A Self-Assembled 3D Model Demonstrates How Stiffness Educates Tumor Cell Phenotypes and Therapy Resistance in Pancreatic Cancer

Ying Liu; Babatunde O Okesola; David Osuna de la Peña; Weiqi Li; Meng-Lay Lin; Sara Trabulo; Marianthi Tatari; Rita T Lawlor; Aldo Scarpa; Wen Wang; Martin Knight; Daniela Loessner; Christopher Heeschen; Alvaro Mata; Oliver M T Pearce

doi:10.1002/adhm.202301941

A Self-Assembled 3D Model Demonstrates How Stiffness Educates Tumor Cell Phenotypes and Therapy Resistance in Pancreatic Cancer

Adv Healthc Mater. 2024 Mar 12:e2301941. doi: 10.1002/adhm.202301941. Online ahead of print.

Authors

Ying Liu^{1

2}, Babatunde O Okesola³, David Osuna de la Peña^{1

2}, Weiqi Li², Meng-Lay Lin¹, Sara Trabulo¹, Marianthi Tatari¹, Rita T Lawlor^{4

5}, Aldo Scarpa^{4

5}, Wen Wang², Martin Knight^{6

7}, Daniela Loessner^{1

8

9

10}, Christopher Heeschen¹¹, Alvaro Mata^{12

13

14}, Oliver M T Pearce¹

Affiliations

¹ Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK.
² School of Engineering and Materials Science, Queen Mary University of London, London, E1 4NS, UK.
³ School of Life Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, NG7 2RD, UK.
⁴ Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, 37134, Italy.
⁵ ARC-Net, Applied Research on Cancer Centre, University of Verona, Verona, 37134, Italy.
⁶ Centre for Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London, E1 4NS, UK.
⁷ Centre for Predictive in vitro Models, Queen Mary University of London, London, E1 4NS, UK.
⁸ Department of Chemical and Biological Engineering, Faculty of Engineering, Monash University, Melbourne, VIC, 3800, Australia.
⁹ Department of Materials Science and Engineering, Faculty of Engineering, Monash University, Melbourne, VIC, 3800, Australia.
¹⁰ Department of Anatomy and Developmental Biology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, 3800, Australia.
¹¹ Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute - FPO - IRCCS, Candiolo (TO), 10060, Italy.
¹² School of Pharmacy, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.
¹³ Biodiscovery Institute, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.
¹⁴ Department of Chemical and Environmental Engineering, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.

PMID: 38471128
DOI: 10.1002/adhm.202301941

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense and stiff extracellular matrix (ECM) associated with tumor progression and therapy resistance. To further the understanding of how stiffening of the tumor microenvironment (TME) contributes to aggressiveness, a three-dimensional (3D) self-assembling hydrogel disease model is developed based on peptide amphiphiles (PAs, PA-E3Y) designed to tailor stiffness. The model displays nanofibrous architectures reminiscent of native TME and enables the study of the invasive behavior of PDAC cells. Enhanced tuneability of stiffness is demonstrated by interacting thermally annealed aqueous solutions of PA-E3Y (PA-E3Y_h) with divalent cations to create hydrogels with mechanical properties and ultrastructure similar to native tumor ECM. It is shown that stiffening of PA-E3Y_h hydrogels to levels found in PDAC induces ECM deposition, promotes epithelial-to-mesenchymal transition (EMT), enriches CD133⁺/CXCR4⁺ cancer stem cells (CSCs), and subsequently enhances drug resistance. The findings reveal how a stiff 3D environment renders PDAC cells more aggressive and therefore more faithfully recapitulates in vivo tumors.

Keywords: 3D disease model; drug resistance; pancreatic cancer; peptide amphiphile; self‐assembling hydrogels; tumor microenvironment; tunable stiffness.

Abstract

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