Periodic Reporting for period 4 - FanCY (Flow and Deformation of Cancer tumours near Yielding)
Periodo di rendicontazione: 2023-10-01 al 2024-09-30
Current research focuses on understanding and suppressing cancer invasion at the molecular and biophysical levels. Metastasis, rather than the primary tumour itself, is often the fatal stage of cancer. This process begins when cancer cells detach from the primary tumour, invade the surrounding extracellular matrix (ECM) and tumour microenvironment (TME), and disseminate to distant organs.
Despite extensive study, the physical and biomechanical mechanisms driving tumour invasion and metastasis remain poorly understood. This project aims to elucidate these processes under physiologically relevant conditions by investigating the physics and biomechanics of tumour cells during metastasis.
We have developed novel three-dimensional (3D) in vitro platforms to study cancer cell invasion and for use in drug screening. These systems will also support the exploration of how external mechanical forces influence cell migration and invasion, advancing our understanding of metastasis and informing therapies that target mechanical pathways.
Our overarching goal is to determine when, how, and why tumour cells detach from the primary tumour from a biophysical perspective. Specifically, we aim to characterize the viscoelastic properties of tumour tissues under solid stress and compression, and correlate these properties with metastatic potential. To achieve this, we are developing optimized 3D microfluidic platforms capable of rheological measurements of tumouroids under physiological conditions.
Finally, we developed a 3D matrix-based microfluidic model that closely mimics in vivo conditions, enabling studies of how interstitial flow and exogenous cytokines affect tumour invasion under mechanical stress. Beyond tumour spheroids, this platform can also be applied to heterogeneous models incorporating stromal cells, cancer-associated fibroblasts (CAFs), and immune cells.
Despite extensive study, the physical and biomechanical mechanisms driving tumour invasion and metastasis remain poorly understood. This project aims to elucidate these processes under physiologically relevant conditions by investigating the physics and biomechanics of tumour cells during metastasis.
We have developed novel three-dimensional (3D) in vitro platforms to study cancer cell invasion and for use in drug screening. These systems will also support the exploration of how external mechanical forces influence cell migration and invasion, advancing our understanding of metastasis and informing therapies that target mechanical pathways.
Our overarching goal is to determine when, how, and why tumour cells detach from the primary tumour from a biophysical perspective. Specifically, we aim to characterize the viscoelastic properties of tumour tissues under solid stress and compression, and correlate these properties with metastatic potential. To achieve this, we are developing optimized 3D microfluidic platforms capable of rheological measurements of tumouroids under physiological conditions.
Finally, we developed a 3D matrix-based microfluidic model that closely mimics in vivo conditions, enabling studies of how interstitial flow and exogenous cytokines affect tumour invasion under mechanical stress. Beyond tumour spheroids, this platform can also be applied to heterogeneous models incorporating stromal cells, cancer-associated fibroblasts (CAFs), and immune cells.
Initially, our research focused on the fabrication of microfluidic devices to study tumor mechanics and invasion under physiologically relevant conditions. Throughout this project, we have published several peer-reviewed articles advancing the understanding of tumor invasion and mechanics. For example, we contributed perspective articles on spheroid mechanics and their implications for cell invasion (Advances in Physics: X), as well as on 3D cell migration using microfluidic platforms (Trends in Cancer). Additionally, we reported on programmable micro-platforms for cancer cell invasion (Small), alongside several studies on microfluidic systems for the mechanical characterization of cancer spheroids and cancer migration under physiological conditions.
We further developed biomimetic extracellular matrices (ECMs) with tunable porosity and stiffness to investigate cancer cell invasion and migration, incorporating key invasion biomarkers such as epithelial–mesenchymal transition (EMT). In parallel, we designed microfluidic devices capable of measuring the viscoelastic properties of breast cancer spheroids under dynamic compression. These studies revealed that benign tissues exhibit higher elasticity and viscosity compared to malignant ones. Moreover, differences in relaxation behavior and morphology among malignant spheroids were correlated with cytoskeletal organization and cell–cell adhesion strength.
Beyond these developments, we introduced several novel microscale platforms for investigating cell invasion under physiological conditions. Notably, we created a 3D matrix-based microfluidic system that uncovered a synergistic relationship between interstitial flow (IF) and transforming growth factor-β (TGF-β) in promoting EMT in lung cancer spheroids. By closely replicating in vivo microenvironments, this platform enables real-time analysis of cancer cell signaling and invasion, offering key insights into the mechanobiology of tumor progression.
Furthermore, we developed a programmable, multifunctional 3D cancer cell invasion “microbucket-hydrogel” platform by integrating function-variable microbuckets with ECM-like hydrogels. This adaptable system effectively mimics dynamic tumor microenvironments and provides a versatile tool for cancer research, biofabrication, cell signaling studies, and drug screening.
As part of this project, we also organized several interdisciplinary workshops in collaboration with medical centers and TU Delft, facilitating knowledge exchange on tumor-on-a-chip technologies and our findings with leading partners and collaborators in oncology and cancer invasion research.
Looking ahead, a key direction for this research is the development of heterogeneous spheroids that replicate the diverse cellular populations within complex tumors, further enhancing the physiological relevance of in vitro tumor models.
We further developed biomimetic extracellular matrices (ECMs) with tunable porosity and stiffness to investigate cancer cell invasion and migration, incorporating key invasion biomarkers such as epithelial–mesenchymal transition (EMT). In parallel, we designed microfluidic devices capable of measuring the viscoelastic properties of breast cancer spheroids under dynamic compression. These studies revealed that benign tissues exhibit higher elasticity and viscosity compared to malignant ones. Moreover, differences in relaxation behavior and morphology among malignant spheroids were correlated with cytoskeletal organization and cell–cell adhesion strength.
Beyond these developments, we introduced several novel microscale platforms for investigating cell invasion under physiological conditions. Notably, we created a 3D matrix-based microfluidic system that uncovered a synergistic relationship between interstitial flow (IF) and transforming growth factor-β (TGF-β) in promoting EMT in lung cancer spheroids. By closely replicating in vivo microenvironments, this platform enables real-time analysis of cancer cell signaling and invasion, offering key insights into the mechanobiology of tumor progression.
Furthermore, we developed a programmable, multifunctional 3D cancer cell invasion “microbucket-hydrogel” platform by integrating function-variable microbuckets with ECM-like hydrogels. This adaptable system effectively mimics dynamic tumor microenvironments and provides a versatile tool for cancer research, biofabrication, cell signaling studies, and drug screening.
As part of this project, we also organized several interdisciplinary workshops in collaboration with medical centers and TU Delft, facilitating knowledge exchange on tumor-on-a-chip technologies and our findings with leading partners and collaborators in oncology and cancer invasion research.
Looking ahead, a key direction for this research is the development of heterogeneous spheroids that replicate the diverse cellular populations within complex tumors, further enhancing the physiological relevance of in vitro tumor models.
Metastasis remains the leading cause of cancer-related mortality, yet physiologically relevant tumor models for studying this process are limited. Conventional 2D and 3D models, though widely used, fail to capture the complexity and heterogeneity of the tumor microenvironment (TME), particularly the spatial organization of tumor–stromal interactions and the dynamic secretion and diffusion of cytokines.
In this project, we developed programmable, adaptable 3D in vitro microplatforms that emulate a dynamically evolving and spatially localized TME. We investigated epithelial–mesenchymal transition (EMT) in lung cancer spheroids under the influence of transforming growth factor-beta (TGF-β) and extracellular matrix (ECM) stiffness. Using in situ video microscopy, we examined cancer cell migration modes under varying TME conditions. To deepen insights into tumor mechanics, we also established a high-throughput microfluidic system to characterize the biophysical properties of tissues and tumors at the microscale.
Using these advanced platforms, we generated multi-cancer cell spheroids and revealed the interplay between single-cell and collective migration during EMT. Our system enables precise temporal and spatial control of 3D cancer cell invasion, overcoming key limitations of traditional models. By integrating microfluidics with soft matter engineering, we present a versatile approach for investigating 3D cancer invasion and replicating the dynamic evolution of the TME. This platform has broad applications in cancer research, biofabrication, and drug discovery, advancing personalized cancer therapy and enabling physiologically accurate 3D in vivo–like environments.
We further explored how interstitial flow and cell–matrix interactions influence cancer migration and spheroid invasion, providing mechanistic insights into how biophysical cues shape tumor behavior. By replicating key TME parameters—ECM stiffness, TGF-β signaling, and mechanical stress—we demonstrate a new methodology for characterizing cancer invasion and establish a direct correlation between tissue mechanics and metastatic potential.
Overall, this work deepens our understanding of cancer cell migration in complex TMEs and integrates experimental and engineering approaches to reveal how physical and biochemical cues jointly drive tumor progression and invasion.
In this project, we developed programmable, adaptable 3D in vitro microplatforms that emulate a dynamically evolving and spatially localized TME. We investigated epithelial–mesenchymal transition (EMT) in lung cancer spheroids under the influence of transforming growth factor-beta (TGF-β) and extracellular matrix (ECM) stiffness. Using in situ video microscopy, we examined cancer cell migration modes under varying TME conditions. To deepen insights into tumor mechanics, we also established a high-throughput microfluidic system to characterize the biophysical properties of tissues and tumors at the microscale.
Using these advanced platforms, we generated multi-cancer cell spheroids and revealed the interplay between single-cell and collective migration during EMT. Our system enables precise temporal and spatial control of 3D cancer cell invasion, overcoming key limitations of traditional models. By integrating microfluidics with soft matter engineering, we present a versatile approach for investigating 3D cancer invasion and replicating the dynamic evolution of the TME. This platform has broad applications in cancer research, biofabrication, and drug discovery, advancing personalized cancer therapy and enabling physiologically accurate 3D in vivo–like environments.
We further explored how interstitial flow and cell–matrix interactions influence cancer migration and spheroid invasion, providing mechanistic insights into how biophysical cues shape tumor behavior. By replicating key TME parameters—ECM stiffness, TGF-β signaling, and mechanical stress—we demonstrate a new methodology for characterizing cancer invasion and establish a direct correlation between tissue mechanics and metastatic potential.
Overall, this work deepens our understanding of cancer cell migration in complex TMEs and integrates experimental and engineering approaches to reveal how physical and biochemical cues jointly drive tumor progression and invasion.