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Cancer is one of the leading causes of death globally according to the World Health Organization. Although improved treatments and early diagnoses have reduced cancer related mortalities, metastatic disease remains a major clinical challenge. The local tumor microenvironment plays a significant role in cancer metastasis, where tumor cells respond and

Cancer is one of the leading causes of death globally according to the World Health Organization. Although improved treatments and early diagnoses have reduced cancer related mortalities, metastatic disease remains a major clinical challenge. The local tumor microenvironment plays a significant role in cancer metastasis, where tumor cells respond and adapt to a plethora of biochemical and biophysical signals from stromal cells and extracellular matrix (ECM) proteins. Due to these complexities, there is a critical need to understand molecular mechanisms underlying cancer metastasis to facilitate the discovery of more effective therapies. In the past few years, the integration of advanced biomaterials and microengineering approaches has initiated the development of innovative platform technologies for cancer research. These technologies enable the creation of biomimetic in vitro models with physiologically relevant (i.e. in vivo-like) characteristics to conduct studies ranging from fundamental cancer biology to high-throughput drug screening. In this review article, we discuss the biological significance of each step of the metastatic cascade and provide a broad overview on recent progress to recapitulate these stages using advanced biomaterials and microengineered technologies. In each section, we will highlight the advantages and shortcomings of each approach and provide our perspectives on future directions.
ContributorsPeela, Nitish (Author) / Nikkhah, Mehdi (Thesis director) / LaBaer, Joshua (Committee member) / Harrington Bioengineering Program (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2017-05
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Description
Difficult to treat cancer patients, specifically those tumors that are metastatic and drug-resistant, prove to have the lowest survival rates when compared to more localized types. The commonplace combination therapies, surgery, chemotherapy, and radiation, do not usually result in remission and sometimes cannot be done with these specific patients. RNA

Difficult to treat cancer patients, specifically those tumors that are metastatic and drug-resistant, prove to have the lowest survival rates when compared to more localized types. The commonplace combination therapies, surgery, chemotherapy, and radiation, do not usually result in remission and sometimes cannot be done with these specific patients. RNA interference therapeutics, especially those that use short-interfering RNA (siRNA), have given rise to a novel field that employs the mechanisms in the body to silence the gene expression post-transcriptionally. The main cell types used in this research were Ewing Sarcoma, Acute Myelogenous Leukemia, and Rhabdomyosarcoma cells. Initial assays involved the testing of the cells' responsiveness to a panel of siRNA compounds, to better understand the most effective ones. The siRNA UBBs1 proved to be the most cytotoxic to all cell lines tested, allowing for further investigation through transfection procedures for cellular assays and RNA purification for expression analysis. The data showed decreased cell viability for the UBBs1 treated group for both RD and RH-30 Rhabdomyosarcoma cell lines, especially at a much lower concentration than traditional chemotherapy drug dose response assays. The RNA purification and quantification of the transfected cells over time showed the biggest decrease in gene expression when treated with UBBs1. The use of siRNA in future therapeutics could be a highly-specific method to induce cytotoxicity of cancer cells, but more successful clinical testing and better manufacturing processes need to be established first.
ContributorsChilders, Robert Valente (Author) / Ankeny, Casey (Thesis director) / Azorsa, David (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
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Description
Glioblastoma multiforme (GBM) is a malignant, aggressive and infiltrative cancer of the central nervous system with a median survival of 14.6 months with standard care. Diagnosis of GBM is made using medical imaging such as magnetic resonance imaging (MRI) or computed tomography (CT). Treatment is informed by medical images and

Glioblastoma multiforme (GBM) is a malignant, aggressive and infiltrative cancer of the central nervous system with a median survival of 14.6 months with standard care. Diagnosis of GBM is made using medical imaging such as magnetic resonance imaging (MRI) or computed tomography (CT). Treatment is informed by medical images and includes chemotherapy, radiation therapy, and surgical removal if the tumor is surgically accessible. Treatment seldom results in a significant increase in longevity, partly due to the lack of precise information regarding tumor size and location. This lack of information arises from the physical limitations of MR and CT imaging coupled with the diffusive nature of glioblastoma tumors. GBM tumor cells can migrate far beyond the visible boundaries of the tumor and will result in a recurring tumor if not killed or removed. Since medical images are the only readily available information about the tumor, we aim to improve mathematical models of tumor growth to better estimate the missing information. Particularly, we investigate the effect of random variation in tumor cell behavior (anisotropy) using stochastic parameterizations of an established proliferation-diffusion model of tumor growth. To evaluate the performance of our mathematical model, we use MR images from an animal model consisting of Murine GL261 tumors implanted in immunocompetent mice, which provides consistency in tumor initiation and location, immune response, genetic variation, and treatment. Compared to non-stochastic simulations, stochastic simulations showed improved volume accuracy when proliferation variability was high, but diffusion variability was found to only marginally affect tumor volume estimates. Neither proliferation nor diffusion variability significantly affected the spatial distribution accuracy of the simulations. While certain cases of stochastic parameterizations improved volume accuracy, they failed to significantly improve simulation accuracy overall. Both the non-stochastic and stochastic simulations failed to achieve over 75% spatial distribution accuracy, suggesting that the underlying structure of the model fails to capture one or more biological processes that affect tumor growth. Two biological features that are candidates for further investigation are angiogenesis and anisotropy resulting from differences between white and gray matter. Time-dependent proliferation and diffusion terms could be introduced to model angiogenesis, and diffusion weighed imaging (DTI) could be used to differentiate between white and gray matter, which might allow for improved estimates brain anisotropy.
ContributorsAnderies, Barrett James (Author) / Kostelich, Eric (Thesis director) / Kuang, Yang (Committee member) / Stepien, Tracy (Committee member) / Harrington Bioengineering Program (Contributor) / School of Mathematical and Statistical Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Description

Cancer perception is different across each region of the world, which can lead to late diagnosis and death, especially in cancers associated with greater stigma. These perceptions are largely affected by sociocultural, economic, and healthcare infrastructure of the region. It is crucial that effective methods are implemented, so that patients

Cancer perception is different across each region of the world, which can lead to late diagnosis and death, especially in cancers associated with greater stigma. These perceptions are largely affected by sociocultural, economic, and healthcare infrastructure of the region. It is crucial that effective methods are implemented, so that patients do not avoid getting diagnosed and treated

ContributorsSarkar, Shivangi (Author) / Maley, Carlo (Thesis director) / Baciu, Cristina (Committee member) / Barrett, The Honors College (Contributor) / Harrington Bioengineering Program (Contributor)
Created2023-05
Description

Advancing the understanding and treatment of many neurological disorders can be achieved by improving methods of neuronal detection at increased depth in the mammalian brain. Different cell subtypes cannot be detected using non-invasive techniques beyond 1 mm from cortical surface, in the context of targeting particular cell types in vivo

Advancing the understanding and treatment of many neurological disorders can be achieved by improving methods of neuronal detection at increased depth in the mammalian brain. Different cell subtypes cannot be detected using non-invasive techniques beyond 1 mm from cortical surface, in the context of targeting particular cell types in vivo (Wang, 2012). These limitations in the depth of imaging and targeting are due to optical scattering (Ntziachristos, 2010). In order to overcome these restrictions, longer wavelength fluorescent proteins have been utilized by researchers to see tagged cells at depth. Optical techniques such as two-photon and confocal microscopy have been used in combination with fluorescent proteins to expand depth, but are still limited by the penetration depth of light due to optical scattering (Lee, 2015). This research aims to build on other detection methods, such as the photoacoustic effect and automated fluorescence-guided electrophysiology, to overcome this limitation.

ContributorsAridi, Christina (Author) / Smith, Barbara (Thesis director) / Marschall, Ethan (Committee member) / Barrett, The Honors College (Contributor) / Watts College of Public Service & Community Solut (Contributor) / Harrington Bioengineering Program (Contributor)
Created2023-05
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Description
Cancer is a disease that takes the lives of almost 10 million people every year, and due to humans’ nature as multicellular organisms, it is both inevitable and incurable. Therefore, management of the disease is of utmost importance. Due to the complexity of cancer and its development, numerous computational models

Cancer is a disease that takes the lives of almost 10 million people every year, and due to humans’ nature as multicellular organisms, it is both inevitable and incurable. Therefore, management of the disease is of utmost importance. Due to the complexity of cancer and its development, numerous computational models have been developed that allow for precise diagnostic and management input. This experiment uses one of these said models, CancerSim, to evaluate the effect of proliferation rates on the order in which the hallmarks of cancer evolve in the simulations. To do this, the simulation is run with initial telomere length increased to simulate the effects of more living cells proliferating at every time step. The results of this experiment show no significant effect of initial telomere length on the order that hallmarks evolved, but all simulations ended with cancers that were dominant with cells that contained limitless replication and evade apoptosis hallmarks. These results may have been affected by limitations in the CancerSim model such as the inability to model metastasis and the lack of a robust angiogenesis solution. This study reveals how individual cell characteristics may not have a large effect on cancer evolution, but rather individual hallmarks can affect evolution significantly. Further studies with a revised version of CancerSim or another model could confirm the behavior demonstrated in this experiment
ContributorsLankalapalli, Aditya (Author) / Maley, Carlo (Thesis director) / Daymude, Joshua (Committee member) / Barrett, The Honors College (Contributor) / Harrington Bioengineering Program (Contributor)
Created2022-05
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Description

Evolution has driven organisms to develop a wide range of biological mechanisms to protect against cancer. Some organisms, including the sponge Tethya wilhelma and the Placozoa Trichoplax adhaerens have developed particularly effective mechanisms to suppress cancer and repair DNA damage. While these mechanisms are rooted in DNA damage repair and

Evolution has driven organisms to develop a wide range of biological mechanisms to protect against cancer. Some organisms, including the sponge Tethya wilhelma and the Placozoa Trichoplax adhaerens have developed particularly effective mechanisms to suppress cancer and repair DNA damage. While these mechanisms are rooted in DNA damage repair and prevention, evidence of bacteria may suggest that endosymbionts living within the organisms may plays a role as well. Likewise, other organisms, such as the flatworm Macrostomum lignano, are proven model organisms whose extensive documentation enables more in-depth analysis of biological mechanisms associated with cancer. Sponges, flatworms, and Placozoa were exposed to X-ray radiation totaling 600 Gy, 25 Gy, and up to 240 Gy, respectively. RNA sequencing and bioinformatics analyses were undergone to determine the differential gene expression of the animals at different time points. No common response to the X-ray radiation was discovered amongst all organisms. Instead, sponges showed evidence of tumor suppression and DNA repair gene upregulation including CUBN, bacterial endosymbionts showed evidence of lateral gene transfer and different DNA repair genes including FH, and flatworms showed evidence of allelic and mutational shifts in which tumorous populations became more reliant on alternate alleles and a single variant signature. This study highlights the varying mechanisms that have evolved in different organisms and the importance of studying these novel model organisms further.

ContributorsScirone, Jonathan (Author) / Fortunato, Angelo (Thesis director) / Maley, Carlo (Committee member) / Barrett, The Honors College (Contributor) / Harrington Bioengineering Program (Contributor)
Created2022-05
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Description

An immune regulatory network was constructed for the purpose of identifying target regulators in malignant pleural mesothelioma for therapies. An identified causal flow linked a mutation of D-dopachrome tautomerase to a heightened expression of regulator ASH1L and consequent down regulation of chemokine CCL5 and invasion of CD8+ T cells. Experimental

An immune regulatory network was constructed for the purpose of identifying target regulators in malignant pleural mesothelioma for therapies. An identified causal flow linked a mutation of D-dopachrome tautomerase to a heightened expression of regulator ASH1L and consequent down regulation of chemokine CCL5 and invasion of CD8+ T cells. Experimental validation of this initial use case indicates mRNA expression of CCL5 within the tumor cells and subsequent protein expression and secretion. Further analyses will explore the migration of CD8+ T cells in response to the chemotactic CCL5.

ContributorsCook, Margaret (Author) / Plaisier, Christopher (Thesis director, Committee member) / Wilson, Melissa (Committee member) / Barrett, The Honors College (Contributor) / Harrington Bioengineering Program (Contributor) / School of Molecular Sciences (Contributor)
Created2022-05
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Description

Cancer treatments such as chemotherapy and radiation are expensive, painful, and often ineffective, as they compromise the patient’s immune system. Genetically-modified Salmonella Typhimurium (GMS) strains, however, have been proven to target tumors and suppress tumor growth. The GMS then undergo programmed lysis, optimally leaving no trace of Salmonella in the

Cancer treatments such as chemotherapy and radiation are expensive, painful, and often ineffective, as they compromise the patient’s immune system. Genetically-modified Salmonella Typhimurium (GMS) strains, however, have been proven to target tumors and suppress tumor growth. The GMS then undergo programmed lysis, optimally leaving no trace of Salmonella in the body. Additionally, constant culturing of S. Typhimurium changes the pH of the culture medium. The objective of this research is to investigate using Salmonella to induce changes in the typically acidic tumor microenvironment (TME) pH, ideally hindering tumor growth. Future studies involve utilizing Salmonella to treat a multitude of cancers.

ContributorsFleck, Kiera (Author) / Kong, Wei (Thesis director) / Fu, Lingchen (Committee member) / Barrett, The Honors College (Contributor) / School of Mathematical and Statistical Sciences (Contributor) / Harrington Bioengineering Program (Contributor)
Created2022-05
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Description
Glioblastoma (GBM) is an extremely malignant form of brain cancer characterized by rapid progression and poor patient survival. Even after standard of care treatments, less than ten percent of patients with this disease survive five years. More effective therapeutic options are urgently needed to improve outcomes for patients with GBM.

Glioblastoma (GBM) is an extremely malignant form of brain cancer characterized by rapid progression and poor patient survival. Even after standard of care treatments, less than ten percent of patients with this disease survive five years. More effective therapeutic options are urgently needed to improve outcomes for patients with GBM. Adequate drug delivery is a critical challenge in GBM treatment, as drugs delivered systemically must be able to penetrate the blood brain barrier (BBB) and reach the tumor at therapeutic levels. To address this, we developed a resource to catalog BBB penetration information for investigational agents currently in clinical trials in cancer. Using an in silico prediction model and manual annotation to capture existing knowledge from the published literature, BBB content for ~500 investigational drugs was added to the investigational database tool. In addition to BBB content, the database also includes information on the gene targets of the included therapies. The investigational database tool was used to identify investigational agents that (1) may have increased activity against GBM based on the presence of a specific mutation in the tumor sample and (2) have evidence suggesting the compounds may penetrate the BBB. By prioritizing investigational agents for further study based on evidence for BBB penetration, this resource can help the GBM research community pursue more effective treatments for GBM.
ContributorsHerring, Emily Lora (Author) / Coursen, Jerry (Thesis director) / Byron, Sara (Committee member) / Biomedical Informatics Program (Contributor) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05