Engineered matrices reveal stiffness-mediated chemoresistance in patient-derived pancreatic cancer organoids.

Autor: LeSavage BL; Department of Bioengineering, Stanford University, Stanford, CA, USA., Zhang D; Department of Chemical Engineering, Stanford University, Stanford, CA, USA., Huerta-López C; Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA., Gilchrist AE; Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA., Krajina BA; Department of Chemical Engineering, Stanford University, Stanford, CA, USA., Karlsson K; Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA., Smith AR; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA., Karagyozova K; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA., Klett KC; Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA., Huang MS; Department of Chemical Engineering, Stanford University, Stanford, CA, USA., Long C; Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA., Kaber G; Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Madl CM; Department of Bioengineering, Stanford University, Stanford, CA, USA.; Department of Materials Science and Engineering, University of Pennsylvania, Philadelphia, PA, USA., Bollyky PL; Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Curtis C; Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA., Kuo CJ; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA., Heilshorn SC; Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA. heilshorn@stanford.edu.
Jazyk: angličtina
Zdroj: Nature materials [Nat Mater] 2024 Aug; Vol. 23 (8), pp. 1138-1149. Date of Electronic Publication: 2024 Jul 04.
DOI: 10.1038/s41563-024-01908-x
Abstrakt: Pancreatic ductal adenocarcinoma (PDAC) is characterized by its fibrotic and stiff extracellular matrix. However, how the altered cell/extracellular-matrix signalling contributes to the PDAC tumour phenotype has been difficult to dissect. Here we design and engineer matrices that recapitulate the key hallmarks of the PDAC tumour extracellular matrix to address this knowledge gap. We show that patient-derived PDAC organoids from three patients develop resistance to several clinically relevant chemotherapies when cultured within high-stiffness matrices mechanically matched to in vivo tumours. Using genetic barcoding, we find that while matrix-specific clonal selection occurs, cellular heterogeneity is not the main driver of chemoresistance. Instead, matrix-induced chemoresistance occurs within a stiff environment due to the increased expression of drug efflux transporters mediated by CD44 receptor interactions with hyaluronan. Moreover, PDAC chemoresistance is reversible following transfer from high- to low-stiffness matrices, suggesting that targeting the fibrotic extracellular matrix may sensitize chemoresistant tumours. Overall, our findings support the potential of engineered matrices and patient-derived organoids for elucidating extracellular matrix contributions to human disease pathophysiology.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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