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.
