Periodic Reporting for period 1 - Design2Guide (Cell-instructive matrices to deconstruct tumour tissues)
Reporting period: 2024-01-01 to 2025-06-30
Context: The project addresses a clinical problem with an innovative approach. Pancreatic cancer is one of the deadliest cancers and only 10% of people diagnosed with this disease survive 5 years after diagnosis. To find better therapies, patient-specific models that mimic the biology of tumour tissues and interactions between different cell types are needed. The objective of ‘Design2Guide’ is to build a controllable platform for studying the human disease in the laboratory. It is expected that the new platform will be used to discover better ways of treating the disease.
Background: Pancreatic cancer has a fibrotic, or scar-like, microenvironment and a collagenous extracellular matrix, which correlate with poor prognosis and patient survival. Important cell functions are associated with the presence of certain matrix proteins. Current experimental models fail to replicate the specific microenvironment and matrix of this disease. Several studies, including our previous research, highlight the key role of many matrix components in driving cell functions, emphasizing the need to design cell-instructive matrices.
The problem: The extracellular matrix of pancreatic cancer is very complex and consists of many fibrotic proteins, including collagens, proteoglycans, laminins and fibronectin. In tumour tissues, the remodelling of the matrix induces the growth of cancer cells, which in turn interact with the matrix through integrins, a major class of cell surface and adhesion receptors. Integrins facilitate cell-cell and cell-matrix interactions in the tumour microenvironment and guide signalling pathways, leading to disease progression and metastasis. Thus, integrins have become an important target for anti-cancer therapeutics, which are tested in clinical trials. Despite the critical role of the adhesion requirements in guiding cell behaviour, a robust engineering approach to mimic the specific adhesion profile of cancer cells and instruct the disease-relevant integrin profile in experimental models is missing.
The solution: ‘Design2Guide’ integrates a rational design strategy of a disease-relevant 3D model based on two fundamental aspects: firstly, a minimalistic synthetic matrix that incorporates essential matrix components of tumour tissues in the form of polyethylene glycol hydrogels, and secondly, the capacity to instruct integrin profiles and subsequently activate signalling pathways. The ‘Design2Guide’ platform addresses the need for developing cell-instructive matrices to deconstruct tumour tissues and study the cell-cell and cell-matrix interactions present in people diagnosed with pancreatic cancer. The research will benefit scientists in the field of tumour tissue engineering, an interdisciplinary research area combining tissue engineering and cell biology.
Significance: The long-term impact of the new platform will be a generalized approach for targeting tissue-level adhesion requirements in synthetic matrices, enabling new knowledge about how to treat solid tumours.
Background: Pancreatic cancer has a fibrotic, or scar-like, microenvironment and a collagenous extracellular matrix, which correlate with poor prognosis and patient survival. Important cell functions are associated with the presence of certain matrix proteins. Current experimental models fail to replicate the specific microenvironment and matrix of this disease. Several studies, including our previous research, highlight the key role of many matrix components in driving cell functions, emphasizing the need to design cell-instructive matrices.
The problem: The extracellular matrix of pancreatic cancer is very complex and consists of many fibrotic proteins, including collagens, proteoglycans, laminins and fibronectin. In tumour tissues, the remodelling of the matrix induces the growth of cancer cells, which in turn interact with the matrix through integrins, a major class of cell surface and adhesion receptors. Integrins facilitate cell-cell and cell-matrix interactions in the tumour microenvironment and guide signalling pathways, leading to disease progression and metastasis. Thus, integrins have become an important target for anti-cancer therapeutics, which are tested in clinical trials. Despite the critical role of the adhesion requirements in guiding cell behaviour, a robust engineering approach to mimic the specific adhesion profile of cancer cells and instruct the disease-relevant integrin profile in experimental models is missing.
The solution: ‘Design2Guide’ integrates a rational design strategy of a disease-relevant 3D model based on two fundamental aspects: firstly, a minimalistic synthetic matrix that incorporates essential matrix components of tumour tissues in the form of polyethylene glycol hydrogels, and secondly, the capacity to instruct integrin profiles and subsequently activate signalling pathways. The ‘Design2Guide’ platform addresses the need for developing cell-instructive matrices to deconstruct tumour tissues and study the cell-cell and cell-matrix interactions present in people diagnosed with pancreatic cancer. The research will benefit scientists in the field of tumour tissue engineering, an interdisciplinary research area combining tissue engineering and cell biology.
Significance: The long-term impact of the new platform will be a generalized approach for targeting tissue-level adhesion requirements in synthetic matrices, enabling new knowledge about how to treat solid tumours.
Current organoid technologies are powerful for modelling tissue organization and disease, but they offer limited control over cell states beyond genetic or environmental setups. Approaches that rely on genetic engineering or exogenous biochemical factors lack flexibility and fail to accurately reflect the complexity and plasticity of in vivo systems. A major unmet need in the field is a framework that can steer transcriptional programs from the outside in, using defined environmental inputs to drive cell behaviour. Addressing this challenge will unlock new possibilities for modelling development, disease progression, and therapeutic response with greater fidelity and control.
In our work, we developed a strategy to program organoid state transitions by systematically modelling how matrix-anchored adhesion cues influence gene expression. Using epithelial-mesenchymal transition as a well-characterized paradigm, we identified minimal matrix conditions that reproducibly induce epithelial-mesenchymal-like transcriptional changes across multiple donors. Our work shows that small, quantitative shifts in the extracellular environment drive large-scale, emergent reprogramming of cell states. While epithelial-mesenchymal transition served as the proof-of-concept, the underlying platform enables generalizable, quantitative control over organoid behaviour without relying on genetic editing or exogenous signalling factors.
In our work, we developed a strategy to program organoid state transitions by systematically modelling how matrix-anchored adhesion cues influence gene expression. Using epithelial-mesenchymal transition as a well-characterized paradigm, we identified minimal matrix conditions that reproducibly induce epithelial-mesenchymal-like transcriptional changes across multiple donors. Our work shows that small, quantitative shifts in the extracellular environment drive large-scale, emergent reprogramming of cell states. While epithelial-mesenchymal transition served as the proof-of-concept, the underlying platform enables generalizable, quantitative control over organoid behaviour without relying on genetic editing or exogenous signalling factors.
Our findings establish a new paradigm for the bottom-up control of complex cell states through the rational design of extracellular environments. We established a scalable strategy for probing how environmental cues shape gene regulatory networks and can be adapted to study diverse state transitions such as differentiation, drug resistance, or immune evasion. Moreover, the integration of quantitative modelling with bottom-up matrix design lays the foundation for developing responsive or adaptive culture systems, accelerating efforts in personalized medicine, regenerative engineering, and systems-level interrogation of cell-matrix interactions in disease.