Cancer Biology Commons^™

Characterization Of Cell Type-Specific Molecular Heterogeneity In Cancer Using Multi-Omic Approaches, Min Kyung Lee

Dartmouth College Ph.D Dissertations

Tumors are composed of heterogeneous cell types each with its own unique molecular profiles. Recent advances in single cell genomics technologies have begun to increase our understanding of the molecular heterogeneity that exists in tumors with particular focus on gene expression and chromatin accessibility profiles. However, due to limitations in methods for certain sample types and high cost for single cell genomics, bulk tumor molecular profiling has been and remains widely used. In addition, other facets of single cell epigenomic profiling, particularly methylation and hydroxymethylation, remains underexplored. Thus, investigations to understand the cell type specific epigenetic heterogeneity and the cooperation …

Analysis Of Biologically Effective Dose For Retroactive Yttrium-90 Trans-Arterial Radioembolization Treatment Optimization, Mj Lindsey

CMC Senior Theses

Trans-arterial radioembolization (TARE) is a protracted modality of radiation therapy where radionuclides labeled with Yttrium-90 (⁹⁰Y) are inserted inside a patient's hepatic artery to treat hepatocellular carcinoma (HCC). While TARE has been shown to be a clinically effective and safe treatment, there is little understanding of the radiobiological relationship between absorbed dose and tissue response, and thus there is no dosimetric standard for treatment planning. The Biologically Effective Dose (BED) formalism, derived from the Linear-Quadratic model of radiobiology, is used to weigh the absorbed dose by the time pattern of delivery. BED is a virtual dose that can …

Visualization And Characterization Of The Immunological Synapse Between Chlorotoxin Chimeric Antigen (Cltx-Car) Redirected T Cells And Targeted Glioblastoma Tumors, Arianna Livi

CMC Senior Theses

Chimeric Antigen Receptor T (CAR-T) cells have demonstrated anti-tumor activity against aggressive and invasive cancers such as glioblastoma (GBM); however, clinical response rates remain low in clinical trial studies. Tumor heterogeneity and tumor microenvironment conditions pose significant challenges for treatment of GBM, thus continuous optimization of CAR-T cell therapies and identification of novel, widely expressed, and highly specific GBM antigens are vital to better patient outcomes. A newly developed CAR-T cell construct incorporating chlorotoxin (CLTX) as the targeting domain exhibited broad GBM-targeting capabilities and elicited potent cytotoxic effects during preclinical studies and is currently being tested in a phase I …

Revolutionary Advances In The Treatment Of Genetic Disease, Emma Kaitlyn Carrigan

Honors Theses and Capstones

No abstract provided.

Enhancing The Conformational Stability Of The Cl-Par-4 Tumor Suppressor Via Site-Directed Mutagenesis, Samjhana Pandey, Krishna K. Raut, Antoine Baudin, Lamya Djemri, David S. Libich, Komala Ponniah, Steven M. Pascal

Chemistry & Biochemistry Faculty Publications

Intrinsically disordered proteins play important roles in cell signaling, and dysregulation of these proteins is associated with several diseases. Prostate apoptosis response-4 (Par-4), an approximately 40 kilodalton proapoptotic tumor suppressor, is a predominantly intrinsically disordered protein whose downregulation has been observed in various cancers. The caspase-cleaved fragment of Par-4 (cl-Par-4) is active and plays a role in tumor suppression by inhibiting cell survival pathways. Here, we employed site-directed mutagenesis to create a cl-Par-4 point mutant (D313K). The expressed and purified D313K protein was characterized using biophysical techniques, and the results were compared to that of the wild-type (WT). We have …

Bioinformatic Analysis Of Proteomic And Genomic Data From Nsclc Tumors On Prognostic And Predictive Factors Of Immunotherapy Treatment, Mark Wuenschel

Theses and Dissertations--Pharmacy

Recent lung cancer research has led to advancements in molecular immunology, resulting in development of small molecule inhibitors, or immune checkpoint inhibitors, that propagate an anti-tumor T cell response. Despite increased overall and progression-free survival with reduced adverse effects compared to traditional chemotherapy, treating advanced stage lung adenocarcinoma patients remains non-curative, and evidence of non-responders or tumor recurrence to immune checkpoint inhibitor therapy is growing. Also, compared to traditional chemotherapy, there is a lower percentage of patients who respond to small molecule inhibitors. In this analysis of proteomic and genomic data from The Cancer Proteome Atlas and Global Data Commons …

Investigation Of Inflammation And Apoptosis Mediated Toxicity In Response To Metal Oxide Nanoparticles In Ml-1 And Ca77 Cancer Cell Lines, Alyse N. Peters

Graduate Theses/Dissertations

Metal oxide nanoparticles (MONPs) are becoming more popular in today’s environment. They contribute significantly to the technologies in agriculture and food development but there is little understanding to how MONPs, including ZnO, CuO, TiO2, and SnO2, impact human health and the environment. Our growth assay revealed that none of these negatively affects viability in the budding yeast, Saccharomyces cerevisiae. In contrast, both human thyroid cancer cells (ML-1) and rat medullary thyroid cancer cells (CA77) displayed a significant reduction in viability with the treatment of CuO and ZnO. The production of ROS in these cell lines when treated with CuO and …

The Links To Cancer: How Golf Became Dangerous And What We Can Do To Save The Game, Meredith Boos

Undergraduate Theses, Professional Papers, and Capstone Artifacts

This study is a comprehensive meta-analysis on health claims linked to exposure to golf courses, more specifically the chemicals used to maintain their appearance. It provides a brief history of the golf industry and how its growth exacerbated the environmental impact as well as an explanation of the legal landscape that will affect golf course management. Golf courses can disrupt local ecologies, contaminate ground water, rivers, lakes and streams with run-off, and be responsible for the bioaccumulation of chemicals which remain dangerous for decades. Despite the adverse effects of golf courses on the environment, there remains an opportunity to transform …

Comparison Of Cell Cycle Gene Expression Between Ovarian Cancer Cell Line Skov3 And Non-Cancerous Cell Lines, Akayla Weatherby

Dissertations, Master's Theses and Master's Reports

Roughly 1% of women will be diagnosed with ovarian cancer during their lifetime. There are many different factors that impact how likely someone is to develop ovarian cancer including age, lifestyle, and family history. Ovarian cancer, like all cancers, occurs due to the accumulation of cancer cells that result from errors in the cell cycle or its regulation. Here, we studied how cell cycle gene expression was altered in the epithelial-like ovarian cancer cell line SKOV3, as compared to the pre-cancerous ovarian cell line FT282, and the non-cancerous foreskin fibroblast cell line BJ5Ta. The three cell lines were synchronized into …

Dissecting The Role Of Selenoprotein P And Thioredoxin Reductase In Pancreatic Cancer Metabolism, Alyssa A. Abbas

Dissertations, Master's Theses and Master's Reports

Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of US cancer-related deaths, has a stark 5-year survival rate of 9%, emphasizing an urgent need for effective therapies. A well-established characteristic of cancer, metabolic dysregulation, presents an opportunity for developing therapies that target specific metabolic susceptibilities inherent in cancer cells. Our recent studies have discovered a susceptibility in PDAC; deprivation of cystine or blocking its uptake by erastin (a cystine transport inhibitor) triggers significant lipid peroxidation, thereby inducing ferroptosis specifically in the mesenchymal subtype of PDAC, but not in the epithelial subtype. This study aims to elucidate the roles of Selenoprotein …

Deep Learning-Based Technique For The Perception Of The Cervical Cancer, Aya Haraz, Hossam El-Din Moustafa, Abeer Twakol Khaleel, Ahmed H. Eltanboly

Mansoura Engineering Journal

In third-world countries, cervical cancer is the most prevalent and leading cause of death. It is affected by a variety of factors, including smoking, poor nutritional status, immunological inadequacy, and prolonged use of contraception. The Pap smear test, which is intended to prevent cervical cancer, finds preneoplastic changes in cervical epithelial cells. This study framework classified cervical cancer cells from Pap smears into five specified cell types using machine learning-based classification algorithms. The SIPaKMeD database is used in this investigation. This public dataset, which was manually cropped from 966 cluster cell images taken from Pap smear slides, has 4045 isolated …

Advancements In Glycogen Detection And Spatial Profiling Reveals A New Therapeutic Path For Ewing Sarcoma: A Non-Traditional Glycogen Storage Disease, Lyndsay E. A. Young

Theses and Dissertations--Molecular and Cellular Biochemistry

Glycogen is the primary glucose storage carbohydrate in mammals, and it is synthesized in most tissues. As glycogen architecture modulates its role in metabolism, it is essential to accurately evaluate and quantify glycogen, glycogen phosphate, and chain length of glucose monomers. Simultaneous quantitation of glycogen architecture is challenging. This work describes a highly-sensitive method for the detection of both glycogen-derived glucose and glucose-phosphate esters utilizing gas-chromatography coupled mass spectrometry (GCMS). We then integrated this glycogen quantitation workflow into a routinely utilized metabolomics-based assay. The work presented describes a workflow for the normalization of polar metabolites utilizing amino acids derived from …

The Role Of Dynamin Related Protein 1-Mediated Mitochondrial Dynamics In Colorectal Cancer, Sumati Raj Hasani

Theses and Dissertations--Molecular and Cellular Biochemistry

Cancer cells are known for their ability to adapt variable metabolic programs depending on the availability of specific nutrients. Consequently, metabolic reprogramming has been increasingly recognized as a major mechanism that fuels tumorigenesis and disease progression. Here, we have investigated the role of a pro-fission factor, Dynamin-Related Protein 1 (Drp1), in promoting metabolic adaptation in colon cancer.

Our studies have shown that fatty acid (FAs) uptake alters cellular metabolic pathways in colon cancer cells to favor fatty acid oxidation through the activation of Drp1. Uptake of FAs induces mitochondrial fragmentation by promoting ERK-dependent phosphorylation of Drp1 at the S616 site, …

Exploring The Relationship Between The Epigenome And Metabolism In Mycn-Amplified Neuroblastoma, Krista M. Dalton

Theses and Dissertations

High risk neuroblastoma (NB) is responsible for nearly 15% of all cancer related deaths in the pediatric population. The transcription factor MYCN is the most studied oncogene in NB, automatically conferring high-risk and has been found to be difficult to target. One way that MYCN amplification in NB functions to support tumorigenicity is through altered metabolism, satisfying the demand for rapid proliferation by increasing the nutrient flux through biosynthetic pathways. We performed an unbiased screen on select metabolic targeted therapy combinations and correlated sensitivity with over 20 subsets of cancer. We found that MYCN-amplified NB is hypersensitive to the …

Pre-Clinical Trials With Precision-Medicine Based Therapeutics In Basal-Like Patient-Derived Xenografts, David C. Boyd

Theses and Dissertations

Breast cancer treatments have improved over time, but the diseases seeing the most benefit from these improvements have the estrogen receptor, progesterone receptor, or are positive for HER2. Basal-like breast cancer tends to not have these biomarkers, which necessitates their treatment to be traditional, untargeted therapeutics which are less effective and tend to have harsh adverse effect profiles – this is an important unmet need. These studies utilize a variety of techniques, including tissue culture, viability assays, high-throughput screening, in vivo drug treatments and imaging, pathway analyses, molecular techniques such as Western blot, antibody arrays, RNA sequencing, sc RNA sequencing, …

The Hepatic Immunological Pattern Shaped By Dominant-Subdominant Cellular Interactions Creates A Collective Function Beyond The Function Of Each Cellular Constituent To Orchestrate Progression Of Hepatocellular Carcinoma, Nicholas J. Koelsch

Theses and Dissertations

Abundance of data on the role of inflammatory immune responses in the progression or inhibition of hepatocellular carcinoma (HCC) has failed to offer a curative immunotherapy for HCC. This is largely because of taking reductionist approaches and missing the collective function of the hepatic immune system by focusing on specific immune cell types. To this end, we propose that focusing on the dominant-subdominant patterns of the immune cells would allow understanding of the mechanism by which a collective immune function emerges. To identify the collective immune function through a systems immunology perspective, we performed high-throughput analysis of snRNAseq data collected …

Protacs – A Novel And Rapidly Developing Field Of Targeted Protein Degradation, Hannah R. Gatley

Theses and Dissertations

There is a continued need for new technology and strategies for tackling cancer and other diseases, and within the current century a novel therapeutic strategy has emerged in the realm of targeted protein degradation called Proteolysis-Targeting Chimeras (PROTACs). This technology specifically targets and degrades disease-causing proteins via the ubiquitin-proteasome system, and has seen an explosion of research and intrigue in both academia and industry over the past two decades. The diversity of PROTAC classes based on the E3 ligase recruiting ligand and the target protein allows for a universal molecular structure that can be customized for a specific target and …

Kpt-330 Synergizes With Everolimus To Reduce Mtorc1-Overactive Basal-Like Triple-Negative Breast Cancer Brain Metastasis Burden, Aaron D. Valentine

Theses and Dissertations

Triple-negative breast cancer (TNBC), a highly metastatic breast cancer subtype, accounts for approximately 20% of all breast cancer diagnoses. Basal-like TNBC is notably difficult to treat due to the lack of actionable drug targets such as estrogen and progesterone receptors, as well as HER2. Due to the deficiency in TNBC-targeting drugs that are able to cross the blood-brain barrier (BBB) for breast-to-brain metastasis, there is a need to develop novel BBB-permeable treatments. After preliminary testing, KPT-330 (XPO1 inhibitor) and everolimus (FKBP1A/mTOR inhibitor) were selected as drug candidates for this study. Patient-derived xenograft (PDX) models for in vitro and in vivo …

Cellular Glycosphingolipid Imbalance Modulates Emt In Cancer Cells, Laura E. Clark, Amanda Dickinson, Santiago Lima

UROP Posters

Sphingolipids are key components of the plasma membrane and are regulators of complex biological processes often altered in cancer cells. In human tumors, genes of key enzymes that regulate levels of glucosylceramide and lactosylceramide are often amplified. However, it is unknown why these traits are positively selected in transformed cells. In this work, we used CRISPR-Cas9 to knockout two key enzymes amplified in tumors in HeLa and H1703 tumor-derived cell-lines. As expected, the knockout lines had dramatic accumulation of GlcCer and LacCer. However, unexpectedly, they showed significantly decreased in-vitro wound-healing capacity and an almost complete loss of in-vitro extra-cellular matrix …

Modulatory Effects Of Deacetylated Sialic Acids On Breast Cancer Resistance Protein-Mediated Multidrug Resistance And Receptor Tyrosine Kinase-Targeted Therapy, Isaac Tuffour

Electronic Theses and Dissertations

Multidrug resistance (MDR) remains a major challenge in cancer treatment, accounting for over 90% of chemotherapeutic failures. Cancers utilize sugar residues to engage in multidrug resistance. The underlying mechanism of action involving glycans, specifically the glycan sialic acid (Sia) and its various functional group alterations, has not been explored. ATP-binding cassette (ABC) transporter proteins, key proteins utilized by cancers to engage in MDR pathways, contain Sias in their extracellular domains. Modulating the expression of acetylated-Sias on Breast Cancer Resistance Protein (BCRP), a significant ABC transporter implicated in MDR, in lung and colon cancer cells directly impacted the ability of cancer …