Cancer Biology Commons^™

A Computational Model Of The Line-1 Retrotransposon Life Cycle And Visualization Of Metabolic Networks In 3-Dimensions., Michael D. Martin

Electronic Theses and Dissertations

Computational modeling of metabolic reactions and cellular systems is evolving as a tool for quantitative prediction of metabolic parameters and reaction pathway analysis. In this work, the basics of computational cell biology are presented as well as a summary of physical processes within the cell, and the algorithmic methods used to find time dependent solutions. Protein-protein and enzyme-substrate interactions are mathematically represented via mass action kinetics to construct sets of linear differential equations that describe reaction rates and formation of protein complexes. Using mass action methods, examples of reaction networks and their solutions are presented within the Virtual Cell simulation …

Investigating A Novel Function For Phosphoserine Aminotransferase 1 (Psat1) In Epidermal Growth Factor Receptor (Egfr)-Mediated Lung Tumorigenesis., Rumeysa Biyik-Sit

Electronic Theses and Dissertations

Phosphoserine aminotransferase 1 (PSAT1) catalyzes the second enzymatic step within the serine synthetic pathway (SSP) and its expression is elevated in numerous human cancers, including non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) mutant NSCLC is characterized by activating mutations within its tyrosine kinase domain and accounts for 17% of lung adenocarcinomas. Although elevated SSP activity has been observed in EGFR-mutant lung cancer cells, the involvement of PSAT1 in EGFR-mediated oncogenesis is still unclear. Here, we explore a putative non-canonical function for PSAT1 using biochemical approaches to elucidate unknown interacting proteins and genomic RNA-seq profiling to identify cellular …

Metabolic Reprogramming By Dna Tumour Viruses, Martin Prusinkiewicz

Electronic Thesis and Dissertation Repository

Viruses are the etiological agents of approximately 12% of human cancers. However, only a subset of viral infections eventually progress to cancer. As obligate intracellular parasites, viruses create a host-cell environment that is amenable to virus replication. These changes to host-cell processes during infection are enacted by virally-encoded proteins that act as molecular hubs. When these processes intersect with pathways that encourage the development of cancer, such as the p53 tumour suppressor pathway, these virally-encoded molecular hub proteins function as viral oncoproteins. One major requirement of both virus infected cells and rapidly growing cancer cells is an altered metabolism that …

Delineating The Role Of Fatty Acid Metabolism To Improve Therapeutic Strategies For Colorectal Cancer, James Drury

Theses and Dissertations--Toxicology and Cancer Biology

Colorectal cancer (CRC) remains a leading cause of cancer-related deaths in the world, comprising over 1 million new cases each year and over 500,000 deaths. CRC, when detected at an early stage of disease development, can be effectively treated, with a 5-year survival rate of over 90%. Such standard treatments include surgical resection of the primary tumor in combination with adjuvant chemotherapy. However, even with advancements in surgical procedures and chemotherapeutic targets, when CRC progresses to a more advance stage, the 5-year survival rate decreases significantly to just under 14%. This stark decrease in patient survival rate can be directly …

Targeted Therapies In Select Gastrointestinal Cancers And Cancer Cachexia, Scott Mulder

Theses & Dissertations

Hepatocellular carcinomas exhibit metabolic alterations to support their proliferative and biosynthetic needs. We identified that elevated expression of the mitochondrial oxidative carboxylase, malic enzyme 2 (ME2), correlates with poorer hepatocellular carcinoma patient survival. Hepatocellular carcinoma patient tumors with high ME2 expression exhibit transcriptomic alterations indicative of PI3K/AKT/mTOR and c-Myc signaling as well as elevated central carbon, fatty acid, and redox metabolism pathways. Depletion of ME2 in the hepatocellular carcinoma cell line PLC or in the livers of mice treated with diethylnitrosamine to chemically induce hepatocellular carcinomas, results in impaired proliferation and reduced tumor formation. Additionally, the loss of …

Mitochondrial Metabolism As A Therapeutic Target For Pancreatic Cancer, Simon Shin

Theses & Dissertations

Mitochondria are biosynthetic and bioenergetic hubs that confer cancer cells the metabolic flexibility to survive and grow in harsh tumor microenvironments. Accordingly, mitochondrial metabolism represents a promising target for pancreatic ductal adenocarcinoma (PDAC), which is frequently characterized as desmoplastic and nutrient poor. The findings presented in the first set of studies highlight the importance of mitochondria-dependent metabolic flexibility in PDAC cells upon exposure to acidic conditions. An acidic tumor microenvironment is a common feature of many solid tumors and exerts a profound influence on cancer biology. Similar to previous findings, we demonstrated that low extracellular pH induces epithelial-to-mesenchymal transition (EMT) …

Glucose Metabolism Of Breast Cancer Sub-Clones That Preferentially Metastasize To The Lungs And Bone, Anna G. Skubiz

Honors Theses

Malignant breast cancers exhibit preferential metastasis to bone and lung (1). While changes in gene expression in lung-specific (LM) and bone-specific metastasis (BoM) lines derived from the MDA-MB-231 breast cancer line have been identified, few metabolic genes are differentially expressed; thus it is unknown if tissue-specific metabolic reprogramming occurs. Two hallmarks of cancer cells are an altered metabolic phenotype characterized by enhanced conversion of glucose to lactate in spite of adequate oxygen availability for complete mitochondrial oxidation of this substrate (referred to as aerobic glycolysis or the Warburg effect) and a greater dependence on glutamine. These changes in primary tumor …

In Vivo Metabolic And Vascular Response To Hypoxia In Twist Knockdown Murine Breast Cancer, Brandon Sturgill

Graduate Theses and Dissertations

Twist transcription factor is often overexpressed in aggressive tumors. Although needed in early embryonic development for organogenesis, Twist is known to induce an epithelial to mesenchymal transition in cells. In cancer, epithelial to mesenchymal transitions can lead to increased motility and invasiveness. It has also been linked to metabolic reprogramming and increased metastatic risk. Furthermore, metabolic preferences can increase proliferation, enhance metastatic potential, and influence the site of metastasis. We hypothesize that Twist directly affects the metabolism of cancer cells. We expect to see in vivo what we have seen in vitro; Twist overexpression should promote a shift away from …

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 …

Phosphorylation Impairs Dicer1 Function To Accelerate Aging And Tumorigenesis In Vivo, Neeraj Aryal

Dissertations & Theses (Open Access)

Altered DICER1 protein levels are associated with developmental disorders, infertility, macular degenerative blindness, aging, and cancer in humans. Recently, post-translational regulation of Dicer1 via phosphorylation has been described in C. elegans. Oscillation of Dicer1 phosphorylation to regulate its activity is essential for germ cell development and embryogenesis in worms. These observations led us to posit that Dicer1 protein levels and activity are under tight regulation for normal mammalian homeostasis. To test whether phosphorylation of Dicer1 regulates its activity in mammals, I generated phospho-mimetic knock-in mouse models by replacing Serines 1712 and 1836 with Aspartic acids individually or together (dual …

Pkm2 Influences The Metabolic Fate Of Butyrate In Colorectal Cancer Cells, Megan Louise Pence

Chancellor’s Honors Program Projects

No abstract provided.

Lipid Sensing By Mammalian Target Of Rapamycin, Deepak Menon

Dissertations, Theses, and Capstone Projects

Mammalian target of Rapamycin (mTOR) is a protein kinase that integrates nutrient and growth factor signals to promote cellular growth and proliferation. mTOR exists in two complexes - mTORC1 and mTORC2 that are distinguished by their binding partners and signaling inputs. mTORC1 is responsive to growth factors, amino acids and glucose and is associated with Raptor; whereas, mTORC2 is responsive primarily to growth factors and is associated with Rictor. Raptor and Rictor confer substrate specificity to mTORC1 and mTORC2 respectively. Phosphatidic acid (PA), a lipid second messenger and a central metabolite for membrane phospholipid biosynthesis, is required for the stability …

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 …

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

Dissertations & 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 & 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 …