2026
Bergonzini, Cecilia
2026, ISBN: 9789465370484.
@phdthesis{nokey,
title = {Acquired resistance in pancreatic cancer: characterization and exploration of actionable targets of a multifactorial disease.},
author = {Cecilia Bergonzini},
url = {https://hdl.handle.net/1887/4289790},
isbn = {9789465370484},
year = {2026},
date = {2026-01-27},
urldate = {2026-01-27},
abstract = {Pancreatic ductal adenocarcinoma (PDAC) is among the cancers with the highest mortality rate, despite a relatively low incidence. Most patients are diagnosed at unresectable stages and response to chemotherapy is often limited due to rapid emergence of resistance. The stiff desmoplastic tumor microenvironment (TME) has been suggested to play a role in chemoresistance, but insights on this aspect are limited. Therefore, this thesis investigates molecular mechanisms of chemoresistance and the mechanobiological traits associated with them. Through a multidisciplinary approach, across multiple PDAC models with acquired resistance to paclitaxel or gemcitabine, we elucidated recurrent functional mechanisms causing resistance and identified potential targets and strategies to restore sensitivity. Furthermore, Integrin subunit α2 (ITGA2) emerged as a mechanosensitive regulator with a prognostic role, with its expression increasing with substrate stiffness and correlating with poor survival in gemcitabine-treated patients. Finally, resistant cells displayed enhanced traction forces and motility, independent of the resistance mechanism, highlighting the complexity of the mechanical adaptation associated with therapeutic escape. Together, these findings provide actionable insights into the complex process of PDAC acquired chemoresistance and its connection with the mechanical properties of the tumor microenvironment.},
keywords = {},
pubstate = {published},
tppubtype = {phdthesis}
}
Pancreatic ductal adenocarcinoma (PDAC) is among the cancers with the highest mortality rate, despite a relatively low incidence. Most patients are diagnosed at unresectable stages and response to chemotherapy is often limited due to rapid emergence of resistance. The stiff desmoplastic tumor microenvironment (TME) has been suggested to play a role in chemoresistance, but insights on this aspect are limited. Therefore, this thesis investigates molecular mechanisms of chemoresistance and the mechanobiological traits associated with them. Through a multidisciplinary approach, across multiple PDAC models with acquired resistance to paclitaxel or gemcitabine, we elucidated recurrent functional mechanisms causing resistance and identified potential targets and strategies to restore sensitivity. Furthermore, Integrin subunit α2 (ITGA2) emerged as a mechanosensitive regulator with a prognostic role, with its expression increasing with substrate stiffness and correlating with poor survival in gemcitabine-treated patients. Finally, resistant cells displayed enhanced traction forces and motility, independent of the resistance mechanism, highlighting the complexity of the mechanical adaptation associated with therapeutic escape. Together, these findings provide actionable insights into the complex process of PDAC acquired chemoresistance and its connection with the mechanical properties of the tumor microenvironment.
Beslmüller, Klara
Extracellular Matrix Mechanics in the Regulation of the early steps of the Metastatic Cascade PhD Thesis
2026, ISBN: 9789465370217.
@phdthesis{nokey,
title = {Extracellular Matrix Mechanics in the Regulation of the early steps of the Metastatic Cascade},
author = {Klara Beslmüller},
url = {https://hdl.handle.net/1887/4288012},
isbn = {9789465370217},
year = {2026},
date = {2026-01-23},
urldate = {2026-01-23},
abstract = {Metastasis is responsible for over 90% of cancer-related deaths and arises from the ability of a small subset of tumor cells to detach from the primary tumor, overcome multiple biochemical and mechanical barriers, disseminate through the body, and colonize distant organs. These metastatic cells often exhibit increased resistance to therapy, making metastasis a major challenge in clinical oncology. Tumor cell dissemination is driven by interconnected biological and biophysical processes, including epithelial–mesenchymal transition (EMT), solid–fluid-like transitions, and dynamic interactions with the tumor microenvironment (TME). The TME, composed of stromal cells and extracellular matrix (ECM) components such as collagens, laminins, and proteoglycans, plays a decisive role in regulating tumor invasion. Alterations in ECM stiffness, composition, and organization—especially collagen remodeling and basement membrane breakdown—modulate cell migration, influence signaling pathways, and support metastatic niche formation. Both insufficient and excessive cell–ECM adhesion or stiffness exhibit biphasic effects on migration, underscoring the complexity of mechanical regulation. Additionally, changes in cell–cell adhesion, particularly involving cadherins, determine whether tumor cells migrate individually or collectively. As tumors grow, increasing solid stress further shapes invasive behavior through mechanotransduction. Understanding how these physical parameters cooperate to facilitate escape from the primary tumor is critical for identifying new therapeutic vulnerabilities. This thesis investigates individual ECM-related mechanical factors—including ECM stiffness, collagen remodeling, cell stiffness, and laminin-mediated regulation—to elucidate their contributions to metastatic progression. Through computational and experimental approaches, we reveal how specific mechanical cues modulate invasion, highlight the tumor-suppressive potential of laminin-111, and identify signatures of early collagen remodeling associated with metastatic potential. Collectively, these findings advance the mechanistic understanding of metastasis and may inform the development of future therapies aimed at restricting cancer spread.},
keywords = {},
pubstate = {published},
tppubtype = {phdthesis}
}
Metastasis is responsible for over 90% of cancer-related deaths and arises from the ability of a small subset of tumor cells to detach from the primary tumor, overcome multiple biochemical and mechanical barriers, disseminate through the body, and colonize distant organs. These metastatic cells often exhibit increased resistance to therapy, making metastasis a major challenge in clinical oncology. Tumor cell dissemination is driven by interconnected biological and biophysical processes, including epithelial–mesenchymal transition (EMT), solid–fluid-like transitions, and dynamic interactions with the tumor microenvironment (TME). The TME, composed of stromal cells and extracellular matrix (ECM) components such as collagens, laminins, and proteoglycans, plays a decisive role in regulating tumor invasion. Alterations in ECM stiffness, composition, and organization—especially collagen remodeling and basement membrane breakdown—modulate cell migration, influence signaling pathways, and support metastatic niche formation. Both insufficient and excessive cell–ECM adhesion or stiffness exhibit biphasic effects on migration, underscoring the complexity of mechanical regulation. Additionally, changes in cell–cell adhesion, particularly involving cadherins, determine whether tumor cells migrate individually or collectively. As tumors grow, increasing solid stress further shapes invasive behavior through mechanotransduction. Understanding how these physical parameters cooperate to facilitate escape from the primary tumor is critical for identifying new therapeutic vulnerabilities. This thesis investigates individual ECM-related mechanical factors—including ECM stiffness, collagen remodeling, cell stiffness, and laminin-mediated regulation—to elucidate their contributions to metastatic progression. Through computational and experimental approaches, we reveal how specific mechanical cues modulate invasion, highlight the tumor-suppressive potential of laminin-111, and identify signatures of early collagen remodeling associated with metastatic potential. Collectively, these findings advance the mechanistic understanding of metastasis and may inform the development of future therapies aimed at restricting cancer spread.
2025
Mytiliniou, Maria
Biophysical studies of intracellular and cellular motility. PhD Thesis
2025.
@phdthesis{nokey,
title = {Biophysical studies of intracellular and cellular motility.},
author = {Maria Mytiliniou},
url = {https://hdl.handle.net/1887/4176388},
year = {2025},
date = {2025-01-16},
urldate = {2025-01-16},
abstract = {This dissertation combines the use of defined microenvironments, high-resolution fluorescence microscopy, and time-resolved analysis, to study intracellular and cellular motility. The first part of the thesis focuses on intracellular transport, particularly organelle motion which occurs inside neurites of neuron-like cells. Changes in organelle transport are investigated for two distinct neurite morphologies, namely neurites that orient randomly on the two-dimensional surface, and neurites which are guided along one-dimension via chemical surface patterning. Additionally, perturbations are introduced which disrupt the intracellular homeostasis, and their effect in combination with the two neurite configurations on organelle transport is explored. The second part, which consists of the last chapter of this thesis, focuses on single-cell migration inside microenvironments comprising topographical features in the form of micropillars. Using two different cell types, we compare two main categories of motile behavior, namely amoeboid and mesenchymal, and furthermore, having arranged the micropillars such as to create different crowding regimes, we explore the effects of the varying space availability on each cell motion type.},
keywords = {},
pubstate = {published},
tppubtype = {phdthesis}
}
This dissertation combines the use of defined microenvironments, high-resolution fluorescence microscopy, and time-resolved analysis, to study intracellular and cellular motility. The first part of the thesis focuses on intracellular transport, particularly organelle motion which occurs inside neurites of neuron-like cells. Changes in organelle transport are investigated for two distinct neurite morphologies, namely neurites that orient randomly on the two-dimensional surface, and neurites which are guided along one-dimension via chemical surface patterning. Additionally, perturbations are introduced which disrupt the intracellular homeostasis, and their effect in combination with the two neurite configurations on organelle transport is explored. The second part, which consists of the last chapter of this thesis, focuses on single-cell migration inside microenvironments comprising topographical features in the form of micropillars. Using two different cell types, we compare two main categories of motile behavior, namely amoeboid and mesenchymal, and furthermore, having arranged the micropillars such as to create different crowding regimes, we explore the effects of the varying space availability on each cell motion type.
2024
Gregori, Alessandro
2024.
@phdthesis{nokey,
title = {Overcoming the inaccessible fortress: Exploration of resistance patterns in pancreatic cancer to foster novel therapeutics},
author = {Alessandro Gregori},
url = {https://hdl.handle.net/1871.1/eb617835-2818-4646-9c10-633a3029572b},
year = {2024},
date = {2024-12-10},
urldate = {2024-12-10},
keywords = {},
pubstate = {published},
tppubtype = {phdthesis}
}
2022
Eckert, Julia
Forces and symmetries in cells and tissues PhD Thesis
2022.
@phdthesis{nokey,
title = {Forces and symmetries in cells and tissues},
author = {Julia Eckert},
url = {https://hdl.handle.net/1887/3492626},
year = {2022},
date = {2022-12-06},
abstract = {The way organisms develop from the initial single-cellular state to a complex final assembly like the human body, and how the final body is maintained throughout life, is one of the greatest mysteries and it’s understanding one of the biggest scientific challenges. Lately, it came as a surprise that the initial assembly and the later maintenance of integrity is not only determined by intricate biochemical communication networks, but in part by physical forces that cells, their neighbors, and their environment apply in a bidirectional manner. The resulting collectivity of cell behavior determines the development of organisms, and are crucial to the health and disease state of the organism.In this thesis, we developed and utilized concepts from physics to quantitatively understand forces that develop between cells and their environment, and towards neighboring cells, and how the interplay between these forces regulates the arrangement, shape, and topology of tissue. The topics range from the development of novel experimental methods to the combination of experimental observations with theoretical descriptions. Our results contribute to a better understanding of cell and tissue integrity.},
keywords = {},
pubstate = {published},
tppubtype = {phdthesis}
}
The way organisms develop from the initial single-cellular state to a complex final assembly like the human body, and how the final body is maintained throughout life, is one of the greatest mysteries and it’s understanding one of the biggest scientific challenges. Lately, it came as a surprise that the initial assembly and the later maintenance of integrity is not only determined by intricate biochemical communication networks, but in part by physical forces that cells, their neighbors, and their environment apply in a bidirectional manner. The resulting collectivity of cell behavior determines the development of organisms, and are crucial to the health and disease state of the organism.In this thesis, we developed and utilized concepts from physics to quantitatively understand forces that develop between cells and their environment, and towards neighboring cells, and how the interplay between these forces regulates the arrangement, shape, and topology of tissue. The topics range from the development of novel experimental methods to the combination of experimental observations with theoretical descriptions. Our results contribute to a better understanding of cell and tissue integrity.
Iendaltseva, Olga
Force sensing and transmission in human induced pluripotent stem-cell-derived pericytes PhD Thesis
2022, ISBN: 9789085935391.
@phdthesis{nokey,
title = {Force sensing and transmission in human induced pluripotent stem-cell-derived pericytes},
author = {Olga Iendaltseva},
url = {https://hdl.handle.net/1887/3485923},
isbn = {9789085935391},
year = {2022},
date = {2022-11-15},
abstract = {Pericytes, the mural cells of blood microvessels, are important regulators of vascular morphogenesis and function that have been postulated to mechanically control microvascular diameter through as yet unknown mechanisms. Their disfunction has been implicated in several pathologies, including cerebral ischemia, Alzheimer's disease and diabetic retinopathy.To reveal mechanisms used by pericytes for mechanical interactions within microvessels we designed models bringing human induced pluripotent stem cell (hiPSC)-derived pericytes in contact with various micropatterned substrates representing the microvascular basement membrane organization. Our findings shed light on how pericytes can mechanically regulate microvascular morphogenesis and function, and open possibilities for testing therapeutic strategies.},
keywords = {},
pubstate = {published},
tppubtype = {phdthesis}
}
Pericytes, the mural cells of blood microvessels, are important regulators of vascular morphogenesis and function that have been postulated to mechanically control microvascular diameter through as yet unknown mechanisms. Their disfunction has been implicated in several pathologies, including cerebral ischemia, Alzheimer's disease and diabetic retinopathy.To reveal mechanisms used by pericytes for mechanical interactions within microvessels we designed models bringing human induced pluripotent stem cell (hiPSC)-derived pericytes in contact with various micropatterned substrates representing the microvascular basement membrane organization. Our findings shed light on how pericytes can mechanically regulate microvascular morphogenesis and function, and open possibilities for testing therapeutic strategies.
2018
Keizer, Veer I. P.
Quantitative live cell imaging of glucocorticoid receptor dynamics in the nucleus PhD Thesis
2018, ISBN: 9789463324212.
@phdthesis{nokey,
title = {Quantitative live cell imaging of glucocorticoid receptor dynamics in the nucleus},
author = {Veer I. P. Keizer},
url = {https://hdl.handle.net/1887/66716},
isbn = {9789463324212},
year = {2018},
date = {2018-11-01},
abstract = {In this thesis, the focus lies on studying glucocorticoid receptor dynamics in living cells with the aim of understanding how this transcription factor finds its DNA target sites to regulate transcription. We have uncovered several GR dynamics states and obtained insight into how the receptor finds its target, which includes repetitive switching between states. In addition, we have made a quantitative description of the static distribution of this transcription factor in the nucleus and compared this to a homologous transcription factor, the estrogen receptor. We have advanced the experimental techniques used to answer this question through development of novel analysis tools. These include a method to correct analytically for observation bias of different diffusion modes in a two dimensional plane. Furthermore, we have investigate the use of an alternative labeling method, namely the gold nanorod. To this end, the behavior and functionalization of gold nanorods was characterized in live cells.},
keywords = {},
pubstate = {published},
tppubtype = {phdthesis}
}
In this thesis, the focus lies on studying glucocorticoid receptor dynamics in living cells with the aim of understanding how this transcription factor finds its DNA target sites to regulate transcription. We have uncovered several GR dynamics states and obtained insight into how the receptor finds its target, which includes repetitive switching between states. In addition, we have made a quantitative description of the static distribution of this transcription factor in the nucleus and compared this to a homologous transcription factor, the estrogen receptor. We have advanced the experimental techniques used to answer this question through development of novel analysis tools. These include a method to correct analytically for observation bias of different diffusion modes in a two dimensional plane. Furthermore, we have investigate the use of an alternative labeling method, namely the gold nanorod. To this end, the behavior and functionalization of gold nanorods was characterized in live cells.
2016
Balcioglu, Hayri Emrah
Role of Integrin Adhesions in Cellular Mechanotransduction PhD Thesis
2016, ISBN: 978-94-6295-460-1.
@phdthesis{nokey,
title = {Role of Integrin Adhesions in Cellular Mechanotransduction},
author = {Hayri Emrah Balcioglu},
url = {https://hdl.handle.net/1887/38405},
isbn = {978-94-6295-460-1},
year = {2016},
date = {2016-03-31},
urldate = {2016-03-31},
booktitle = {Role of Integrin Adhesions in Cellular Mechanotransduction.},
abstract = {Cells receive mechanical cues from the surrounding extracellular matrix (ECM). This has a strong impact on physiology and pathology in a wide range of biological settings. Integrin receptors couple the ECM to the intracellular cytoskeleton across the cell membrane through a dynamic multiprotein adhesion complex and mediate bidirectional force transmission. In this research the mechanism of cellular mechanotransduction and its role in aspects of cancer progression are studied, focusing on integrins and other integrin associated proteins. We find that the integrin expression profile of cells regulates the orientation and dynamics of force transmission at cell-matrix adhesions. Additionally, using a novel method to quantify the abundance of a molecule in a cellular complex, we show that substrate rigidity modulates the association between traction forces and molecular composition of cell-matrix adhesions. Using cell microprinting in 3D ECM scaffolds, we determine the relation between tumor-induced remote ECM network orientation and angiogenesis. Lastly, genes that regulate cancer cell migration, force application, and adhesion dynamics are identified. Overall, the work described in this thesis unravels the role of cellular mechanotransduction in different aspects of cancer progression and reveals how the molecular composition of cell-matrix adhesions relates to traction force generation.},
keywords = {},
pubstate = {published},
tppubtype = {phdthesis}
}
Cells receive mechanical cues from the surrounding extracellular matrix (ECM). This has a strong impact on physiology and pathology in a wide range of biological settings. Integrin receptors couple the ECM to the intracellular cytoskeleton across the cell membrane through a dynamic multiprotein adhesion complex and mediate bidirectional force transmission. In this research the mechanism of cellular mechanotransduction and its role in aspects of cancer progression are studied, focusing on integrins and other integrin associated proteins. We find that the integrin expression profile of cells regulates the orientation and dynamics of force transmission at cell-matrix adhesions. Additionally, using a novel method to quantify the abundance of a molecule in a cellular complex, we show that substrate rigidity modulates the association between traction forces and molecular composition of cell-matrix adhesions. Using cell microprinting in 3D ECM scaffolds, we determine the relation between tumor-induced remote ECM network orientation and angiogenesis. Lastly, genes that regulate cancer cell migration, force application, and adhesion dynamics are identified. Overall, the work described in this thesis unravels the role of cellular mechanotransduction in different aspects of cancer progression and reveals how the molecular composition of cell-matrix adhesions relates to traction force generation.
Harkes, Rolf
Quantitative Super-Resolution Microscopy PhD Thesis
2016, ISBN: 9789085932413 .
@phdthesis{nokey,
title = {Quantitative Super-Resolution Microscopy},
author = {Rolf Harkes},
url = {https://hdl.handle.net/1887/37175},
isbn = {9789085932413 },
year = {2016},
date = {2016-01-13},
abstract = {Super-Resolution Microscopy is an optical fluorescence technique. In this thesis we focus on single molecule super-resolution, where the position of single molecules is determined. Typically these molecules can be localized with a 10 to 30nm precision. This technique is applied in four different studies. To determine the spatial distribution of Ras-protein in live cells, Ripley's analysis is used on localization data to quantify size an diffusion parameters of nanodomains. Particle image correlation spectroscopy (PICS) is a second order spatial distribution analysis to determine diffusion properties of single molecule populations. A mathematical framework to correct the data when applied on 3D diffusion is presented in the second chapter. In the fourth chapter the uptake of alpha-synuclein aggregates by the cells is observed using super-resolution microscopy. Their partial degradation was followed and showed the importance of the lysosome-dependent mechanism for protecting cells from exposure to potentially toxic a-synuclein. In the fifth chapter we correlate the number of vinculin proteins in a focal adhesion protein complex, to the local force generated by the cell via this complex. A method was developed to determine the local stoichiometry of molecules by their correlated distances as obtained from SMLM.},
keywords = {},
pubstate = {published},
tppubtype = {phdthesis}
}
Super-Resolution Microscopy is an optical fluorescence technique. In this thesis we focus on single molecule super-resolution, where the position of single molecules is determined. Typically these molecules can be localized with a 10 to 30nm precision. This technique is applied in four different studies. To determine the spatial distribution of Ras-protein in live cells, Ripley's analysis is used on localization data to quantify size an diffusion parameters of nanodomains. Particle image correlation spectroscopy (PICS) is a second order spatial distribution analysis to determine diffusion properties of single molecule populations. A mathematical framework to correct the data when applied on 3D diffusion is presented in the second chapter. In the fourth chapter the uptake of alpha-synuclein aggregates by the cells is observed using super-resolution microscopy. Their partial degradation was followed and showed the importance of the lysosome-dependent mechanism for protecting cells from exposure to potentially toxic a-synuclein. In the fifth chapter we correlate the number of vinculin proteins in a focal adhesion protein complex, to the local force generated by the cell via this complex. A method was developed to determine the local stoichiometry of molecules by their correlated distances as obtained from SMLM.
2015
Beletkaia, Elena
Mechanisms of Ewing sarcoma metastasis : biochemistry and biophysics PhD Thesis
2015, ISBN: 9789085932345 .
@phdthesis{nokey,
title = {Mechanisms of Ewing sarcoma metastasis : biochemistry and biophysics},
author = {Elena Beletkaia},
url = {https://hdl.handle.net/1887/37000},
isbn = {9789085932345 },
year = {2015},
date = {2015-12-09},
abstract = {Ewing sarcoma (ES) is a special type of bone cancer, first described by Dr. James Ewing in his paper __Diffusive endothelioma of bone__. Today Ewing sarcoma represents the second most common bone cancer among adolescents and young adults. Contrary to the positive achievement in treatment of localized tumors, the long-term (5-years) survival for Ewing sarcoma patients with metastasis, however, remain below the 30% mark. In this thesis a report on experimental work aiming for a better understanding of the mechanisms underlying Ewing sarcoma metastasis is presented. Two distinct mechanisms are investigated: (1) a biochemical approach in which the initial steps in the CXCR4 signaling cascade are followed, and (2) a biophysical approach in which the guidance of Ewing sarcoma metastasis by the stiffness of their microenvironment is demonstrated. The results presented in this thesis provide deeper insights into the mechanisms controlling signaling of the chemokine receptor CXCR4 and into the role of the micro-environment in Ewing sarcoma cells behavior.Through various experimental approaches it was shown that both biochemical and biophysical guidance control how Ewing sarcoma develops into its distinct metastatic phenotype.},
keywords = {},
pubstate = {published},
tppubtype = {phdthesis}
}
Ewing sarcoma (ES) is a special type of bone cancer, first described by Dr. James Ewing in his paper __Diffusive endothelioma of bone__. Today Ewing sarcoma represents the second most common bone cancer among adolescents and young adults. Contrary to the positive achievement in treatment of localized tumors, the long-term (5-years) survival for Ewing sarcoma patients with metastasis, however, remain below the 30% mark. In this thesis a report on experimental work aiming for a better understanding of the mechanisms underlying Ewing sarcoma metastasis is presented. Two distinct mechanisms are investigated: (1) a biochemical approach in which the initial steps in the CXCR4 signaling cascade are followed, and (2) a biophysical approach in which the guidance of Ewing sarcoma metastasis by the stiffness of their microenvironment is demonstrated. The results presented in this thesis provide deeper insights into the mechanisms controlling signaling of the chemokine receptor CXCR4 and into the role of the micro-environment in Ewing sarcoma cells behavior.Through various experimental approaches it was shown that both biochemical and biophysical guidance control how Ewing sarcoma develops into its distinct metastatic phenotype.
