Cancer Biology Commons^™

The Tumor Suppressor Notch Inhibits Head And Neck Squamous Cell Carcinoma (Hnscc) Tumor Growth And Progression By Modulating Proto-Oncogenes Axl And Ctnnal1 (Α-Catulin), Shhyam Moorthy, Shhyam Moorthy

Dissertations & Theses (Open Access)

Background: Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common malignancy worldwide, with roughly 300,000 cancer related deaths occurring globally each year. The survival of patients with HNSCC has not changed significantly over the past decade, leading investigators to search for promising molecular targets. To identify new treatment targets and biomarkers that could better guide therapy, we previously characterized the genomic alterations from primary HNSCC patient samples. We were among the first to discover that NOTCH1 is one of the most frequently mutated genes in this cancer type. The spectrum of inactivating NOTCH1 mutations in HNSCC suggested …

Identifying Protein Kinase Tbk1 As A Novel Inhibitor Of Intestinal Tumorigenesis, Amber L. Mathews

Dissertations & Theses (Open Access)

Colorectal cancer (CRC) is the third most common cancer diagnosed in women and men， causing almost 600,000 annual deaths worldwide. There is a clear need to understand how CRC forms and progresses in order to improve the strategies of CRC prevention and therapy. A major factor that drives the development of CRC is genetic mutations that lead to activation of oncogenes and inactivation of tumor suppressor genes in intestinal epithelial cells (IECs). In addition, the initiation and progression of CRC involve environmental and immunological factors. In particular, chronic inflammatory conditions are known as an important risk factor for CRC. Intestinal …

Normal Glycolytic Enzyme Activity Is Critical For Hypoxia Inducible Factor-1a Activity And Provides Novel Targets For Inhibiting Tumor Growth, Geoffrey Grandjean Phd

Dissertations & Theses (Open Access)

Normal Glycolytic Enzyme Activity is Critical for Hypoxia Inducible Factor-1α Activity and Provides Novel Targets for Inhibiting Tumor Growth

By Geoffrey Grandjean

Advisory Professor: Garth Powis, D. Phil

Unique to proliferating cancer cells is the observation that their increased need for energy is provided by a high rate of glycolysis followed by lactic acid fermentation in a process known as the Warburg Effect, a process many times less efficient than oxidative phosphorylation employed by normal cells to satisfy a similar energy demand ^[1]. This high rate of glycolysis occurs regardless of the concentration of oxygen in the cell and …

Direct Regulation Of Apoptosis By Linear Ubiqutin Chain Assembly Complex (Lubac) And Feedback Regulation Of Lubac Function By Caspases, Donghyun Joo

Dissertations & Theses (Open Access)

Tumor Necrosis Factor-alpha (TNF-α) is a cytokine that plays a role in various cellular processes such as proliferation, differentiation (mainly through NF-κB signaling) and death (via apoptosis signaling). Recently, linear ubiquitination by LUBAC (linear ubiquitin chain assembly complex) was reported to have a regulatory function in TNF-α mediated NF-κB activation. Although LUBAC is suggested to control not only NF-kB signaling but also the apoptosis pathway, the precise mechanism of apoptosis regulation remains unknown. Moreover, NF-κB and apoptosis pathways have opposed but fundamental functions for various cellular processes. Although these two pathways actively interplay to balance the death and survival, the …

Investigating The Role Of Cholesterol Metabolism And Synthesis In Metastasis And Radiation Response In Aggressive Subtypes Of Breast Cancer, Adam Wolfe

Dissertations & Theses (Open Access)

Aggressive breast cancers, triple-negative breast cancer (TNBC) and inflammatory breast cancer (IBC), metastasize at a high rate and are notoriously resistant to standard treatments. Research has shown diets high in cholesterol increase the incidence of aggressive breast cancers and pre-clinical research has shown cholesterol can fuel the growth of breast cancer in vivo. Studies at MD Anderson have shown that IBC patients taking cholesterol lowering drugs, statins, have improved survival outcomes, and also statins can improve the response to radiation in vitro. Furthermore, statins have been shown to target the cells with stem like-properties called cancer stem cells (CSCs) which …

Impact Of Differentiation Status Of Kidney Progenitors In Wilms Tumor Development, Le Huang

Dissertations & Theses (Open Access)

Wilms tumor is one of the most common solid tumors in children. It is an embryonic cancer of the kidney and is thought to arise from undifferentiated renal mesenchyme. However, the differentiation status of cells in the mesenchyme that can give rise to Wilms tumors is unknown. Gene expression analysis of a large panel of Wilms tumor patients has identified different subsets of Wilms tumors that are distinct in their clinical outcomes and gene expression signatures. These subsets express specific genes that correspond to different stages of differentiation during renal development, suggesting that Wilms tumors may arise from transformed cells …

Cancer Associated Fibroblast Derived Angiogenic Factor Mfap5 In Ovarian Cancer Progression, Sze Lee Cecilia Leung

Dissertations & Theses (Open Access)

Advanced stage ovarian cancer is the most lethal gynecologic malignancy. No major improvement on patient survival has been achieved in the past decade. Therefore, identification of predictive or prognostic markers and further understanding of the molecular mechanisms in ovarian cancer progression are of paramount importance.

While cancer cells have always been the targets for the identification of prognostic and predictive markers, the potential for developing new diagnosis and treatments based on the tumor supporting stromal microenvironment is relatively unexplored. Using transcriptome profiling analysis on microdissected stromal and epithelial components of normal and malignant ovarian tissues, we identified a gene signature …

Understanding The Role Of Sumoylation In Regulating Lkb1 Function, Joan W. Ritho

Dissertations & Theses (Open Access)

Energy homeostasis in a cell is critical for its survival during metabolic stress. Liver kinase B1 (LKB1), one of the key regulators of cellular energy balance, was initially discovered as a tumor suppressor mutated in patients with Peutz-Jeghers syndrome. Germline mutations in LKB1 predispose patients to develop several benign and malignant tumors including gastrointestinal and lung cancers. In 2003, several groups demonstrated that LKB1is a major upstream kinase of the energy sensor AMP-activated protein kinase (AMPK), directly associating it with the regulation of energy balance in cells. During energy stress, LKB1 phosphorylates AMPK at threonine 172 (T172) resulting in AMPK …

Microrna-200 Regulates Ecm-Dependent Β1-Integrin/Fak Signaling And Cancer Cell Invasion, Christin Ungewiss

Dissertations & Theses (Open Access)

The microRNA-200 family is known to be a master regulator of the epithelial-to-mesenchymal transition, partially through its double-negative feedback loop with the transcriptional repressor Zeb1, yet the mechanisms on how miR-200 controls the invasive phenotype are not fully understood. Recent studies have shown that the miR-200/Zeb1 axis regulates cell-cell and cell-matrix interactions, but it has also been demonstrated that cell-intrinsic changes are insufficient to drive cancer cell invasion, leading us to focus on specific cell-matrix interactions required to activate tumor cell invasion and metastases. We have shown through 3D studies that the Integrin β1-collagen I contact is critical in mediating …

Dna Polymerase Θ (Polq) And The Cellular Defense Against Dna Damage, Matthew J. Yousefzadeh

Dissertations & Theses (Open Access)

In mammalian cells, DNA polymerase θ (POLQ) is an unusual specialized DNA polymerase whose in vivo function is under active investigation. The protein is comprised of an N-terminal helicase-like domain, a C-terminal DNA polymerase domain, and a large central domain that spans between the two. This arrangement is also found in the Drosophila Mus308 protein, which helps confer resistance to DNA interstrand crosslinking agents. Homologs of POLQ and Mus308 are found in eukaryotes, including plants, but a comparison of phenotypes suggests that not all of these genes are functional orthologs. Flies with defective Mus308 are sensitive to DNA interstrand crosslinking …

Investigating The Roles Of P63 And P73 Isoforms To Therapeutically Treat P53-Altered Cancers, Avinashnarayan Venkatanarayan

Dissertations & Theses (Open Access)

Investigating the roles of p63 & p73 isoforms to therapeutically treat

p53-altered cancers

Avinashnarayan Venkatanarayan, M.S.

Supervisory Professor: Elsa R. Flores, Ph.D.

The TP53 tumor suppressor is mutated in approximately 50% of human cancers rendering cancer therapies ineffective. p53 reactivation suppresses tumor formation in mice. However, this strategy has proven difficult to implement therapeutically. An alternate approach to overcome p53 loss is to manipulate the p53-family members, p63 and p73, which interact and share structural similarities to p53. p63 and p73, unlike p53 are less frequently mutated and have two major isoforms with distinct functions …

Igfbp2 Potentiates Egfr-Stat3 Signaling In Glioma, Yingxuan Chua

Dissertations & Theses (Open Access)

Gliomas are clinically challenging brain tumors with dismal survival rates due to its infiltrative nature and ineffective standard therapy. Insulin-like growth factor binding protein 2 (IGFBP2) is a pleiotropic oncogenic protein that has both extracellular and intracellular functions. Despite a clear causal role in cancer development, the contributions of intracellular IGFBP2 to tumor development and progression are poorly understood. Here we present evidence that both exogenous IGFBP2 treatment and cellular IGFBP2 overexpression lead to aberrant activation of EGFR, which subsequently activates STAT3 signaling. Furthermore, we demonstrate that IGFBP2 augments the nuclear accumulation of EGFR to potentiate STAT3 transactivation activities, via …

Atp-Citrate Lyase Links Cyclin E To Cellular Metabolism In Breast Cancer, Kim Lucenay

Dissertations & Theses (Open Access)

Cyclin E is altered or overexpressed in approximately one-third of tumors from patients with invasive breast cancer and is a powerful independent predictor for survival in women with stage I-III breast cancer. Full-length cyclin E (EL) is post-translationally cleaved into two low-molecular-weight isoforms, LMW-E (T1) and LMW-E (T2). LMW-E have been shown to exhibit greater binding affinity for cyclin-dependent kinase 2 (CDK2) , cyclin dependent kinase inhibitors (CKIs), p21 and p27, but are resistant to p21 and p27 inhibition. In addition, transgenic mice expressing LMW-E have increased mammary tumor development and metastasis compared to EL transgenic mice. Therefore, LMW-E are …

Induction Of Caspase-Dependent Death By Proteasome Targeted Therapy In Glioblastoma, Christa A. Manton

Dissertations & Theses (Open Access)

New therapeutic options are needed for glioblastoma, a deadly disease with a median survival of only 14 months with current treatment. The proteasome inhibitor bortezomib (BTZ) shows efficacy in cancers like myeloma, but its clinical utility in other cancer types has been more limited. Newer proteasome inhibitors such as marizomib (MRZ) have unique inhibitory and death inducing properties that have not been well examined in GBM. Additionally, targeting other components of the ubiquitin-proteasome system is possible, but has not been explored in GBM. Questions also still remain about the ability of BTZ and MRZ to be delivered to brain tumors …

The Role Of Autophagy In The Sensitivity Of Osteosarcoma Cells To Gemcitabine Treatment, Janice M. Santiago-O'Farrill

Dissertations & Theses (Open Access)

Despite treatment improvement for osteosarcoma (OS), overall survival has remained unchanged in the last 20 years. Pulmonary metastasis continues to be the main cause of death; novel therapeutic strategies are urgently needed to improve the survival rate of these patients. Previous data in our laboratory has demonstrated that aerosol gemcitabine (GCB) treatment has a significant therapeutic effect on metastatic OS. However, treatment efficacy is decreased due to acquired resistance by a population of tumor cells that fails to respond to treatment. Recent studies have implicated autophagy as a resistance mechanism in various types of cancer. The purpose of this study …

Actions Of Pi3k-Delta Inhibitor, Idelalisib, And Its Combination With Bendamustine In Chronic Lymphocytic Leukemia, Prexy Modi

Dissertations & Theses (Open Access)

Class I phosphatidylinositol 3-kinase isoforms (α, β, δ, and γ) play a major role in cancer cell growth and survival. PI3K α and β are most studied. PI3K pathway is highly dysregulated in many cancers and aberrant PI3K signaling is associated with oncogene mutations and disease progression in solid tumors and in hematologic malignancies.

Chronic lymphocytic leukemia (CLL) is driven by B-cell receptor (BCR) signaling that promotes B-cell proliferation and survival. PI3K is a critical node in BCR pathway and PI3Kδ has a pivotal role in B-cell development and maintenance and this isoform is over-expressed in many B-cell malignancies, including …

Regulation Of Cell Adhesion By The Ferm Proteins, Ptpn14 And Merlin, Patty Dimarco Hewitt

Dissertations & Theses (Open Access)

Cell-cell adhesion is critical for the control of tissue organization and homeostasis. A family of proteins that regulate cell-cell adhesions is the FERM (4.1 protein, Ezrin, Radixin, Moesin) domain-containing proteins.One FERM domain protein, the non-receptor tyrosine phosphatase PTPN14, is mutated or deleted in several human cancers suggesting that it may be involved in tumor development and/or progression. Additionally, the loss of the FERM domain protein Merlin is associated with tumor development and metastasis.Both PTPN14 and Merlin have been shown to localize and possibly regulate adherens junction (AJ) functions. This work sought to determine if …

Measuring Single Cell Responses To Lapatinib In A Heterogeneous Population, Preety Priya

Dissertations & Theses (Open Access)

Cancer is notonedisease butasaga of diseases and is the outcome of disturbed homeostasis in the normal cells due to the deregulation of its genetic makeup. With advent of technologies thatallowdetailed molecular characterizationoftumors, targeted therapies have emerged as a more promising and specific mode of treatment. However, a major challenge with targeted therapy is the acquired resistance in the cancer cells to these therapies, quite often very rapidly in the course of a few months. One of the major targets in cancer has been the EGFR/ErbB2 network in breast and other cancer types. Prior work from our lab and others have …