Medicine and Health Sciences Commons^™

The Role Of Streptococcus Gallolyticus Subspecies Gallolyticus In Colon Cancer Development, Jennifer L. Herold

Dissertations & Theses (Open Access)

Colorectal cancer (CRC) is the third most common cancer in men and women and is also the third most common cause of cancer death. A large body of evidence points towards the possibility that bacteria can have a significant impact on the development of cancer. It has been suggested that Streptococcus gallolyticus subsp. gallolyticus, a group D streptococci, may play a role in the development of CRC. Sg, formerly S. bovis biotype I, has been shown to be highly associated with CRC. In observing patients with either Sg bacteremia or endocarditis it was found that 25-80% of …

Microenvironment-Induced Pten Loss By Exosomal Microrna Primes Brain Metastasis Outgrowth, Lin Zhang

Dissertations & Theses (Open Access)

Development of life-threatening cancer metastases at distant organs requires disseminated tumor cells’ adaptation to and co-evolution with the drastically different microenvironments of metastatic sites. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs. Clearly, the dynamic interplay between metastatic tumor cells and extrinsic signals at individual metastatic organ sites critically impacts the subsequent metastatic outgrowth. Yet, it is unclear when and how disseminated tumor cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that primary tumor cells with normal expression of PTEN, an important …

Concomitant Targeting Of The Mtor/Mapk Pathways: Novel Therapeutic Strategy In Subsets Of Non-Small Cell Lung Cancer, Dennis Ruder

Dissertations & Theses (Open Access)

Over the last decade, a paradigm-shift in lung cancer therapy has evolved into targeted-driven medicinal approaches. However, patients frequently relapse and develop resistance to available therapies. Herein, we utilized genomic mutation data from advanced chemorefractory non-small cell lung cancer (NSCLC) patients enrolled in the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE-2) clinical trial to characterize novel actionable genomic alterations potentially of clinical relevance. We identified RICTOR alterations (mutations, amplifications) in 17% of lung adenocarcinomas and found RICTOR expression correlates to worse overall survival. There was enrichment of MAPK pathway genetic aberrations in key oncogenes (e.g. KRAS, BRAF, …

Investigating The Roles Of Δnp63 As A Suppressor Of Migration, Invasion, And Metastasis, Ramon E. Flores Gonzalez

Dissertations & Theses (Open Access)

Cancer is one of the leading causes of death and disease in the world. Considerable resources are spent to study and understand cancer, with the hope of developing new treatments and eventually cures that will help millions of people. Efforts to understand cancer are hindered by its inherent complexity and instability. Nonetheless, understanding the basics of tumor development and progression are the key to focused on studying the role of ΔNp63 in cancer, a p53 family member known to be involved in epithelial development, microRNA biogenesis, and stem cell maintenance. Using the strength of in vivo mouse models, we found …

Novel Mechanisms Of Β-Adrenergic Signaling In Prostate Cancer Progression, Mohit Hulsurkar

Dissertations & Theses (Open Access)

Prostate cancer is the second leading cause of cancer death among American men. The American Cancer Society estimates that 180,890 men will be will be diagnosed with prostate cancer in 2016 in the USA. (http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-key-statistics). Androgen deprivation therapy (ADT) is the standard treatment for early stage prostate cancer. But most patients relapse with aggressive variants of prostate cancer, with survival time between 1-3 years. In order to develop cure for such aggressive variants of prostate cancer, our present understanding of the mechanisms underlying its progression needs to be advanced.

Recently, it has been found that activation of β-adrenergic signaling pathway …

¬¬Define The Epigenetic Profiles And Subtype-Specific Genes Of Breast Cancer, Wenqian Li

Dissertations & Theses (Open Access)

Molecular profiling has identified 5 distinct subtypes of breast cancer, luminal A, luminal B, HER2-enriched, basal-like, and claudin-low breast cancer. These 5 subtypes correlate with hormone response, patient prognosis, and response to therapy. Although steady state gene expression patterns have been explored using expression microarrays, very little is known about the initial, disease-driving transcriptional changes in these cancers or epigenetic changes associated with the differential gene expression signatures. Defining these changes may provide new insights into the mechanisms by which these subtypes arise, as well as new avenues for breast cancer prevention, diagnosis, and treatment. Using Chromatin Immunoprecipitation sequencing and …

Regulation Of Breast Cancer Initiation And Progression By 14-3-3zeta, Chia-Chi Chang

Dissertations & Theses (Open Access)

14-3-3ζ is a ubiquitously expressed family member of proteins that have been implicated to have oncogenic potential through its interactions and involvement in cancer initiation and progression. 14-3-3ζ belongs to the highly conserved 14-3-3ζ protein family and modulates numerous pathways in cancer. Overexpression of 14-3-3ζ is an early event, occurs in more than 40% of human breast cancer cases, and is associated with disease recurrence and poor prognosis. Metabolic reprogramming is a hallmark of cancer. Cancer cells elevate aerobic glycolysis to produce metabolic intermediates and reducing equivalents, thereby facilitating cellular adaptation to the adverse environment and sustaining fast proliferation. Interestingly, …

Characterization Of Stem Cell Turnover In A Living Epithelial Bilayer, Elizabeth Sumner

Dissertations & Theses (Open Access)

Homeostatic maintenance of epithelia requires the renewal and replacement of old or dying cells while sustaining a functional barrier. Imbalance between cell production and elimination are hypothesized to underlie many pathological conditions. However, our knowledge of cell turnover within living tissues remains largely restricted to static images due to the limited ability to study epithelia in their native context. Here we report that clearance of damaged basal stem cells promotes compensatory proliferation of neighboring stem cells to maintain overall population numbers in a bilayered epithelium. Time-lapse imaging and electron microscopy experiments reveal that dying cells are rapidly cleared as nearby …

Gsk3Beta-Mediated Ezh2 Phosphorylation Suppresses Methylation Of H3k27 And Ezh2’S Oncogenic Functions, How-Wen Ko

Dissertations & Theses (Open Access)

During the process of tumorigenesis, inactivation of tumor suppressors is a critical step. Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and the enzymatic core subunit of polycomb repressive complex 2 (PRC2), promotes cell growth and migration through catalyzing trimethylation of histone H3 at Lys 27 (H3K27me3) and plays an important role in tumorigenesis. Its expression can be controlled by phosphorylation. However, the regulation of EZH2 activity by tumor suppressor kinase is not well understood. Glycogen synthase kinase 3 beta (GSK3b), a multifunctional serine/threonine kinase, is involved in many cellular processes. GSK3b also participates in neoplastic transformation, tumor development …

The Roles Of Malt1 In Nf-Κb Activation And Solid Tumor Progression, Deng Pan

Dissertations & Theses (Open Access)

The transcription factor NF-κB plays a central role in many aspects of biological processes and diseases, such as inflammation and cancer. Although it has been suggested thatNF-κB is critical in tumorigenesis and tumor progression, the molecular mechanism by which NF-κB is activated in solid tumor remains largely unknown. In the current work, we focus on growth factor receptor-induced NF-κB activation and tumor progression, including epidermal growth factor receptor (EGFR)-induced NF-κB in lung cancer and heregulin receptor (HER2)-induced NF-κB in breast cancer. We found that Mucosa-associated lymphoma translocation protein 1 (MALT1), also known as paracaspase, is required for EGFR-induced NF-κB activation …

In Vivo Kinome Screen Reveals Non-Canonical Cdk-Driven Metabolic Adaptation In Brain Metastasis, Frank J. Lowery Iii

Dissertations & Theses (Open Access)

Brain metastasis, which frequently arises from breast cancer, lung cancer, melanoma, and colorectal cancer, remains a severely unmet medical need and its incidence continues to rise while treatment options remain palliative. To better understand the biology underlying its aggressive, incurable nature, I performed an unbiased in vivo kinome screen to identify potential driver kinases of experimental brain metastasis in a nude xenograft model using the human breast cancer cell line MDA-MB-231. Several of the kinase pools led to decreased brain metastasis-specific survival in nude mice, shortening survival time by up to 50% relative to controls. Targeted next-generation sequencing (NGS) was …

The Role Of Amp-Activated Protein Kinase (Ampk) In Tumorigenesis, Fei Han

Dissertations & Theses (Open Access)

AMPK plays a central role in controlling cellular and whole body energy level. Increasing studies have also discovered the diverse function of AMPK in cancer, such as autophagy and mitochondria biogenesis. However, how AMPK promotes cancer progression is still not clear. Here, we show that AMPK is essential for EGF-induced Akt activation, Glut1 expression, and glucose uptake. AMPK is also required for various stresses induced Akt activation and promote cell survival, including hypoxia and glucose deprivation. In addition, we found glucose deprivation-induced VEGF expression and secretion is also depend on AMPK, which may contribute to angiogenesis of surrounding endothelial cell …

Genomic Drivers Of Cutaneous Squamous Cell Carcinoma Development, Vida Chitsazzadeh

Dissertations & Theses (Open Access)

Skin cancer is the most common malignancy in humans. Annually, in U.S. there are over 3 million cases with an estimated overall economic impact of $2 billion. Cutaneous Squamous Cell Carcinoma (cuSCC) comprises 15-20% of all skin cancers. cuSCC has the best-defined progression from a distinct precancerous lesion, the Actinic Keratosis (AK), to invasive cuSCC. Destructive therapies for AK treatment must be used repetitively, causing significant morbidity. There is a tremendous need for targeted diagnostics and therapy for AKs, representing an important opportunity for secondary skin cancer prevention. Our knowledge of the molecular and cellular events that lead to the …