Matching Items (21)
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- All Subjects: Cancer
- Creators: School of Molecular Sciences
- Resource Type: Text
Description
Cancer rates vary between people, between cultures, and between tissue types, driven by clinically relevant distinctions in the risk factors that lead to different cancer types. Despite the importance of cancer location in human health, little is known about tissue-specific cancers in non-human animals. We can gain significant insight into how evolutionary history has shaped mechanisms of cancer suppression by examining how life history traits impact cancer susceptibility across species. Here, we perform multi-level analysis to test how species-level life history strategies are associated with differences in neoplasia prevalence, and apply this to mammary neoplasia within mammals. We propose that the same patterns of cancer prevalence that have been reported across species will be maintained at the tissue-specific level. We used a combination of factor analysis and phylogenetic regression on 13 life history traits across 90 mammalian species to determine the correlation between a life history trait and how it relates to mammary neoplasia prevalence. The factor analysis presented ways to calculate quantifiable underlying factors that contribute to covariance of entangled life history variables. A greater risk of mammary neoplasia was found to be correlated most significantly with shorter gestation length. With this analysis, a framework is provided for how different life history modalities can influence cancer vulnerability. Additionally, statistical methods developed for this project present a framework for future comparative oncology studies and have the potential for many diverse applications.
ContributorsFox, Morgan Shane (Author) / Maley, Carlo C. (Thesis director) / Boddy, Amy (Committee member) / Compton, Zachary (Committee member) / School of Mathematical and Statistical Sciences (Contributor) / School of Molecular Sciences (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
The goal of this project was to design and create a genetic construct that would allow for <br/>tumor growth to be induced in the center of the wing imaginal disc of Drosophila larvae, the <br/>R85E08 domain, using a heat shock. The resulting transgene would be combined with other <br/>transgenes in a single fly that would allow for simultaneous expression of the oncogene and, in <br/>the surrounding cells, other genes of interest. This system would help establish Drosophila as a <br/>more versatile and reliable model organism for cancer research. Furthermore, pilot studies were <br/>performed, using elements of the final proposed system, to determine if tumor growth is possible <br/>in the center of the disc, which oncogene produces the best results, and if oncogene expression <br/>induced later in development causes tumor growth. Three different candidate genes were <br/>investigated: RasV12, PvrACT, and Avli.
ContributorsSt Peter, John Daniel (Author) / Harris, Rob (Thesis director) / Varsani, Arvind (Committee member) / School of Molecular Sciences (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
Current studies in Multiple Myeloma suggest that patient tumors and cell lines cluster separately based on gene expression profiles. Hyperdiploid patients are also extremely underrepresented in established human myeloma cell lines (HMCLs). This suggests that the average HMCL model system does not accurately represent the average myeloma patient. To investigate this question we performed a combined CNA and SNV evolutionary comparison between four myeloma tumors and their established HMCLs (JMW-1, VP-6, KAS-6/1-KAS-6/2 and KP-6). We identified copy number changes shared between the tumors and their cell lines (mean of 74 events - 59%), those unique to patients (mean of 21.25 events - 17%), and those only in the cell lines (mean of 30.75 events \u2014 24%). A relapse sample from the JMW-1 patient showed 58% similarity to the primary diagnostic tumor. These data suggest that, on the level of copy number abnormalities, HMCLs show equal levels of evolutionary divergence as that observed within patients. By exome sequencing, patient tumors were 71% similar to their representative HMCLs, with ~12.5% and ~16.5% of SNVs unique to the tumors and HMCLs respectively. The HMCLs studied appear highly representative of the patient from which they were derived, with most differences associated with an enrichment of sub-populations present in the primary tumor. Additionally, our analysis of the KP-6 aCGH data showed that the patient's hyperdiploid karyotype was maintained in its respective HMCL. This discovery confirms the establishment and validation of a novel and potentially clinically relevant hyperdiploid HMCL that could provide a major advance in our ability to understand the pathogenesis and progression of this prominent patient population.
ContributorsBenard, Brooks Avery (Author) / Keats, Jonathan (Thesis director) / Anderson, Karen (Committee member) / Jelinek, Diane (Committee member) / School of Molecular Sciences (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Description
Cancer is a disease that occurs in many and perhaps all multicellular organisms. Current research is looking at how different life history characteristics among species could influence cancer rates. Because somatic maintenance is an important component of a species' life history, we hypothesize the same ecological forces shaping the life history of a species should also determine its cancer susceptibility. By looking at varying life histories, potential evolutionary trends could be used to explain differing cancer rates. Life history theory could be an important framework for understanding cancer vulnerabilities with different trade-offs between life history traits and cancer defenses. Birds have diverse life history strategies that could explain differences in cancer suppression. Peto's paradox is the observation that cancer rates do not typically increase with body size and longevity despite an increased number of cell divisions over the animal's lifetime that ought to be carcinogenic. Here we show how Peto’s paradox is negatively correlated for cancer within the clade, Aves. That is, larger, long-lived birds get more cancer than smaller, short-lived birds (p=0.0001; r2= 0.024). Sexual dimorphism in both plumage color and size differ among Aves species. We hypothesized that this could lead to a difference in cancer rates due to the amount of time and energy sexual dimorphism takes away from somatic maintenance. We tested for an association between a variety of life history traits and cancer, including reproductive potential, growth rate, incubation, mating systems, and sexual dimorphism in both color and size. We found male birds get less cancer than female birds (9.8% vs. 11.1%, p=0.0058).
ContributorsDolan, Jordyn Nicole (Author) / Maley, Carlo (Thesis director) / Harris, Valerie (Committee member) / Boddy, Amy (Committee member) / School of Molecular Sciences (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2019-05
Description
Tumor-stroma interactions significantly influence cancer cell metastasis and disease progression. These interactions partly comprise crosstalk between tumor and stromal fibroblasts, but the key molecular mechanisms within the crosstalk governing cancer invasion are still unclear. Here we develop a 3D in vitro organotypic microfluidic to model tumor-stroma interaction by mimicking the spatial organization of the tumor microenvironment on a chip. We co-culture breast cancer and patient-derived fibroblast cells in 3D tumor and stroma regions respectively and combine functional assessments, including cancer cell migration, with transcriptome profiling to unveil the molecular influence of tumor-stroma crosstalk on invasion. This led to the observation that cancer associated fibroblasts enhanced invasion in 3D by inducing the expression of a novel gene of interest, GPNMB, in breast cancer cells resulting in increased migration speed. Importantly, knockdown of GPNMB blunted the influence of CAFs on enhancing cancer invasion. Overall, these results demonstrate the ability of our model to recapitulate patient specific tumor microenvironment to investigate cellular and molecular consequences of tumor-stroma interactions.
ContributorsBarrientos, Eric Salvador (Author) / Nikkhah, Mehdi (Thesis director) / Veldhuizen, Jaime (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2019-05
Description
Trichoplax adhaerens (Placozoa) is the simplest multicellular animal to be described. This organism lacks nervous tissue, muscle tissue and organs, and is composed of only five cell types organized into three layers. Placozoa are gaining popularity as a model organism due to their simple make-up and completely sequenced genome. The complete sequencing of this organism’s genome has revealed the presence of important genes in cancer such as TP53 and MDM2 genes. Along with the presence of these genes, there are also additional pathways commonly deregulated in cancer that are well conserved in this organism. T. adhaerens are able to survive exposure to 160Gy and even 240Gy of X-ray radiation. Though small dark bodies form within the main body, they tend to extrude those masses, and continue to reproduce afterwards. After exposure to both grades of radiation, there was a greater increase in the apparent population size of the treated population than the control population. There was also a greater decrease in surface area of the organisms exposed to 160Gy than the control organisms. This increase in population and decrease in surface area of the treated organisms could be due to the extruded bodies. We hypothesize that the observed extrusion is a novel cancer defense mechanism for ridding the animal of damaged or mutated cells. This hypothesis should be tested through longitudinal observation and genetic analysis of the extruded bodies.
ContributorsYi, Avalon (Author) / Fortunato, Angelo (Thesis director) / Maley, Carlo (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2019-12
Description
Developments in structural biology has led to advancements in drug design and vaccine development. By better understanding the macromolecular structure, rational choices can be made to improve factors in such as binding affinity, while reducing promiscuity and off-target interactions, improving the medicines of tomorrow. The majority of diseases have a macromolecular basis where rational drug development can make a large impact. Two challenging protein targets of different medical relevance have been investigated at different stages of determining their structures with the ultimate goal of advancing in drug development. The first protein target is the CapBCA membrane protein complex, a virulence factor from the bacterium Francisella tularensis and the causative agent of tularemia and classified as a potential bioterrorism weapon by the United States. Purification of the individual protein targets from the CapBCA complex is a key and challenging step that has been, so far, a limiting factor towards the structure determination of the whole complex. Here, the purification protocols for the CapB and CapC subunits have been establish, which will allow us to progress towards biophysical and structural studies. The second protein target investigated in this thesis is the catalytically active Taspase1. Taspase1 functions as a non-oncogene addiction protease that coordinates cancer cell proliferation and apoptosis and has been found to be overexpressed in many primary human cancers. Here the structure is presented to 3.04A with the goal of rational drug design of Taspase1 inhibitors. Development of Taspase1 inhibitors has no completion in the drug discovery arena and would function as a new anti-cancer therapeutic. Solving the structures of medically relevant proteins such as these is critical towards rapidly developing treatments and prevention of old and new diseases.
ContributorsJernigan, Rebecca J. (Author) / Fromme, Petra (Thesis director) / Hansen, Debra T. (Committee member) / Martin-Garcia, Jose M. (Committee member) / School of Molecular Sciences (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Description
The rate of cancer incidence is a morbid figure. Twenty years ago, 1 in 2 men and 1 in 3 women were predicted to be afflicted by cancer throughout their lifetime (Cancer Facts & Figures- 1998). In 2017, the rate remains the same ("Cancer Statistic Center"). Every year, more people are affected by cancer, which is a physiologically, psychologically, emotionally and socially devastating disease. And yet the language and metaphors we use to describe cancer focus our attention on the "fight" of the heroic individual against the brutal disease or on finding a cure. Despite this narrow rhetoric, there are many meaningful, supportive, and palliative measures designed to substantively and holistically care for cancer patients, beyond their medical treatment. Many of these interventions help the patient feel supported (and less alone in this "battle") by building robust communities. In this thesis, I argue the summer camps for children affected by cancer are meaningful interventions that offer palliative care throughout their treatment by creating support networks with peers going through similar medical procedures. Drawing on anecdotal evidence from three cancer camps and a detailed literature review of a subset of palliative interventions designed to promote well-being, this thesis proposes a new model for a summer camp that focuses on emotional processing emotional expression, positive psychology in order to improve palliative care for cancer patients.
ContributorsPearce, Spencer Taylor (Author) / Miller, April (Thesis director) / Brian, Jennifer (Committee member) / School of Molecular Sciences (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2017-12
Description
PD-L1 blockade has shown recent success in cancer therapy and cancer vaccine regimens. One approach for anti-PD-L1 antibodies has been their application as adjuvants for cancer vaccines. Given the disadvantages of such antibodies, including long half-life and adverse events related to their use, a novel strategy using synbodies in place of antibodies can be tested. Synbodies offer a variety of advantages, including shorter half-life, smaller size, and cheaper cost. Peptides that could bind PD-L1 were identified via peptide arrays and used to construct synbodies. These synbodies were tested with inhibition ELISA assays, SPR, and pull down assays. Additional flow cytometry analysis was done to determine the binding specificity of the synbodies to PD-L1 and the ability of those synbodies to inhibit the PD-L1/PD-1 interaction. Although analysis of permeabilized cells expressing PD-L1 indicated that the synbodies could successfully bind PD-L1, those results were not replicated in non-permeabilized cells. Further assays suggested that the binding of the synbodies was non-specific. Other tests were done to see if the synbodies could inhibit the PD-1/PD-L1 interaction. This assay did not yield any conclusive results and further experimentation is needed to determine the efficacy of the synbodies in inhibiting this interaction.
ContributorsMujahed, Tala (Author) / Johnston, Stephen (Thesis director) / Blattman, Joseph (Committee member) / Diehnelt, Chris (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
Prevalence of esophageal adenocarcinoma (EAC) has increased six-fold in the United States over the past four decades due to increases in associated risk factors, namely obesity and gastroesophageal reflux disease. The most common genomic driver of EAC, tumor protein 53 (TP53) mutation, has previously been therapeutically intractable, affirming the unmet clinical need to deploy novel therapeutic strategies targeting this genomic driver in this tumor type. 72 percent of EAC patients have mutations in TP53, making tumors more reliant on the G2/M checkpoint to repair DNA damage, increasing likelihood of efficacious G2/M abrogation via targeting WEE1 G2 checkpoint kinase (WEE1), a modulator of this checkpoint. We hypothesize that the G2/M checkpoint represents a viable therapeutic avenue against the most common genomic driver of EAC. We investigated the efficacy of the WEE1 inhibitor AZD1775 on EAC cells. WEE1 mRNA expression levels in EAC are elevated compared to normal tissue controls. AZD1775 was shown to induce cyclin dependent kinase 1 (CDK1) mediated cell cycle progression and increased DNA damage markers as exposure increased via immunoblot analysis. SK-GT- 4 EAC cell line viability was significantly reduced by up to 30 percent when treated with AZD1775 and cisplatin when compared to cisplatin alone. AZD1775 monotherapy showed high efficacy in some EAC settings. Simultaneous dual therapy demonstrated the highest overall efficacy, and stepwise sequential treatments offered negligible benefit. Future research will explore the genomic contexts of the EAC celllines used in order to understand the different responses to AZD1775 monotherapy regimens. Ionizing radiotherapy will be employed in order to understand the DNA damage response timeline, providing more information on the mechanisms of G2/M checkpoint inhibitors in this disease setting. This research will provide insight into novel therapeutic targets for EAC leading to therapeutic testing and improved patient outcome.
ContributorsBone, Landon David (Co-author) / Carson, Vashti M. (Co-author, Committee member) / Blomquist, Mylan (Co-author) / Inge, Landon J. (Co-author) / Lake, Douglas F. (Thesis director) / Whitsett, Timothy (Committee member) / School of Molecular Sciences (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05