Cancer Biology Commons^™

Characterizing The Combination Of Rpa Inhibitors With Parp Inhibitors In High-Grade Serous Ovarian Cancer, Yat Tang

Theses & Dissertations

High-grade serous ovarian cancer (HGSC) is the most common and deadly gynecologic malignancy. HGSC patients with BRCA1/2 mutations have homologous recombination deficiency (HRD), requiring parallel pathways to maintain genome integrity (e.g., PARP1, PARP2). Approximately 50% of ovarian carcinomas are estimated to exhibit HRD. For the remaining 50% and the large percentage of HRD patients with acquired or innate resistance to single-agent PARP inhibitors, there is a need to develop alternative therapeutic strategies.

Replication Protein A (RPA) is a heterotrimeric protein crucial for genome maintenance. Phosphorylation of RPA in DNA damage response (DDR) is a negative regulator of DNA end resection. …

Mechanism Of Bax/Bak Activation In Apoptotic Signaling, Kai Huang

Theses & Dissertations

The Bcl-2 family proteins, including the anti-apoptotic members, pro-apoptotic effectors Bax/Bak, and the BH3-only proteins, are key components of the mitochondrial apoptotic pathway. The BH3-only protein Bid is critical for the mitochondrial pathway of apoptosis after TRAIL-induced death receptor activation. However, the mechanism of Bid activation during TRAIL-induced apoptosis is unclear. By putting back wild-type and mutants of Bid in Bid deficient (Bid KO) and Bid/Bax/Bak TKO colon cancer cells, we demonstrated that cleavage by caspase 8 and mitochondrial targeting are critical events for Bid activation. One of the biggest mysteries in apoptosis is how Bax/Bak was activated by BH3-only …

Hdac1 Is A Required Cofactor Of Cbfβ-Smmhc And A Therapeutic Target In Inversion 16 Acute Myeloid Leukemia, Lisa E. Richter

Theses & Dissertations

Acute myeloid leukemia (AML) is a neoplastic disease characterized by the uncontrolled proliferation and accumulation of immature myeloid cells. A common mutation in AML is the inversion of chromosome 16 [inv(16)], which generates a fusion between the genes for core binding factor beta (CBFB) and smooth muscle myosin heavy chain (MYH11), forming the oncogene CBFB-MYH11. The expressed protein, CBFβ-SMMHC, forms a heterodimer with the key hematopoietic transcription factor RUNX1. Although CBFβ-SMMHC was previously thought to dominantly repress RUNX1, recent work suggests that CBFβ-SMMHC functions together with RUNX1 to activate transcription of specific target genes.

Targeting the …

The Role Of Reactive Oxygen Species In Regulating Macrophage And Fibroblast Activation Within The Breast Cancer Tumor Microenvironment, Brandon J. Griess

Theses & Dissertations

The tumor microenvironment (TME) is a key determining factor in breast cancer, especially the more aggressive subtype triple negative breast cancer (TNBC). The activated fibroblasts and macrophages within the TME have many tumor promoting functions. Therefore, targeting their activation presents a novel therapeutic approach in TNBC. My work studied the role of reactive oxygen species (ROS) during fibroblast and macrophage activation in breast cancer.

My studies showed that expression of the secreted antioxidant enzyme, EcSOD, is silenced in breast cancer samples, in part, via increased promoter methylation. The re-expression of EcSOD inhibited c-Met activation in the TNBC cell line, MDA-MB231. …

The Role Of E3 Ubiquitin Ligase Fbxo9 In Normal And Malignant Hematopoiesis, R. Willow Hynes-Smith

Theses & Dissertations

Hematopoiesis is a critical system that provides blood cells necessary for nutrient and oxygen transfer throughout an organism and for protection from harmful agents. It is maintained throughout life by the hematopoietic stem cells (HSCs) that reside within the bone marrow (BM) and are responsible for providing billions of new cells each day. HSCs maintain a careful balance between a quiescent state, that sustains the integrity of the stem cells, and a proliferative state, that provides new cells to replenish those that undergo apoptosis. Hematopoiesis is regulated by a variety of intrinsic pathways and extrinsic signals such as cytokine signaling, …

Brca1 & Ctdp1 Brct Domainomics In The Dna Damage Response, Kimiko L. Krieger

Theses & Dissertations

Genomic instability is one of the enabling characteristics of cancer. DNA damage response pathways are important for genomic integrity and cell cycle progression. Defects in DNA damage repair can often lead to cell cycle arrest, cell death, or tumorigenesis. The activation of the DNA damage response includes tightly regulated signaling cascades that involve kinase phosphorylation and modular domains that scaffold phosphorylated motifs to coordinate recruitment of DNA repair proteins. Modular domains are conserved tertiary structures of a protein that can fold, function, and evolve independently from an intact protein. One of the most common modular domains involved in DNA damage …

The Role Of Histone Chaperone Fact Complex In Base Excision Repair Pathway And Its Therapeutic Potential In Colon Cancer And Medulloblastoma, Heyu Song

Theses & Dissertations

Base excision repair (BER) pathway is required for the removal of damaged bases caused by alkylation, oxidation and ring-saturation. Human apurinic/apyrimidinic endonuclease 1 (APE1) plays a central role in BER pathway. Although repair of damaged bases by recombinant APE1 has been well investigated in vitro, how APE1 gains access to damaged bases in the context of chromatin is largely unknown. A prominent member of the histone chaperone family, FACT (Facilitates Chromatin Transcription) is thought to reorganize nucleosomes through the destabilization of multiple intra-nucleosome contacts. FACT complex is composed of two polypeptides identified as SPT16 (Suppressor of Ty 16) and SSRP1 …

Molecular Insights Into Major Peripheral T-Cell Lymphoma Entities With Advances In A Representative Model System, Tayla B. Heavican

Theses & Dissertations

Peripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities associated with an aggressive clinical course. Angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) are the two most frequent categories accounting for more than 50% of PTCLs. Gene expression profiling (GEP) defined molecular signatures for AITL and delineated biological and prognostic subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21). Genomic copy number analysis and targeted sequencing revealed unique genomic abnormalities and oncogenic pathways, indicating distinct oncogenic evolution. PTCL-GATA3 exhibited higher genomic complexity characterized by frequent loss or mutation of tumor suppressor genes targeting the CDKN2A/B-TP53 axis and PTEN-PI3K pathways. …

Il-17-Cxcr2 Axis Promotes Breast Cancer Metastasis And Therapy Resistance, Lingyun Wu

Theses & Dissertations

Cancer-related fatalities rank as the second leading cause of death in all ages and both genders in the United States. Moreover, breast cancer-related mortality rank as the second leading cause of death in females in the United States in 2019. The main concerns regarding breast cancer management include chemotherapy resistance and metastasis. Thus, the advanced understanding of cancer progression is required to develop improved therapeutic methods for breast cancer patients.

Recent studies demonstrate that neutrophils, as the most abundant leukocytes, play an essential role in breast progression. However, the mechanisms regarding neutrophils recruitment to the tumor sites, and the precise …

Molecular Mechanisms Governing Muscle Wasting In Cancer, Aneesha Dasgupta

Theses & Dissertations

Pancreatic cancer is the third-leading cause of cancer-related deaths in the United States. About 80 percent of the pancreatic cancer patients suffer from cachexia and, about one-third die due to complexities related to the syndrome. Cachexia leads to a loss in body weight and cachectic patients are refractory to chemotherapy. Despite recent advances, the mechanisms of pancreatic cancer- cachexia and the potential therapeutic interventions remain poorly evaluated.

Sirtuins represent a class of proteins that are regulated by metabolic fluctuations in tissues. We observed a reduced expression of Sirt1 in spontaneous PDAC mice muscles, human pancreatic cancer muscles, and myotubes treated …

Identification Of Pathways Required For The Survival Of Inversion(16) Acute Myeloid Leukemia, Yiqian Wang

Theses & Dissertations

Inversion of chromosome 16 [inv(16)] acute myeloid leukemia (AML) generates a fusion gene CBFB-MYH11. Approximately half of inv(16) AML patients eventually relapse mainly due to the existence of leukemia stem cells (LSCs). Previous work using a Cbfb-MYH11 knockin mouse model showed that the LSCs are enriched within CSF2RB^- population. Another gene upregulated by Cbfb-MYH11 encodes the cytokine receptor IL1RL1. Using Cbfb-MYH11 knockin mice, we showed that LSCs exist in multiple sub-populations defined by their immunophenotype, and IL1RL1 is expressed by cell populations with high LSC activity. We also found that treatment of IL-33, the ligand for IL1RL1, promoted …

The Cxcr2-Dependent Role Of Cancer-Associated Fibroblasts In Pancreatic Ductal Adenocarcinoma, Mohammad Awaji

Theses & Dissertations

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, the fourth leading cause of cancer-related deaths in the USA with over 40,000 deaths per year. Unlike other major cancer types, the progress in dealing with PDAC is plodding, attributed mainly to the asymptomatic nature of the disease, the late diagnosis and the ineffectiveness of current therapies. A better understanding of the biology of the disease could permit the discovery of novel diagnostic and therapeutic tools. With that in mind, we present this dissertation that investigates the tumor-stromal interaction underlined by genetic alterations and inflammation. PDAC develop as …

Induction And Metastasis Of Cancer Stem Cells In Pancreatic Cancer, Rama Krishna Nimmakayala

Theses & Dissertations

Pancreatic cancer is one of the most lethal of all types of cancer with an overall 5-year survival rate of less than 8%. Cancer cells in pancreatic tumor are heterogeneous, and it is poorly understood which population is most responsible for the cancer initiation, progression and metastasis. Recent studies provide evidence for the existence of a highly tumorigenic and metastatic cells within a heterogeneous tumor known as the cancer stem cells (CSCs). Studies also provided ample evidence for the existence of distinct types of CSC populations in a heterogeneous tumor with type specific genotypic, phenotypic and functional characteristics. But, it …

Developing Targeted Therapy Against Pancreatic Cancer, Garima Kaushik

Theses & Dissertations

Not available.

Targeting Oncogenic Protein Sythesis In Myc-Driven B Cell Lymphoma, Xuan Zhang

Theses & Dissertations

Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) are aggressive tumors of mature B cells that can be distinguished based on histomorphological, phenotypic, and genetic features. B-cell lymphoma unclassifiable, with features intermediate between BL and DLBCL (BCL-U) is a subset of mature B cell lymphoma contains one or more features that overlap BL and DLBCL. Previous molecular analyses prove there is a biological continuum between BL and DLBCL based on the activity of MYC. Herein, in order to resolve the molecular heterogeneity of BCL-U, we tested whether a targeted expression profiling panel could categorize tumors as BL and DLBCL. …

Human Leukocyte Antigen (Hla) Class I Molecule Components And Amyloid Precursor-Like Protein 2 (Aplp2): Roles In Pancreatic Cancer Cell Migration, Bailee Sliker

Theses & Dissertations

Human leukocyte antigen (HLA) class I molecules are composed of a light chain (beta 2-microglobulin (β₂m)) and HLA heavy chain. The heavy chains of these molecules have three different isotypes (–A, -B, and –C) and are highly polymorphic with thousands of sequence variations termed allotypes. The best-known role for these molecules is within the immune system, however, recent research implicates components of this molecule can function outside of this known immune role by contributing to cell migration. However, no studies have been published thus far investigating this non-immune function in pancreatic cancer. Therefore, I examined the role of …

The Role Of Ros In The Progression And Treatment Of Castration-Resistant Prostate Cancer, Dannah R. Miller

Theses & Dissertations

Prostate cancer is the second leading cause of cancer-related deaths in U.S. men, primarily due to the development of castration-resistant (CR) prostate cancer (PCa), of which there are no effective treatment options. Reactive oxygen species (ROS) plays a critical role in prostate carcinogenesis, including the progression of the CR PCa phenotype. ROS regulates both cell proliferation and apoptosis; a moderate increase in ROS can promote proliferation; however, a substantial rise in ROS levels will result in apoptosis. Oxidase p66Shc is elevated in clinical PCa cells and has been associated with a metastatic phenotype of CR PCa cells, promoting PCa cell …

The Role Of Zyxin And Limd1 In Mitosis And Cancer, Jiuli Zhou

Theses & Dissertations

The Hippo signaling pathway, originally discovered in Drosophila, consists of a core kinase cascade and has been subsequently demonstrated to control tissue growth and tumorigenesis. The core of this pathway contains MST1/2 (Mammalian sterile 20-like kinase 1/2), LATS1/2 (large tumor suppressor 1/2) and downstream effector named Yes-associated protein (YAP) and PDZ-binding motif (TAZ). MST1/2 transduce their kinase activity mainly through directly phosphorylating LATS1/2. Once phosphorylated and activated, LATS1/2 subsequently phosphorylate and inhibit YAP/TAZ from translocating to nucleus, thereby suppressing the expression of downstream pro-growth and survival genes. While recent studies provide important insight into the tumor suppressor properties of …

Regulation Of Canonical And Non-Canonical Hippo Pathway Components In Mitosis And Cancer, Seth Stauffer

Theses & Dissertations

The Hippo pathway is conserved regulator of organ size through control of proliferation, apoptosis, and stem-cell self-renewal. In addition to this important function, many of the canonical signaling members have also been shown to be regulated during mitosis. Importantly, Hippo pathway components are frequently dysregulated in cancers and have attracted attention as possible targets for improved cancer therapeutics. Further exploration of Hippo-YAP (yes-associated protein) signaling has revealed new regulators and effectors outside the canonical signaling network and has revealed a larger non-canonical network of signaling proteins in which canonical Hippo pathway components crosstalk with important cellular homeostasis and apoptosis signaling …

Delineation Of New Mechanisms Of Dna Double Strand Break Repair, Songli Zhu

Theses & Dissertations

DNA damage is frequently induced in cells by both endogenous and exogenous agents. DNA damage, particular double strand breaks (DSBs) may lead to genomic instability, and the progression of cancer, aging, neurodegeneration, and other human diseases. The cell employs two major DSB repair pathways, including homologous recombination (HR) and Non-homologous end joining (NHEJ), but the detailed mechanisms of DSB repair remain to be further revealed.

In the first part of this study, we characterized a plasmid-based assay to investigate NHEJ repair in Xenopus egg extracts. Our data argued for a preference for the precise repair by the NHEJ machinery and …

Foxm1 Expression And Contribution To Genomic Instability And Chemoresistance In High-Grade Serous Ovarian Cancer, Carter J. Barger

Theses & Dissertations

High-grade serous ovarian cancer (HGSC) is the most common and deadly subtype of epithelial ovarian cancer. Understanding the molecular basis of HGSC will improve diagnosis and treatment approaches. The Cancer Genome Atlas (TCGA) discovered that Forkhead Box M1 (FOXM1) transcription factor activation is the second most frequent molecular alteration in HGSC (84% of cases), second only to mutations of TP53 (100%). We subsequently defined several genetic mechanisms that underlie increased FOXM1 expression in HGSC, including genomic amplifications and RB-E2F deregulation, and showed that FOXM1 promotes cell cycle progression in cell models relevant to HGSC.

TCGA analyses revealed that genomic instability, …

Elucidating The Roles Of Lunatic Fringe In Pancreatic Ductal Adenocarcinoma, Prathamesh Patil

Theses & Dissertations

Pancreatic cancer is an aggressive form of cancer that is very difficult to detect, treat resulting in a high rate of mortality. Understanding the molecular basis of pancreatic cancer and identifying new molecular targets for designing therapeutic interventions is paramount for improving outcomes in this disease. Notch signaling is a vital developmental signaling pathway that has been implicated to play both oncogenic and tumor suppressive roles in pancreatic cancer. Previous studies from other groups have shown that O-linked glycosylation of Notch signaling plays a key role in the regulation of Notch signaling. Lunatic fringe (Lfng) is one of the glycosyltransferases …

Functional Role Of Protein Kinase C Alpha In Endometrial Carcinogenesis, Alice Hsu

Theses & Dissertations

Protein kinase Cα (PKCα) is a member of the PKC family of serine/threonine kinases that regulate many fundamental cellular processes, including cell proliferation, differentiation, survival and transformation. The impact of PKCα on tumorigenesis, and whether it acts as an oncogene or tumor suppressor, has been debated over the years. The overall goal of this study was to establish the functional role of PKCα in endometrial carcinogenesis. Results from this study broaden our knowledge of PKCα signaling and add to our understanding of its role in tumor development.

As understanding of the role of PKCα signaling in the uterus is limited, …

Overcoming Tcf4-Driven Bcr Signaling In Diffuse Large B-Cell Lymphoma, Keenan Hartert

Theses & Dissertations

Diffuse Large B-cell Lymphoma (DLBCL) is the most common subtype of lymphoma. Despite a cure rate of 40% with standard R-CHOP therapy, patients that refract or relapse are subject to a dismal prognosis. Cases of DLBCL can be classified by their molecular expression phenotype, with the GCB-like subtype aligning with the profile of a germinal center B-cell and the ABC-like subtype aligning to that of an activated B-cell. Aggressive disease is often characterized by high levels of B-cell Receptor (BCR) signaling. This pathway engages downstream kinases responsible for stimulating proliferation and survival that play a key role under the normal …

The Beta-Catenin/Muc1.Ct Interaction In Pancreatic Cancer, Edwin Wiest

Theses & Dissertations

MUC1 is overexpressed in over 90% of pancreatic cancer cases, and its interaction with beta-catenin promotes progression of the disease. Various in vitro and in vivo methods show that beta-catenin and MUC1 interact by way of the cytoplasmic tail of MUC1 (MUC1.CT). This interaction occurs in the membrane of pancreatic cancer cells but is found to a smaller extent in the nucleus as well. Biophysical methods suggest that MUC1 interacts with beta-catenin through a sequence of amino acids in the tail of MUC1 that sit very near the transmembrane domain of MUC1. In pancreatic ductal adenocarcinoma cells, it appears that …

Functional Signature Ontology-Based Identification And Validation Of Novel Therapeutic Targets And Natural Products For The Treatment Of Cancer, Beth Neilsen

Theses & Dissertations

Multiple studies have revealed that Ras-driven tumors acquire vulnerabilities by adapting cellular mechanisms that promote uncontrolled proliferation and suppress apoptosis. Kinase Suppressor of Ras 1 (KSR1) modulates ERK activation downstream of oncogenic Ras, and knockdown of KSR1 selectively kills malignant, Ras-driven cancer cells, but does not kill immortalized, non-transformed human colon epithelial cells (HCECs). KSR1^-/- mice are fertile and phenotypically normal, but resistant to Ras-driven tumor formation suggesting KSR1 represents a vulnerability in cancer cells.

To identify additional vulnerabilities in cancer, a screening approach termed Functional Signature Ontology (FUSION) was used to screen 14,355 genes and 1,200 natural product …

The Role Of Hippo Pathway In Mitosis And Cancer, Xingcheng Chen

Theses & Dissertations

The Hippo signaling pathway has been recently elucidated as a tumor suppressor pathway controlling cell proliferation and apoptosis. The core of this pathway is a kinase cascade which contains MST1/2 (Mammalian sterile 20-like kinase 1/2), LATS1/2 (large tumor suppressor 1/2) and downstream effector named Yes-associated protein (YAP). MST1/2 transduce their kinase activity mainly through directly phosphorylating LATS1/2. Once phosphorylated and activated, LATS1/2 subsequently phosphorylate and inhibit YAP from translocating to nucleus. Current studies involving the Hippo pathway focus on determining its oncogenic role in various organs/tissues. While those studies provide important insight into the tumor suppressor properties of this pathway, …

The Role Of Yes-Associated Protein 1 In Ovarian Physiology And Pathology, Xiangmin Lv

Theses & Dissertations

Ovarian granulosa cells are the major somatic components of the ovarian follicle. Proper proliferation and differentiation of ovarian granulosa cells are essential for successful follicle development. Accumulating evidence indicates that the Hippo-YAP signaling pathway plays critical roles in both development and tumorigenesis of several organs. The present study aims to investigate the role of Yes-associated protein 1 (YAP) in ovarian granulosa cell proliferation, differentiation, and malignant transformation. At first, we found that nuclear YAP (active) was highly expressed in proliferative granulosa cells, whereas cytoplasmic YAP (inactive) was detected mainly in terminally-differentiated luteal cells. Further studies suggested that endogenous YAP activity …

Perturbing Anti-Apoptotic Proteins To Develop Novel Cancer Therapies, Jacob Contreras

Theses & Dissertations

The apoptotic pathway involves a tightly regulated network of proteins which respond to various stimuli. Previous studies have indicated Mcl-1 and Bcl-xL are intimately involved in determining cell fate, and if both are concurrently neutralized, it activates the apoptotic pathway. The inactivation of Bcl-xL and Mcl-1 as a mechanism to trigger the intrinsic apoptotic response can be used as a platform to develop therapeutic strategies to target cancer cells. The apoptotic pathway is largely dysregulated and often leads to therapy resistance in cancer cells. Although direct inhibitors of Bcl-xL have been developed and have advanced to clinical trials, development of …

Comparative Molecular Characterization Of Typical And Exceptional Responders In Glioblastoma, Kristin Wipfler

Theses & Dissertations

Glioblastoma (GBM) is the most common and the deadliest type of primary brain tumor, with a median survival time of only 15 months despite aggressive treatment. Although most patients have an extremely poor prognosis, a small number of patients survive far beyond the median survival time. Investigation of these “exceptional responders” has sparked a great deal of interest and is becoming an important focus in the field of cancer research. To investigate the molecular differences between typical and exceptional responders in GBM, comparative analyses of copy number, methylation, gene expression, miRNA expression, and protein expression data sets from The Cancer …