Abstract
Patient-derived in vivo models of human cancer have become a reality, yet their turnaround time is inadequate for clinical applications. Therefore, tailored ex vivo models that faithfully recapitulate in vivo tumour biology are urgently needed. These may especially benefit the management of pancreatic ductal adenocarcinoma (PDAC), where therapy failure has been ascribed to its high cancer stem cell (CSC) content and high density of stromal cells and extracellular matrix (ECM). To date, these features are only partially reproduced ex vivo using organoid and sphere cultures. We have now developed a more comprehensive and highly tuneable ex vivo model of PDAC based on the 3D co-assembly of peptide amphiphiles (PAs) with custom ECM components (PA-ECM). These cultures maintain patient-specific transcriptional profiles and exhibit CSC functionality, including strong in vivo tumourigenicity. User-defined modification of the system enables control over niche-dependent phenotypes such as epithelial-to-mesenchymal transition and matrix deposition. Indeed, proteomic analysis of these cultures reveals improved matrisome recapitulation compared to organoids. Most importantly, patient-specific in vivo drug responses are better reproduced in self-assembled cultures than in other models. These findings support the use of tuneable self-assembling platforms in cancer research and pave the way for future precision medicine approaches.
Highlights
Patient-derived in vivo models of human cancer have become a reality, yet their turnaround time is inadequate for clinical applications
Similar structures were observed when peptide amphiphiles (PAs) are co-assembled with collagen, fibronectin, laminin and hyaluronan (Fig. 1e), which we subsequently used as our standard PA-extracellular matrix (ECM) hydrogels
The Young’s modulus of PAECM co-assembled hydrogels was around 1 kPa, which is within the range of pancreatic Patient-derived xenografts (PDX) tissues (Fig. 1h), as well as published data for primary PDAC26, while Matrigel, used for the generation of organoids, was much softer than pancreatic ductal adenocarcinoma (PDAC) tissue at around 90 Pa
Summary
Patient-derived in vivo models of human cancer have become a reality, yet their turnaround time is inadequate for clinical applications. Tailored ex vivo models that faithfully recapitulate in vivo tumour biology are urgently needed These may especially benefit the management of pancreatic ductal adenocarcinoma (PDAC), where therapy failure has been ascribed to its high cancer stem cell (CSC) content and high density of stromal cells and extracellular matrix (ECM). Ex vivo platforms based on hybrid biomaterials, such as methacrylated hyaluronan[10] and gelatin methacryloyl[11], have shown excellent physical tuneability, but have limitations in mimicking biological signals other than hyaluronan and gelatin (denatured collagen) Advances in biofabrication, such as 3D printing[12] and microfluidic systems[13] have enabled control over PDAC culture microarchitecture and fluid flow, respectively. To enhance the molecular complexity and biological relevance of these matrices, we have established methodologies to use PAs to co-assemble with and organise ECM macromolecules and other proteins, such as keratins[19] into hydrogel matrices with tuneable signalling capabilities[20], structures[21,22] and physical properties[23]
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