Bioengineered 3D models of human pancreatic cancer recapitulate in vivo tumour biology

Osuna de la Peña, David; Trabulo, Sara Maria David; Collin, Estelle; Liu, Ying; Sharma, Shreya; Tatari, Marianthi; Behrens, Diana; Erkan, Mert; Lawlor, Rita T.; Scarpa, Aldo; Heeschen, Christopher; Mata, Alvaro; Loessner, Daniela

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.

Citation

Osuna de la Peña, D., Trabulo, S. M. D., Collin, E., Liu, Y., Sharma, S., Tatari, M., …Loessner, D. (2021). Bioengineered 3D models of human pancreatic cancer recapitulate in vivo tumour biology. Nature Communications, 12, Article 5623. https://doi.org/10.1038/s41467-021-25921-9

• Journal Article Type: Article
• Acceptance Date: Aug 25, 2021
• Online Publication Date: Sep 24, 2021
• Publication Date: 2021-12
• Deposit Date: Oct 20, 2021
• Publicly Available Date: Oct 20, 2021
• Journal: Nature Communications
• Electronic ISSN: 2041-1723
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Article Number: 5623
• DOI: https://doi.org/10.1038/s41467-021-25921-9
• Keywords: General Physics and Astronomy; General Biochemistry, Genetics and Molecular Biology; General Chemistry
• Public URL: https://nottingham-repository.worktribe.com/output/6504875
• Publisher URL: https://www.nature.com/articles/s41467-021-25921-9