer specimens and breast cancer cell lines. Here, we propose that additional functions of BRIT1 include a direct interaction with the p53 tumor suppressor protein to promote p53 stability, and binding and recruitment of TopBP1 to sites …

Nuclear Translocation Of Met Via Internet Mechanism, Mei-Kuang Chen

Dissertations and Theses (Open Access)

MET is one of the receptor tyrosine kinases (RTKs) that are overexpressed in malignant cancer types, including breast cancer. While RTKs are traditionally known for their roles in signaling transduction from the cell surface, recent studies have provided evidence demonstrating that most of RTKs can translocate into nucleus to regulate cellular processes in response to both ligand and stress stimulation. Oxidative stress is a common stress in cancer cells due to alteration of metabolism, and constitutive oxidative stress related to reactive oxygen species (ROS) has been observed in breast cancer cells. Here, we show that hepatocyte growth factor (HGF) as …

Angiomotin Is A Novel Cadherin-11 Interacting Protein That Mediates Migration In Prostate Cancer Cells, Angelica Ortiz

Dissertations and Theses (Open Access)

Prostate cancer (PCa), the second leading cause of cancer-related deaths among men in the United States, has the proclivity to metastasize to bone resulting in sclerotic lesions. These cancer induced bone growths cause bone pain and fractures. Therefore, understanding the molecular mechanisms contributing to PCa bone metastasis is required in order to find better prognostic tools and suitable targets for metastasis treatment and/ or prevention. Previous work in our laboratory showed increased expression of cadherin-11 (Cad11), a mesenchymal cadherin, during PCa progression. Furthermore, Cad11 expression endows PCa cells with increased migratory potential and metastasis to bone. Deletion of the Cad11 …

Caspase-Dependent Signaling Underlies Glioblastoma Cell Death In Response To The Fungal Metabolite, Fusarochromanone, Elahe Mahdavian, Monique Marshall, Patrick M. Martin, Patrice Cagle, Brian A. Salvatore, Quincy A. Quick

Biology Faculty Research

Fungal metabolites continue to show promise as a viable class of anticancer agents. In the present study, we investigated the efficacy of the fungal metabolite, fusarochromanone (FC101), for its antitumor activities in glioblastomas, which have a median survival of less than two years and a poor clinical response to surgical resection, radiation therapy and chemotherapy. Using clinically applicable doses, we demonstrated that FC101 induced glioblastoma apoptotic cell death via caspase dependent signaling, as indicated by the cleavage of poly(ADP-ribose) polymerase, glioblastoma (PARP). FC101 also induced differential reactive oxygen species (ROS) levels in glioblastoma cells, contrasting a defined role of oxidative …

Impedimetric Detection Of Mutant P53 Biomarker-Driven Metastatic Breast Cancers Under Hyposmotic Pressure, Menglu Shi, Nataly Shtraizent, Alla Polotskaia, Jill Bargonetti, Hiroshi Matsui

Publications and Research

In cancer cells, the oncogenic mutant p53 (mtp53) protein is present at high levels and gain-of-function (GOF) activities with more expression of mtp53 proteins contribute to tumor growth and metastasis. Robust analytical approaches that probe the degree of metastasis of cancer cells in connection with the mtp53 activity will be extremely useful not only for establishing a better cancer prognosis but also understanding the fundamental mechanism of mtp53 oncogenic action. Here we assessed the influence of mtp53 in breast cancers to the mechanical property of breast cancer cells. Recently, ovarian and kidney cancer cell lines have been shown to have …

Branching Into Rnai: Synthesis, Characterization And Biology Of Branch And Hyperbranch Sirnas, Anthony Muriithi Maina

Seton Hall University Dissertations and Theses (ETDs)

The cancer epidemic continues to afflict millions of humans world-wide each year and despite a renewed hope with the development of new and improved forms of therapy, a cure for cancer remains an elusive goal. This is partly related to the rise of resilient forms of tumors that have evolved with resistance towards conventional chemotherapy and radiation treatments. Moreover, these non-specific therapeutic regimens are highly toxic, leading to severe immunosuppressive effects which poisons the body and compromises the road towards remission. In an effort to mitigate these limitations, cancer-targeting approaches are currently experiencing a renaissance in the translation of new …

Defining The Sites Of Interaction Of The Fancd2, Fance, And Fancl Proteins, Joseph Mcclanaghan

Senior Honors Projects

Fanconi anemia (FA) is a rare genetic disease characterized by congenital defects, bone marrow failure and increased cancer susceptibility. FA is caused by mutations in any one of 16 genes. These genes encode for proteins that function in the FA-BRCA pathway to repair damaged DNA. Because of its important r­­­ole in DNA repair, this pathway is considered a major cellular tumor suppressor pathway, i.e. is critical for the prevention of cancer. Underscoring this fact, several of the FA genes - including BRCA2, BRIP1, PALB2, and RAD51C - are bona fide breast and ovarian cancer susceptibility genes.

My …

Phthalates And Phthalate Alternatives: Effects On Proliferative And Estrogenic Target Genes In Ishikawa Cells, Ranjani Sundar '15, Ping Yin, Serdar E. Bulun

Student Publications & Research

Phthalates are used as plasticizers in many of the products found in medical, household, and industrial applications. Much research has not been completed on the effects of these phthalates as potential endocrine disrupting chemicals (EDCs). As these chemicals are ingested, the mechanism by which they affect the reproductive system is largely unknown. The purpose of this study was to observe how 2 phthalates, Di-n-butyl phthalate (DBP) and Diisononyl phthalate (DINP), and 2 phthalate alternatives, Dioctyl terephthalate (DOTP) and BHT (butylated hydroxytoluene)affect uterine cells in comparison to a vehicle treatment and 17β-Estradiol treatment. Changes in expression of mRNA were observed using …

The Effect Of Small Molecule 390 On Cxcr4 Receptors, Selam B. Zenebe-Gete '14, Shruti R. Topudurti '14, Shum Andrew, Richard J. Miller

Student Publications & Research

CXCR4 is the chemokine receptor which aids in chemotaxis of stem cells, such as those in the bone marrow or the brain. SDF-1 is the natural ligand for the CXCR4 receptor. Similarities between novel molecule 390 synthesized by the Miller Lab and SDF-1 make this novel small molecule a possible agonist of the CXCR4 receptor. To determine whether 390 is an agonist to the CXCR4 receptor, we transfected cells with CXCR4 and exposed them to no agonist [vehicle control], SDF-1, or varying concentrations of our agonist drug. Next, we took calcium images using the dye fura-2, which indicates changes in …

Modeling The Adaptive Immune Response To Mutation-Generated Antigens, Rory J. Geyer

University Scholar Projects

Somatic mutations may drive tumorigenesis or lead to new, immunogenic epitopes (neoantigens). The immune system is thought to represses neoplastic growths through the recognition of neoantigens presented only by tumor cells. To study mutations as well as the immune response to mutation-generated antigens, we have created a conditional knockin mouse line with a gene encoding, 5’ to 3’, yellow fluorescent protein (YFP), ovalbumin (which is processed to the immunologically recognizable peptide, SIINFEKL), and cyan fluorescent protein (CFP), or, YFP-ovalbumin-CFP. A frame shift mutation has been created at the 5’ end of the ovalbumin gene, hence YFP should always be expressed, …

Modulated Functions Of The Fanconi Anemia Core Complex, Yaling Huang

Dissertations and Theses (Open Access)

Cells derived from Fanconi anemia (FA) patients are characterized by hypersensitivity to DNA interstrand crosslinks (ICLs), suggesting that FA genes play a role in ICL repair. Fanconi anemia core complex (including A, B, C, E, F, G, L, FAAP20, and FAAP100) activates the Fanconi pathway by providing the essential E3 ligase activity for FANCD2 mono-ubiquitination. Previous studies suggested the existence of three protein-protein interaction groups. However, the functions of most FA core complex protein are still limited to their presence in the complex. How the spatially-defined FANCD2 ubiquitination is accomplished by the core complex remains unknown.

To elucidate the roles …

Modeling The Adaptive Immune Response To Mutation-Generated Antigens, Rory J. Geyer

Honors Scholar Theses

Somatic mutations may drive tumorigenesis or lead to new, immunogenic epitopes (neoantigens). The immune system is thought to represses neoplastic growths through the recognition of neoantigens presented only by tumor cells. To study mutations as well as the immune response to mutation-generated antigens, we have created a conditional knockin mouse line with a gene encoding, 5’ to 3’, yellow fluorescent protein (YFP), ovalbumin (which is processed to the immunologically recognizable peptide, SIINFEKL), and cyan fluorescent protein (CFP), or, YFP-ovalbumin-CFP. A frame shift mutation has been created at the 5’ end of the ovalbumin gene, hence YFP should always be expressed, …

Mechanisms Underlying Distinct Egfr Versus Fgfr-3 And -1 Dependency In Human Bladder Cancer Cells, Tiewei Cheng

Dissertations and Theses (Open Access)

The epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR) are activated by gene amplification, mutation and overexpression in bladder cancer, which drives tumor development and progression. Both EGFR and FGFR inhibitors are currently being tested in clinical trials. However, bladder cancer (BC) cells show remarkably heterogeneous sensitivities to both inhibitors, and the molecular determinants of this heterogeneity are presently unclear. Therefore, in this study, using selective EGFR and FGFR inhibitors in BC cells, we demonstrated that FGFR3 and FGFR1 play largely non-overlapping roles in mediating proliferation and invasion in the distinct “epithelial” and “mesenchymal” subsets of human …

The Association Between The Il-1 Pathway, Isaac C. Wun

Dissertations and Theses (Open Access)

Cutaneous malignant melanoma (CMM) is a potentially lethal malignancy that warrants attention and further research, as it is known to that there is an increasing rate of incidence in theUnited States, and it is also known that exposure to UV light is its most crucial risk factor, and family history of melanoma is also an important risk factor. Melanoma is an aggressive and lethal cancer in humans. There are an estimated new 132,000 melanoma cases annually worldwide, and the trend has doubled in the past 20 years. However, attempts to treat melanoma have encountered considerable resistance and remained ineffective. The …

Imbalance Between Neutrophil Elastase And Elafin Promotes Breast Cancer Growth And Progression, Joseph Anthony Caruso

Dissertations and Theses (Open Access)

Elafin, an endogenous serine protease inhibitor, is a critical component of the epithelial barrier against neutrophil elastase (NE) activity. The central hypothesis examined in this dissertation was that elafin has tumor suppressive properties in breast cancer. In support of this hypothesis, immunohistochemical (IHC) analysis revealed that elafin was downregulated in the majority of invasive breast tumors and a subset of pre-invasive ductal carcinoma in situ (DCIS) compared to elafin expression in the normal mammary epithelium. To understand the role of elafin in the mammary epithelium and the impetus for its downregulation during breast tumorigenesis, primary and immortalized human mammary epithelial …

Role Of Talin1 Phosphorylation In Beta1 Integrin Activation And Prostate Cancer Metastasis, Jung-Kang Jin

Dissertations and Theses (Open Access)

Talins are adaptor proteins that regulate focal adhesion signaling by conjugating integrins to the cytoskeleton. Talins directly bind and activate integrins but the mechanism by which this occurs is unknown. As integrin activation and overexpression of talins promote prostate cancer metastasis, understanding the mechanism by which talins activate integrins will better elucidate their roles in Prostate cancer metastasis. Phosphorylation of talins on serine 425 has been associated with β1 integrin functions. Work in this dissertation tested the hypothesis that increased talin1 S425 phosphorylation was required for β1 integrin activation and promotion of prostate cancer metastasis.

I first used shRNA to …

Metadherin Functions As A Laminin Receptor That Is Essential For Metastasis And Is Associated With Poor Survival In Osteosarcoma, Limin Zhu

Dissertations and Theses (Open Access)

Osteosarcoma is a highly invasive bone malignancy in which metastasis accounts for the vast majority of death and morbidity in patients. Understanding the mechanisms controlling metastasis is essential for improving patient survival in this disease. In order to improve the clinical outcomes for patients with poor prognosis, it is urgent to find new therapeutic targets to block metastasis in this disease. Recent studies have shown that Metadherin (MTDH) plays an essential role in mediating tumorigenesis and metastasis in a variety of human cancers. Our study assessed the role of MTDH in osteosarcoma metastasis and elucidated the mechanisms underlying its metastasis-promoting …

Anti-Insulin Resistance Treatments Suppress Her2+ Breast Cancer Growth Via Altering Metabolism, Ping-Chieh Chou

Dissertations and Theses (Open Access)

Epidemiological studies have identified that type 2 diabetes mellitus (DM2) is a significant risk factor for carcinogenesis and cancer death, including breast cancer. Our previous finding in patients showed that anti-insulin resistance treatments are associated with improved HER2⁺ breast cancer survival of diabetic women. However, there were no transgenic mouse models to study the correlation and explain the detailed mechanism. We generated a mouse model of HER2⁺ breast cancer with DM2 by crossing leptin receptor point mutation (Lepr ^db/+) and MMTV-ErbB2 (neu) mice. The MMTV-ErbB2/Lepr ^db/db mice had a poor survival rate compared …

Diabetes And Obesity Induce Transcriptomic And Metabolomic Changes Enhancing Pancreatic Cancer Aggressiveness, Guermarie Velázquez Torres

Dissertations and Theses (Open Access)

Pancreatic cancer is one of the most aggressive types of cancer, with poor prognosis that lacks effective diagnostic markers and therapies. It is expected that in 2014 the incidence and the mortality of pancreatic cancer in the United States will be 46,420 and 39,590 respectively. Diabetes and obesity are modifiable risk factors associated with accelerated pancreatic carcinogenesis and tumor progression, but the biological mechanisms are not completely understood. The purpose of this study is to demonstrate direct evidence for the mechanisms mediating these epidemiologic phenomena. Our hypothesis is that obesity and diabetes mellitus type 2 (DM2) accelerate pancreatic cancer and …

Car-Modified T Cells Capable Of Distinguishing Normal Cells From Malignant Cells, Hillary G. Caruso

Dissertations and Theses (Open Access)

T cells can be redirected to target tumor-associated antigen (TAA) by genetic modification to express a chimeric antigen receptor (CAR), which fuses the specificity derived from an antibody to T-cell activation domains to result in lysis of TAA-expressing cells. Due to the potential for on-target, off-tissue toxicity, CAR⁺ T-cell therapy is currently limited to unique or lineage-restricted TAAs. Glioblastoma, a grade IV brain malignancy, overexpresses epidermal growth factor receptor (EGFR) in 40-50% of patients. EGFR also has widespread normal tissue expression. To target EGFR on glioblastoma while reducing the potential for normal tissue toxicity, EGFR-specific CAR generated from cetuximab, …

The Regulation Of Microrna Biogenesis By Ribosome-Interacting Proteins, Brian Pickering

Dissertations and Theses (Open Access)

MicroRNA (miRNA) are small, non-coding RNAs that affect gene expression through degradation of complementary mRNA targets or inhibition of translation. As they affect approximately 50% of all cellular processes, miRNA are tightly regulated by the cell through transcriptional and post-transcriptional mechanisms. Transcribed miRNA are capped and polyadenylated (referred to as pri-miRNA) which are cleaved by Drosha and DGCR8 to generate 60-90 nucleotide precursor miRNA. The precursors are cleaved again by Dicer and loaded into the RNA-induced silencing complex (RISC) of which Argonaute 2 is the functional component. Many of the proteins involved in miRNA biogenesis share a common role in …

Regulation Of Mammary Gland Development And Tumorigenesis By 14-3-3 Zeta, Sumaiyah Rehman

Dissertations and Theses (Open Access)

Signaling pathways that play critical roles in organ development are often aberrantly regulated during cancer initiation and progression. 14-3-3z is overexpressed in more than 40% of breast cancers and is associated with poor patient prognosis. Therefore, the function of 14-3-3z in cancer and normal mammary gland development was investigated utilizing multiple in vivo and in vitro approaches. 14-3-3z is a chaperone protein that interacts with a multitude of oncogenes and tumor suppressor genes, thereby functioning as a critical node in multiple oncogenic signaling networks. Mammary gland-specific 14-3-3z transgenic mouse models showed that 14-3-3z overexpression was sufficient to induce mammary tumorigenesis. …

Sumoylation Status And Effects Of Sumylation On Dax-1, Amy E. Scandurra, Hai Nguyen, Christina Tzagarakis -­‐Foster

Creative Activity and Research Day - CARD

DAX-1 (Dosage Sensitive Sex Reversal Adrenal Hypoplasia Congenita on the X Chromosome gene 1) is a Nuclear Hormone Receptor, which acts as a transcriptional repressor in the nucleus. DAX-1 plays an important role in development and also appears to have some influence on the progression of cancer. In an effort to better understand DAX-1 function both in normal and disease states we are examining one type of posttranslational modification, SUMOylation. SUMOylation involves the addition of the small polypeptide conjugate SUMO (Small Ubiquitin-like Modifier) to proteins, this can have a variety of effects on protein activity. To …

The Effects Of Gold Nanorods On The Rate Of Apoptosis Of Triple Negative Breast Cancer Cells, Mattie E. Raiford

Honors College Theses

Triple negative breast cancer (TNBC) is a subtype of breast cancer that is most often found in African American females that is characterized by the lack of the progesterone receptor (PR), the estrogen receptor (ER), and the human epithelial growth factor receptor two (HER2).TNBC is a very aggressive form of breast cancer because it does not respond to hormone therapy, due to the lack of the three vital receptors. Since the current treatment is not affective, the project used porphyrin to specifically target cancer in the body because it has an increased affinity for many cancer types. Gold nanorods were …

Analysis Of The Regulation And Function Of Cip2a To Identify Candidate Biomarkers For Prostate Cancer, Diana Savoly

Graduate School of Biomedical Sciences Theses and Dissertations

Protein Phosphatase 2A (PP2A) is a tumor suppressor involved in the regulation of several signaling pathways and the cell cycle. PP2A becomes inactivated by several inhibitors, including Cancerous Inhibitor of PP2A (CIP2A). CIP2A has been identified as an oncogene, which is over-expressed in cancers and inhibits PP2A through direct interaction. CIP2A is recognized as a biomarker for cancer; however, it is not cancer-specific. Therefore, we identified and examined the use of CIP2A-regulated proteins as potential biomarkers in prostate cancer to better diagnose prostate cancer in patients. Currently, Prostate Specific Antigen (PSA) is widely used to detect prostate cancer; however, it …

Molecular Pap Biomarkers For Cervical Cancer Risk Assessment In Thinprep® Clinical Specimens, Jennifer Taylor

Graduate School of Biomedical Sciences Theses and Dissertations

Approximately 500,000 patients are diagnosed with cervical cancer worldwide each year, thus making it the second most common cause of cancer-related deaths in women. Persistent high-risk human papillomavirus (HR-HPV) infections induce cervical dysplasia by increasing the expression of two viral oncogenes, E6 and E7. Utilization of the Papanicolaous smear test (Pap test) has contributed to a decrease in morbidity and mortality of cervical cancer; however, subjective analysis of cell morphology with a limited amount of cells has led to a substantial rate of false positive and false negative diagnoses. A more objective and sensitive diagnostic tool for the detection of …

A Melanin-Independent Interaction Between Mc1r And Met Signalling Pathways Is Required For Hgf-Dependent Melanoma, Agnieszka Wolnicka-Głubisz, Faith M. Strickland, Albert Wielgus, Miriam Anver, Glenn Merlino, Edward C. De Fabo, Frances P. Noonan

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Melanocortin 1 receptor (MC1R) signaling stimulates black eumelanin production through a cAMP-dependent pathway. MC1R polymorphisms can impair this process, resulting in a predominance of red phaeomelanin. The red hair, fair skin and UV sensitive phenotype is a well-described melanoma risk factor. MC1R polymorphisms also confer melanoma risk independent of pigment. We investigated the effect of Mc1r deficiency in a mouse model of UV-induced melanoma. C57BL/6-Mc1r+/+-HGF transgenic mice have a characteristic hyperpigmented black phenotype with extra-follicular dermal melanocytes located at the dermal/epidermal junction. UVB induces melanoma, independent of melanin pigmentation, but UVA-induced and spontaneous melanomas are dependent on black eumelanin. We …