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

David Osuna de la Peña, Sara Maria David Trabulo, Estelle Collin, Ying Liu, Shreya Sharma, Marianthi Tatari, Diana Behrens, Mert Erkan, Rita T. Lawlor, Aldo Scarpa, Christopher Heeschen (), Alvaro Mata () and Daniela Loessner ()
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David Osuna de la Peña: Barts Cancer Institute, Queen Mary University of London
Sara Maria David Trabulo: Barts Cancer Institute, Queen Mary University of London
Estelle Collin: Queen Mary University of London
Ying Liu: Barts Cancer Institute, Queen Mary University of London
Shreya Sharma: Barts Cancer Institute, Queen Mary University of London
Marianthi Tatari: Barts Cancer Institute, Queen Mary University of London
Diana Behrens: EPO – Experimental Pharmacology and Oncology GmbH
Mert Erkan: Koç University School of Medicine
Rita T. Lawlor: University of Verona
Aldo Scarpa: University of Verona
Christopher Heeschen: Shanghai Jiao Tong University School of Medicine
Alvaro Mata: Queen Mary University of London
Daniela Loessner: Barts Cancer Institute, Queen Mary University of London

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25921-9

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