Life Sciences Commons^™

A Cell Culture Model To Study Tobacco Associated Oral Cancer Progression And Treatment Resistance, Amanda Busch

Theses & Dissertations

Head and Neck Squamous cell carcinoma is the 6^th most common cancer in the world. Risk factors for HNSCC include alcohol and tobacco consumption, infection with Human Papilloma Virus, and exposure to environmental toxins. Unlike many other cancers, the incidence of HNSCC is growing, yet the treatment options and outcomes have not been significantly improved for decades. An increased understanding of the molecular mechanisms of these cancers is needed for improvement in early diagnosis, enhanced treatment effectiveness, and cancer prevention. 4-nitroquinoline 1-oxide (4NQO) is a well-tested, tobacco mimicking, carcinogen. 4NQO produces similar histological and chemical changes found in human …

The Role Of Ubiquitin E3 Ligase Fbxo21 In Steady-State, Stressed, And Malignant Hematopoiesis, Karli J. Wittorf

Theses & Dissertations

Hematopoietic stem cells (HSCs) allow for the formation of all cell types in the blood and maintain these populations throughout a person’s life. The process of hematopoiesis is regulated through a variety of molecular mechanisms that are either signaled from the cell’s environment (extrinsic) or from within the cell itself (intrinsic). One intrinsic mechanism that regulates hematopoietic cell fate decisions is the ubiquitin proteasome system (UPS). The UPS controls protein levels by tagging them with polyubiquitin chains and promoting their degradation through the proteasome. The key component of the UPS is the ubiquitin E3 ligase as this protein is the …

Novel Mechanisms Of Protein Kinase C Α Regulation And Function, Xinyue Li

Theses & Dissertations

Protein kinase Cα (PKCα) is a member of the PKC family of serine/threonine kinases, which have been implicated in regulation of many cellular processes, including cell proliferation, differentiation, survival, and transformation. A large body of evidence from the Black laboratory and others support an anti-proliferative function of PKCα in normal epithelial tissues, including the intestinal mucosa and endometrial epithelium. PKCα is also tumor suppressive in epithelial cancers, such as colorectal cancer (CRC) and endometrial cancer (EC). However, a major obstacle to harnessing the tumor suppressive functions of PKCα to benefit patients is the widespread loss of PKCα expression in tumors. …

Post-Transcriptional Control Of The Epithelial-To-Mesenchymal Transition (Emt) In Ras-Driven Colorectal Cancers, Chaitra Rao

Theses & Dissertations

Colorectal cancer (CRC) originates from epithelial cells lining the colon or rectum of the gastrointestinal tract. Most cancer deaths result from a tumor spreading to distant organs; however epithelial cells do not normally migrate from their tissue of origin. To do so, epithelial cells undergo biochemical changes allowing them to acquire behavior similar to motile mesenchymal cells termed the epithelial-to-mesenchymal transition (EMT), which contributes to tumor invasion and metastasis. Our study demonstrated that CRC cells require a molecular scaffold, Kinase Suppressor of Ras 1 (KSR1), and ERK to promote the EMT-like phenotype through the preferential translation of Epithelial Stromal Interaction …

Dysregulation Of Mir-10a Promotes Cancer Features In Cholangiocarcinoma, Matthieu Spriet

Theses & Dissertations

Cholangiocarcinoma is a primary liver cancer of the bile duct epithelium that exhibits microRNA-mediated control of tumor cell signaling. Strides toward new treatment rest on a better defining of cholangiocarcinoma tumor biology including the RNA-based layer of regulation. Additionally, there is a gap in knowledge on microRNA expression in human tissue. While there is RNA-seq data of microRNA expression in tissue, it does not differentiate between cell types, thus leaving unanswered questions about cell specific microRNA biology and expression.

Here, we identify miR-10a as an oncogenic microRNA acting through MAPK signaling. Using cholangiocarcinoma cell lines, we determined miR-10a is an …

Sox2 Dosage Governs Tumor Cell Identity And Proliferation, Ethan P. Metz

Theses & Dissertations

The stem cell transcription factor SOX2 has been widely recognized for its critical roles during mammalian development. SOX2 expression has also been implicated in more than 20 types of human cancers. Importantly, the expression of SOX2 is regulated at multiple levels, which enables the tight regulation of SOX2 levels. Previous work from our laboratory has shown that elevating SOX2 from an inducible promoter inhibits the proliferation of several human tumor cell types. Other studies have reported that high levels of SOX2 are necessary to maintain lineage plasticity in advanced tumors. Thus, the dosage of SOX2 plays a critical role in …

Evaluating Targets And Therapeutics For The Treatment Of Pancreatic Cancer, Shelby M. Knoche

Theses & Dissertations

Pancreatic cancer has a dismally low survival rate, due to inadequate understanding of the processes that are involved in disease development and progression. Despite the identification of oncogenic drivers such as KRAS and p53, there is a need for the identification of molecular targets to improve and develop novel therapeutic approaches for the treatment of pancreatic cancer. Studies from our laboratory have identified and evaluated targets and therapeutic approaches that can aid in our understanding of pancreatic cancer disease progression and improve patient outcomes. Through the use of epidermal growth factor receptor (EGFR) ligands (EGF and TGF-α) and small molecule …

Characterization Of 1,1-Diarylethylene Foxm1 Inhibitors Against High-Grade Serous Ovarian Carcinoma Cells, Cassie Liu

Theses & Dissertations

Forkhead box M1 (FOXM1) is a member of the conserved forkhead box (FOX) transcription factor family. Over the last two decades, FOXM1 has emerged as a multifunctional oncoprotein and a robust biomarker of poor prognosis in many human malignancies. FOXM1 and its associated oncogenic transcriptional signature are enriched in >85% of ovarian cancer cases, and FOXM1 expression and activity can be enhanced by a plethora of genomic, transcriptional, post-transcriptional, and post-translational mechanisms. As a master transcriptional regulator, FOXM1 promotes critical oncogenic phenotypes in ovarian cancer, including: (1) cell proliferation, (2) invasion and metastasis, (3) chemotherapy resistance, (4) cancer stem cell …

Mechanisms Of Sorting And Fission At The Endosomes, Kanika Dhawan

Theses & Dissertations

Endocytic trafficking is a fundamental cellular process that regulates the transport of lipids and proteins. Our lab focuses on the intracellular trafficking of receptors involved in cellular processes such as cell division, migration, and proliferation. Accordingly, the regulation of these trafficking pathways is tightly controlled, involving a complex series of events, of which a key step is the endosomal fission. Perturbations in the endosomal network can eventually lead to impaired receptor recycling to the plasma membrane (PM) and, therefore, have pathological consequences like Alzheimer’s disease and multiple cancers. Upon internalization, cargo-laden vesicles released from the PM fuse with the sorting …

Visceral Adipose Tissue Remodeling In Pancreatic Ductal Adenocarcinoma Cachexia: The Role Of Activin A Signaling, Pauline Xu

Theses & Dissertations

Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer death in the United States and is projected to become the second leading cause by the year 2030. Prognosis for patients with metastatic disease remains dismal, with cachexia as a main contributor to the low survival rate. Emerging reports indicate that PDAC patients display distinct phenotypes of cachexia development, with either adipose tissue loss preceding skeletal muscle wasting or loss of only adipose tissue. While muscle wasting has been the most frequently studied mechanism in cachexia research, changes in adipose tissue are increasingly understood as important components of …

Use Of Machine Learning Algorithms And Highly Multiplexed Immunohistochemistry To Perform In-Depth Characterization Of Primary Pancreatic Tumors And Metastatic Sites, Krysten Vance

Theses & Dissertations

Pancreatic cancer is currently the third leading cause of cancer death and projected to be the second by 2030. Metastatic pancreatic cancer, the most common form of the disease, has a dismal 3% five-year survival rate. However, understanding of the metastatic disease and particularly the metastatic tumor microenvironment (TME), which includes all non-cancerous cells in and around the tumor, has remained limited. The well-documented impact of the TME on cancer cell proliferation, chemoresistance, and patient survival in the primary tumors, indicates that the study of the microenvironment in metastatic cancer is integral to treating advanced patients. To better comprehend this …

Targeting Androgen Receptor On Glioblastoma, Nan Zhao

Theses & Dissertations

Glioblastoma (GBM) is the most aggressive primary brain malignancy. The standard treatment of this tumor is surgery, followed by radiation with concurrent and adjuvant temozolomide. GBM cancer stem cells (CSCs) have been proposed to be responsible for radioresistance. It is necessary to identify novel therapeutic agent(s) that can pass the blood-brain barrier (BBB) and enhance radiation effects. Targeting the androgen receptor (AR) is promising in treating glioblastoma (GBM) in cell culture, and flank implant models but the mechanisms remain unclear. AR antagonists, including enzalutamide, are available for treating prostate cancer patients in the clinic and can pass the BBB; thus, …

Determining The Role Of Mir-133a In The Diabetic Heart, Tyler Kambis

Theses & Dissertations

Diabetes mellitus (DM) is characterized by hyperglycemia, hyperlipidemia, and hypoinsulemia, each of which disrupt intracellular mechanisms in the heart. DM is a chronic metabolic disease delineated into two categories: insulin deficient-type 1 DM and insulin resistant-type 2 DM. Although they differ in underlying genetic and physiological factors, both significantly increase the risk of heart failure. Impaired insulin signaling shifts energy dependency from glycolysis towards fatty acid β-oxidation in the DM heart. This DM-induced metabolic shift increases mitochondrial stress leading to mitochondrial dysfunction and cell death in the heart. The metabolically entwined ferroptosis is a novel form of myocardial cell death …

Phos-Tag-Based Screens Identify Novel Therapeutic Targets In Ovarian Cancer And Pancreatic Cancer, Renya Zeng

Theses & Dissertations

Multiple Phos-tag-based screens were conducted in anti-tubulin drug (paclitaxel and nocodazole)-treated cells to explore novel targets implicated in cell cycle regulation, resistance against paclitaxel, and yes-associated protein (YAP) nucleocytoplasmic transport. The Phos-tag-based screen of protein kinases identified that several proteins were degraded or phosphorylated in response to anti-tubulin drug treatment. A tyrosine kinase, fibroblast growth factor receptor 4 (FGFR4), was significantly degraded upon anti-tubulin drug treatment, suggesting its potential role in cell response to paclitaxel. Further functional investigations identified that FGFR4 mediated paclitaxel resistance in ovarian cancer, and specific inhibitors targeting FGFR4 could sensitize ovarian cancer cells to paclitaxel. Mechanistically, …

Novel Molecular Mechanisms Of C-Terminal Eps15 Homology Domain (Ehd) Proteins In Endocytic Trafficking And Primary Ciliogenesis, Tyler M. Jones

Theses & Dissertations

Endocytic membrane trafficking is a key cellular process that is critical for regulating the transport of internalized cargoes such as lipids and receptors. Our lab focuses on understanding the mechanisms and cellular functions of the proteins that regulate this pathway. One family of proteins that has seen significant interest over recent years is the C-terminal Eps15 Homology Domain (EHD) family of proteins. Mammalians have four EHD paralogs (EHD1-4) that are expressed ubiquitously in tissues. These proteins have distinct yet overlapping functions in regulating endocytic pathways. EHD1 has been shown to induce constriction and is recruited to induce fission of tubular …