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Authors
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Peerani, E.; Candido, J. B.; Maniati, E.; Tomás-Bort, E.; Sharma, S.; Clegg, J.; Kocher, H. M.; Wang, J.; Curvello, R.; Lössner, D.
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Title
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Matrix stiffness shapes transcriptional profiles and drug responses of pancreatic cancer cells
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Date
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01.01.2026
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Number
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0
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Abstract
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Pancreatic cancer tissues are made of different cell populations surrounded by a dense extracellular matrix. The stiff cancerous matrix impairs the diffusion of cytotoxic drugs, contributing to poor outcomes for patients. Matrix-targeting therapies normalise the extracellular matrix and, therefore, cell-matrix interactions. However, our knowledge of how matrix stiffness influences cancer cell and transcriptional dynamics and responses to anti-cancer compounds is incomplete. Here we developed a 3D cancer model to replicate the stiffness of patient-derived tissues and evaluated the effects of matrix-targeting compounds. Transcriptomic analyses showed that matrix stiffness regulated matrisome-related genes, cytokines and chemokines. The inclusion of stromal cells further increased the mechanical properties of our 3D cancer model. Treatment with the ROCK inhibitor fasudil induced matrix softening and improved sensitivity of cancer and stromal cells to cytotoxic treatment, whereas inhibition of matrix metalloproteinases disrupted cancer cell invasion. Our results indicate that matrix stiffness impacts cancer cell profiles, and targeting the cancerous matrix may lead to improved combination therapies for pancreatic cancer.
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Publisher
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Elsevier
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Wikidata
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Citation
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Acta Biomaterialia 210 (2026) 67-81
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DOI
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https://doi.org/10.1016/j.actbio.2025.12.020
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Tags
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