Cancer Biology Commons^™

The Effect Of Fluid Flow Shear Stress And Substrate Stiffness On Yes-Associated Protein (Yap) Activity And Osteogenesis In Murine Osteosarcoma Cells, Thomas R. Coughlin, Ali Sana, Kevin Voss, Abhilash Gadi, Upal Basu-Roy, Caroline M. Curtin, Alka Mansukhani, Oran D. Kennedy

Publications and Research

Osteosarcoma (OS) is an aggressive bone cancer originating in the mesenchymal lineage. Prognosis for metastatic disease is poor, with a mortality rate of approximately 40%; OS is an aggressive disease for which new treatments are needed. All bone cells are sensitive to their mechanical/ physical surroundings and changes in these surroundings can affect their behavior. However, it is not well understood how OS cells specifically respond to fluid movement, or substrate stiffness—two stimuli of relevance in the tumor microenvironment. We used cells from spontaneous OS tumors in a mouse engineered to have a bone-specific knockout of pRb-1 and p53 in …

Evaluation Of Somatic Mutations In Solid Metastatic Pan-Cancer Patients, Moom Roosan, Isa Mambetsariev, Rebecca Pharaon, Jeremy Fricke, Angel R. Baroz, Joseph Chao, Chen Chen, Mohd W. Nasser, Ramakanth Chirravuri-Venkata, Maneesh Jain, Lynette Smith, Susan E. Yost, Karen L. Reckamp, Raju Pillai, Leonidas Arvanitis, Michelle Afkhami, Edward W. Wang, Vincent Chung, Mihaela Cristea, Marwan Fakih, Marianna Koczywas, Erminia Massarelli, Joanne Mortimer, Yuan Yuan, Surinder K. Batra, Sumanta Pal, Ravi Salgia

Pharmacy Faculty Articles and Research

Metastasis continues to be the primary cause of all cancer-related deaths despite the recent advancements in cancer treatments. To evaluate the role of mutations in overall survival (OS) and treatment outcomes, we analyzed 957 metastatic patients with seven major cancer types who had available molecular testing results with a FoundationOne CDx^® panel. The most prevalent genes with somatic mutations were TP53, KRAS, APC, and LRP1B. In this analysis, these genes had mutation frequencies higher than in publicly available datasets. We identified that the somatic mutations were seven mutually exclusive gene pairs and an additional fifty-two co-occurring gene pairs. Mutations …

Effect Of Her2 Expression On Nupl2 Protein In Cervical Cancer Cells, Mary E. Eichholz, Margaret J. Ballou, Tristan J. Haight, Jennifer L. Minton, Ryan N. Oates, Jacob J. Adler

Kentucky Journal of Undergraduate Scholarship

Recurring cervical cancer patients frequently present overexpressed Human Epidermal Growth Factor Receptor 2 (HER2) protein, which promotes the growth of the cancer. Some HER2-expressing cells and cervical cancer patients have enhanced gene expression of Nucleoporin-like 2 (NUPL2). As part of the nuclear pore complex, the NUPL2 protein serves to selectively export substances from the nucleus to the cytoplasm. In this experiment, HER2 was expressed in cervical cancer cells to examine its effect on NUPL2 protein expression and localization. Interestingly, there was no difference in NUPL2 protein levels between HER2-expressing and non-expressing cells. Importantly, consistent instances of NUPL2 protein …

Co-Targeting Plk1 And Dnmt3a In Advanced Prostate Cancer, Zhuangzhuang Zhang, Lijun Cheng, Qiongsi Zhang, Yifan Kong, Daheng He, Kunyu Li, Matthew Rea, Jianlin Wang, Ruixin Wang, Jinghui Liu, Zhiguo Li, Chongli Yuan, Enze Liu, Yvonne N. Fondufe-Mittendorf, Lang Li, Tao Han, Chi Wang, Xiaoqi Liu

Toxicology and Cancer Biology Faculty Publications

Because there is no effective treatment for late-stage prostate cancer (PCa) at this moment, identifying novel targets for therapy of advanced PCa is urgently needed. A new network-based systems biology approach, XDeath, is developed to detect crosstalk of signaling pathways associated with PCa progression. This unique integrated network merges gene causal regulation networks and protein-protein interactions to identify novel co-targets for PCa treatment. The results show that polo-like kinase 1 (Plk1) and DNA methyltransferase 3A (DNMT3a)-related signaling pathways are robustly enhanced during PCa progression and together they regulate autophagy as a common death mode. Mechanistically, it is shown that Plk1 …

Cancer Salt Nostalgia, Aashish S. Allu, Venkataswarup Tiriveedhi

Biology Faculty Research

High-salt (sodium chloride) diets have been strongly associated with disease states and poor health outcomes. Traditionally, the impact of salt intake is primarily studied in cardiovascular diseases, hypertension and renal diseases; however, recently there has been increasing evidence demonstrating the role of salt in autoimmune diseases. Salt has been shown to modulate the inflammatory activation of immune cells leading to chronic inflammation-related ailments. To date, there is minimal evidence showing a direct correlation of salt with cancer incidence and/or cancer-related adverse clinical outcomes. In this review article, we will discuss the recent understanding of the molecular role of salt, and …

A Forward Genetic Screen To Identify Human Genes Of Interest And Their Roles In Ovarian Cancer, Susan A. Ihejirika

Honors College Theses

Drosophila melanogaster, fruit flies, are very important for modeling and studying human diseases. This study identifies human genes of interest and their contributions to epithelial ovarian carcinogenesis and progression as well as the roles orthologs of these genes play in Drosophila melanogaster. This is important because ovarian cancer is the most common cause of death among the gynecological cancers. This identification of genes was carried out using a forward genetic screen employing the widely used GMR-Gal4 driver/UAS-transgene system. The GMR-Gal4 driver is commonly utilized to express transgenes in the developing eye of the fruit fly. Transgenes that are expressed using …

Growth Suppression Of Erbb2-Driven Breast Cancers By P300/Cbp Inhibition, Sergelen Ariunbaatar

Natural Sciences and Mathematics | Biological Sciences Master's Theses

Breast cancer, which affects 1 in 8 women in the US, is divided into four major subtypes based on the overexpression or lack of expression of three different molecular markers: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2, also referred to as ERBB2). About 20% of all newly diagnosed breast cancer cases are ERBB2-positive, and these breast cancer patients tend to have poorer prognosis with lower overall survival compared to hormone receptor-positive breast cancer (ACS, 2020). Although there are several anti-ERBB2 drugs available there are still many patients at both the early and metastatic stages …

Advancing The Preclinical Development Of Secondary Metabolites From Cacospongia Mycofijiensis For The Treatment Of Cancer, Joseph Morris

Natural Sciences and Mathematics | Biological Sciences Master's Theses

The marine sponge Cacospongia mycofijiensis from the Indo-Pacific has proven to be a source of structurally diverse secondary metabolites that are biologically active against a variety of distinct targets. Current interest in the secondary metabolites of C. mycofijiensis largely stems from a) their potent and preferential cytotoxicity for cancer cell lines versus normal cells, making many of them promising leads as cancer therapeutics and b) the novel mechanisms of action responsible for their impressive cytotoxicity. However, limited compound availability has resulted in a paucity of studies aimed at advancing the preclinical development of these secondary metabolites from C. mycofijiensis for …

Identifying The Cell Composition And Clonal Diversity Of Supratentorial Ependymoma Using Single Cell Rna-Sequencing, James He

University Scholar Projects

Ependymoma is a primary solid tumor of the central nervous system. Supratentorial ependymoma (ST-EPN), a subtype of ependymomas, is driven by an oncogenic fusion between the ZFTA and RELA genes in 70% of cases. We introduced this fusion into neural progenitor cells of mice embryos via in utero electroporation of a non-viral binary piggyBac transposon system containing ZFTA-RELA. From preliminary data in the LoTurco lab, inducing the expression of ZFTA-RELA into different neural progenitor cells produces tumors of varying lethality and cellular composition. To define the cellular composition and subclonal diversity of ST-EPN tumors, we used single cell RNA-sequencing to …

Identifying The Cell Composition And Clonal Diversity Of Supratentorial Ependymoma Using Single Cell Rna-Sequencing, James He

Honors Scholar Theses

Ependymoma is a primary solid tumor of the central nervous system. Supratentorial ependymoma (ST-EPN), a subtype of ependymomas, is driven by an oncogenic fusion between the ZFTA and RELA genes in 70% of cases. We introduced this fusion into neural progenitor cells of mice embryos via in utero electroporation of a non-viral binary piggyBac transposon system containing ZFTA-RELA. From preliminary data in the LoTurco lab, inducing the expression of ZFTA-RELA into different neural progenitor cells produces tumors of varying lethality and cellular composition. To define the cellular composition and subclonal diversity of ST-EPN tumors, we used single cell RNA-sequencing …

Plant Based Compounds Inhibit Proliferation, Alter Cytomorphology And Decrease Migration Of Human Adenocarcinoma Cells, Devapriya Segaran

Electronic Theses & Dissertations

Adenocarcinoma is an aggressive form of lung cancer that has a high risk of recurrence with a survival rate of 33%. In recent years, there has been much interest in the ability of naturally occurring plant derived phenols to inhibit specific type of cancers. Compounds like curcumin derived from turmeric, rutin derived from citrus fruits and resveratrol derived from blueberries have been of particular interest. In this thesis I studied the anti-cancer effects of the above-mentioned compounds on a human a549 adenocarcinoma cell line. Inverted phase contrast microscopy was used to observe alterations to the cytomorphology of cells. An MTT …

Novel Hsp40/J-Domain Protein Inhibitors To Deplete Misfolded Mutant P53, Shigeto Nishikawa

Research Days

Background: Accumulation of oncogenic mutant p53 (mutp53) greatly contributes to cancer progression. Heat shock protein 40 (HSP40), also known as J-domain proteins (JDPs), has been implicated in stabilization of misfolded forms of mutp53. Specifically, we demonstrate that DNAJA1, a member of HSP40/JDPs, binds to and stabilizes misfolded mutp53, while knockdown of DNAJA1 results in CHIP ubiquitin ligase-mediated degradation of misfolded mutp53 and inhibition of tumor growth. Since no HSP40/JDPs inhibitors are currently available in clinics, these findings prompted us to identify inhibitors for DNAJA1 or HSP40/JDPs.

Objectives/Goal: The goal of this study is to identify and characterize potential anti-cancer compounds …

The Effects Of Mapk Signaling On The Development Of Cerebellar Granule Cells, Kerry Morgan

University Scholar Projects

The granule cells are the most abundant neuronal type in the human brain. Rapid proliferation of granule cell progenitors results in dramatic expansion and folding of the cerebellar cortex during postnatal development. Mis-regulation of this proliferation process causes medulloblastoma, the most prevalent childhood brain tumor. In the developing cerebellum, granule cells are derived from Atoh1-expressing cells, which arise from the upper rhombic lip (the interface between the roof plate and neuroepithelium). In addition to granule cells, the Atoh1 lineage also gives rise to different types of neurons including cerebellar nuclei neurons. In the current study, I have investigated the …

The Effects Of Mapk Signaling On The Development Of Cerebellar Granule Cells, Kerry Morgan

Honors Scholar Theses

The granule cells are the most abundant neuronal type in the human brain. Rapid proliferation of granule cell progenitors results in dramatic expansion and folding of the cerebellar cortex during postnatal development. Mis-regulation of this proliferation process causes medulloblastoma, the most prevalent childhood brain tumor. In the developing cerebellum, granule cells are derived from Atoh1-expressing cells, which arise from the upper rhombic lip (the interface between the roof plate and neuroepithelium). In addition to granule cells, the Atoh1 lineage also gives rise to different types of neurons including cerebellar nuclei neurons. In the current study, I have investigated the …

Role Of Endocytic Machinery Regulators In Egfr Traffic And Viral Entry, Insha Mushtaq

Theses & Dissertations

STUDY 1: Role of endocytic regulator EHD1 and its binding partner RUSC2 in EGFR traffic

Abstract

Epidermal growth factor receptor (EGFR) is a prototype receptor tyrosine kinase and an oncoprotein in many solid tumors. Cell surface display of EGFR is essential for cellular responses to its ligands. While post activation endocytic trafficking of EGFR has been well elucidated, little is known about mechanisms of basal/pre-activation surface display of EGFR. Here, we identify a novel role of the endocytic regulator EHD1 and a potential EHD1 partner, RUSC2, in cell surface display of EGFR. EHD1 and RUSC2 colocalize with EGFR in vesicular/tubular …

Biomedical Porcine Models For The Study Of Surgical Hemostasis, Hindlimb Ischemia, And Pancreatic Cancer, Shruthishree Aravind

Theses & Dissertations

Murine models have dominated the world of biomedical research and comparative medicine since their development in the early 1900s. [1] While they may be suitable models to study proteomics and genomics, they may not serve as effective translational models. [2-4] Murine models do not accurately model the pathophysiology of human disease and are limited by their size, application of medical imaging and intervention, which reduces their overall preclinical predictive value. [2-4]

Porcine models on the other hand, are slowly and steadily bridging the gap between murine models and human patients. [5] Pigs …

U-251mg Spheroid Generation Using A Scaffold Based Method Protocol, Lara Carroll, Brijesh K. Tiwari, James F. Curtin, Janith Wanigasekara

Articles

3D cell culture is a technique that is used to grow cells in vitro that will mimic an in vivo environment. 3D cell models are a helpful learning tool for researchers to better understand disease mechanisms and to explore different therapeutic properties of drugs. 3D cell cultures can be developed using patient derived cancer cells. Once they have been grown, these 3D cells can be used to screen for small molecule drugs or for genetic modification in for analysis of disease pathways or to predict drug treatments toxicity or efficacy. 3D cell cultures are a big step towards the more …

U-251mg Spheroid Generation Using Low Attachment Plate Method Protocol, Lara J. Carroll, Brijesh K. Tiwari, James F. Curtin, Janith Wanigasekara

Articles

3D cell culture is a process used to grow cells in vitro to mimic an in vivo environment. 3D cell models are very useful for understanding disease mechanisms and exploring drug therapeutics. 3D cultures can be grown from cells taken from cancer organoids in patients. Once grown, they can be used to screen for small molecule drugs or they can be genetically modified in order to analyse disease pathways or predict the toxicity or efficacy of a drug treatment. These cultures decrease the need to use animals in research and provides more reliable results as it uses human physiology. This …

U-251mg Spheroid Generation Using Hanging Drop Method Protocol, Lara Carroll, Brijesh K. Tiwari, James F. Curtin, Janith Wanigasekara

Articles

The use of 3D cell culture has been a major step in developing cellular models that can mimic physiological tissues. Traditional 2D cell cultures are often unable to accurately represent the cellular functions and responses that are present in tissues, as a result, research findings based on 2D cultures tend to be skewed with limited predictive capability. 3D cell cultures can be grown from cells obtained from cancer organoids in patients. These models are useful for understanding disease mechanisms and exploring drug therapeutics in areas such as toxicity and efficacy. In order to gather more physiologically relevant data, a variety …

Purification Of Pcbp2 And Its Effect On The Formation Of Dna I-Motifs And Secondary Structures, Nathan Redden

Honors Theses

Several secondary, non-B forms of DNA are associated with the promoter regions of many oncogenes, including the intensely studied c-MYC gene that codes for a transcription factor. Two such secondary structures, G-quadruplexes, and i-motifs, have become topics of interest due to their prevalence within oncogenic promoters, as well as their potential accessibility for drug targeting. B-form DNA can adopt alternative structures under certain conditions. These alternative structures are favored when there is an asymmetric distribution of guanosine and cytosine on complimentary DNA strands. The strand rich in guanosine is able to form a quadruple stranded DNA complex termed a G-quadruplex. …