Cancer Biology Commons^™

Determining The Existence And Regulation Of Microlipophagy In Primary Brown And White Adipocytes, Sara C. Arenas De Leon

Biomedical Sciences ETDs

Lipids are one of life’s four main macromolecules and provide essential functions to cells, as they serve as building blocks of cellular membranes, mediate cell signaling, and are a critical energy source. Within cells, esterified fatty acids aggregate into lipid droplets in the form of triglycerides, consisting of a neutral lipid core surrounded by a phospholipid monolayer decorated with various proteins.

The degradation of lipid droplets and mobilization of lipids occurs through lipolysis, a process that hydrolyzes a molecule of triglyceride into a glycerol and three fatty acids. Emerging evidence demonstrates the involvement of a selective form of autophagy in …

Inhibition Of Rad18 By Arsenic, Lindsay B. Volk

Biomedical Sciences ETDs

Arsenite exposure leads to the retention of UV-induced DNA damage, thus burdening translesion synthesis (TLS). Rad18 is an essential factor in initiating TLS through PCNA monoubiquitination and is implicated in homologous recombination. It contains two functionally and structurally distinct zinc fingers that are potential targets for arsenite binding. Results from this study reveal arsenite binding to both zinc fingers of Rad18 and a corresponding loss of domain function. Importantly, arsenite inhibited Rad18 RING-dependent PCNA monoubiquitination and polymerase eta recruitment to DNA damage. Further analysis demonstrated multiple effects of arsenite, including the reduction in the nuclear localization and UV-induced chromatin recruitment …

Cold-Inducible Rna Binding Protein (Cirp) Impedes Proliferation And Inflammation In The Pymt Mouse Model For Breast Cancer, Daniel Albino Lujan

Biomedical Sciences ETDs

RNA binding proteins (RBPs) regulate gene expression by controlling mRNA export, translation, and stability. When altered, some RBPs allow cancer cells to grow, survive, and metastasize. Cold-inducible RNA binding protein (CIRP) is overexpressed in a subset of breast cancers, induces proliferation in breast cancer cell lines, and inhibits apoptosis. We generated a transgenic mouse model overexpressing human CIRP in the mammary epithelium to ask if it plays a role in mammary gland development. We also assessed the effects of CIRP on breast tumorigenesis using breeding crosses with the PyMT mouse model for breast cancer. CIRP decreased proliferation at the lactational …

Mechanisms And Consequences Of Myb Gene Activation In Salivary Gland Tumors, Candace Frerich

Biomedical Sciences ETDs

Salivary gland adenoid cystic carcinoma (ACC) is an aggressive tumor with a tendency to infiltrate surrounding nerves and metastasize to distant sites. The standard treatment often fails to control local tumor recurrence and distant metastases and no approved targeted therapeutic options exist for these tumors. The goal of our studies was to reveal the molecular mechanisms driving ACC tumor development and novel drug targets to improve patient morbidity and mortality.

We first analyzed clinical and RNA-sequencing (RNA-seq) data for 68 formalin-fixed paraffin-embedded (FFPE) ACC tumor samples and described previously unappreciated molecular heterogeneity that predicts patient outcome. The poor outcome subgroup …

Developing Droplet Based 3d Cell Culture Methods To Enable Investigations Of The Chemical Tumor Microenvironment, Jacqueline A. De Lora

Biomedical Sciences ETDs

Adaptation of cancer cells to changes in the biochemical microenvironment in an expanding tumor mass is a crucial aspect of malignant progression, tumor metabolism, and drug efficacy. In vitro, it is challenging to mimic the evolution of biochemical gradients and the cellular heterogeneity that characterizes cancer tissues found in vivo. It is well accepted that more realistic and controllable in vitro 3D model systems are required to improve the overall cancer research paradigm and thus improve on the translation of results, but multidisciplinary approaches are needed for these advances. This work develops such approaches and demonstrates that new droplet-based cell-encapsulation …

Exploring Biological Heterogeneity And Its Consequences At Tissue And Cellular Scales Through Mathematical And Computational Modeling, Romica Kerketta

Biomedical Sciences ETDs

This dissertation explores the effects of heterogeneity across different biological scales in cancer as well as normal cells. At the tissue scale, we investigated the variability present in the tumor microenvironment and its effect on patient chemotherapeutic outcomes using a mathematical model of drug transport. We found that parameters such as tumor blood perfusion and radius of blood vessel had an impact on the tumor cytotoxicity. This indicated that the physical microenvironment of the tumor is an important regulator of the tumor response to chemotherapy. At the cellular scale, we investigated the heterogeneity present on the membrane landscape of ErbB2 …

Cd82 Membrane Scaffolding Regulates Hematopoietic Cell Functions, Christina M. Termini

Biomedical Sciences ETDs

Through their ability to self-renew and differentiate, hematopoietic stem/progenitor cells (HSPCs) maintain the adult blood and immune systems. The microenvironment, or niche, in which HSPCs reside, serves as a critical regulator of HSPC functions. As previous work has identified the tetraspanin CD82 as a mediator of HSPC-niche interactions, we aimed to determine the mechanism by which this occurs. Our data demonstrate that CD82 expression and scaffolding regulate HSPC interactions with niche components by organizing the α4 integrin subunit into tightly packed nanoclusters. The HSPC niche can also protect acute myeloid leukemia (AML) cells from therapeutics. Therefore, we next examined how …