Epithelial-mesenchymal plasticity (EMP) and tumor cell migration play an important role in cancer progression, and an improved understanding of the mechanisms underlying these concepts is essential... Show moreEpithelial-mesenchymal plasticity (EMP) and tumor cell migration play an important role in cancer progression, and an improved understanding of the mechanisms underlying these concepts is essential for developing new targeted approaches. In this thesis, we studied these mechanisms using mathematical and computational approaches.First, we summarized and reviewed previous computational approaches that have been used to decipher EMP regulation. We then created mathematical models to explore (1) how different regulatory networks can explain epithelial-mesenchymal transition (EMT) in different cell contexts, and (2) how EMP and immune regulation can interact to cause tumor immunoevasion.Next, we studied the role of cell density in migration characteristics of triple-negative breast cancer cell lines by using a combined experimental and computational approach. We show how clustering and pseudopodial dynamics, potentially influenced by EMT-related factors, can alter the migratory behavior of these cell lines.Jointly, our work has shown that computational modeling can be used to test hypotheses based on experimental data, and generate testable hypotheses, making it a valuable addition to wet-lab experiments. Importantly, we identified mechanisms related to potential therapeutic targets, hopefully leading to improved targeted therapies and reduced cancer mortality. Show less
G protein-coupled receptors (GPCRs), one of the largest families of membrane proteins, are responsive to a diverse set of physiological endogenous ligands including hormones and neurotransmitters.... Show moreG protein-coupled receptors (GPCRs), one of the largest families of membrane proteins, are responsive to a diverse set of physiological endogenous ligands including hormones and neurotransmitters. Due to the various GPCR ligand binding domains present on GPCRs and their sensitivities to a diverse array of ligands, these proteins have shown to be very ‘druggable’ as they are the main target for an estimated 30% of approved drugs. A growing body of evidence shows a prominent role of GPCRs in all phases of cancer with a mutation frequency of approximately 20% in all cancers. Mutations occurring in GPCRs can severely alter their normal function and may ultimately convert their physiological and pathological roles. One particular class of rhodopsin-like GPCRs included in this thesis are the adenosine receptors (ARs). Due to the accumulation of adenosine in the tumor microenvironment, all four subtypes of ARs might be targets for the development of novel approaches for the treatment of cancer. For each of the four subtypes, a number of somatic mutations have been identified in patient isolates. In this thesis, we examined them on receptor activation and ligand binding using reference adenosine receptor ligands, and determined the impact mutations have on these pharmacological readouts. Show less
Immunotherapies for cancer are an emerging class of therapeutic strategies which aim to treat cancer via augmentation of the immune system. Despite significant success of immunotherapies in the... Show moreImmunotherapies for cancer are an emerging class of therapeutic strategies which aim to treat cancer via augmentation of the immune system. Despite significant success of immunotherapies in the past decade, not all patients will respond to these treatments and the reasons why immunotherapies are successful in some patients, but not others, remain incompletely understood. The immune response to cancer is a complex, multistage process, and mathematical and computational models are a useful tool for understanding such complex systems. In this thesis, I develop mathematical and computational models of cytotoxic T lymphocytes (CTLs), who are key players in the immune system due to their ability to recognise, destroy, and provide long lasting protection against malignant or virally infected cells. Show less
In this thesis, we aim to shed light on the diverse and often opposing roles of integrin α3β1 in cancer. Our work highlights that the role of α3β1 in cancer depends on time and place: the nature of... Show moreIn this thesis, we aim to shed light on the diverse and often opposing roles of integrin α3β1 in cancer. Our work highlights that the role of α3β1 in cancer depends on time and place: the nature of the cell environment (such as extracellular matrix composition), type of cancer and its driving mechanism, as well as the stage of the disease. We provide a new insight into the mechanisms behind the role of α3β1 in HER2-driven breast cancer and in DMBA/TPA-induced non-melanoma skin tumorigenesis. Show less
Traditional drug discovery approaches have been hampered by (in vitro) cell-culture models that poorly represent the situation in the human body. Principally, cells grow in the body in a three... Show moreTraditional drug discovery approaches have been hampered by (in vitro) cell-culture models that poorly represent the situation in the human body. Principally, cells grow in the body in a three-dimensional (3D) environment that cannot generally be captured using cell culture methods. For this reason, cell-culture models have been developed where cells grow in a 3D-environment, which allows them to form structures that are more comparable to tissue in the body. However, the full complexity of these advanced cell-culture models can only be fully used for routine drug testing if the cell culture model can be used on a large scale (also termed high-throughput screening or HTS), and if the readout can capture all of the biological complexity reflected by the 3D-cultured cells (high-content screening or HCS). Due to these technological limitations, 3D cellular models are not yet routinely applied in drug and drug-target discovery. This thesis describes the development of fully-scalable 3D cell-culture screening platforms in the context of cancer and polycystic kidney disease. Show less
Both copy number losses and homozygosity of chromosome 7 are extremely rare events in many tumor types, indicating that the retention of both the maternal and paternal copies of chromosome 7... Show moreBoth copy number losses and homozygosity of chromosome 7 are extremely rare events in many tumor types, indicating that the retention of both the maternal and paternal copies of chromosome 7 is essential for the tumor cells. This thesis compiles our research into the driving force that is behind the retention of heterozygosity on chromosome 7. The retention of heterozygosity on chromosome 7, we hypothesised, is due to the presence of a set of mono-allelically expressed genes on this chromosome, which are essential for tumor cell survival; so called cell survival genes. Loss of either copy of chromosome 7 would result in a complete loss of expression of those cell survival genes which are exclusively expressed from that particular allele. We have identified 6 imprinted cell survival genes on chromosome 7, that play a role in chromosome 7 retention in thyroid cancer. Additionally, we have analysed allele specific expression on chromosome 7 in a set of novel low passage colorectal cancer cell lines. We also report the extensive characterization, as well as the transcriptome and methylome profiling of these cell lines. Show less
Cellular responses to DNA damage are highly variable and strongly depend on the cellular and organismic context. Studying the DNA damage response is crucial for a better understanding of cancer... Show moreCellular responses to DNA damage are highly variable and strongly depend on the cellular and organismic context. Studying the DNA damage response is crucial for a better understanding of cancer formation and ageing as well as genotoxic stress-induced cancer therapy. To do justice to the multifaceted cellular changes, elicited by DNA damage, use of high-throughput techniques and integration with bioinformatics tools is of great value. This thesis summarizes recent advances in the field of systems biology studies of the DNA damage response and furthermore shows integrated approaches of the study of DNA damage response signaling networks in embryonic stem and cancer cells. By integration of transcriptional changes and the phosphorylation and metabolic response of cisplatin-treated embryonic stem cells, with RNAi-based knockdown screens we identify novel DNA damage response signaling networks, linking process such as Wnt signaling, translation arrest or altered metabolic pathways to the cellular response to DNA damage. Furthermore, genes, whose knockdown sensitizes embryonic stem cells to DNA damage-induced killing, are tested in cancer cells of varying genetic backgrounds identifying a small subset of genes, which represent potential drug targets for sensitization of cancer cells. Altogether, our systems approach for studying the DNA damage response identifies novel DNA damage-induced signaling networks and molecules, which modulate survival in the presence of DNA damage, potentially providing new targets for therapeutic intervention or biomarker discovery. Show less
The aim of this thesis is to address how integrin-mediated signaling regulates cellular processes that have profound effects on cell morphology, motility, cancer metastasis, and FN fibrillogenesis,... Show moreThe aim of this thesis is to address how integrin-mediated signaling regulates cellular processes that have profound effects on cell morphology, motility, cancer metastasis, and FN fibrillogenesis, and how these findings can be utilized for relevant medical purposes or advancement of drug discovery. Show less
