A self‐assembled 3D model demonstrates how stiffness educates tumor cell phenotypes and therapy resistance in pancreatic cancer

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

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‐E3Yh) with divalent cations to create hydrogels with mechanical properties and ultrastructure similar to native tumor ECM. It is shown that stiffening of PA‐E3Yh 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.

Citation

Liu, Y., Okesola, B. O., de la Peña, D. O., Li, W., Lin, M., Trabulo, S. M. D., Tatari, M., Lawlor, R. T., Scarpa, A., Wang, W., Knight, M., Loessner, D., Heeschen, C., Mata, A., & Pearce, O. M. (in press). A self‐assembled 3D model demonstrates how stiffness educates tumor cell phenotypes and therapy resistance in pancreatic cancer. Advanced Healthcare Materials, Article 2301941. https://doi.org/10.1002/adhm.202301941

• Journal Article Type: Article
• Acceptance Date: Jan 25, 2024
• Online Publication Date: Mar 12, 2024
• Deposit Date: Mar 17, 2024
• Publicly Available Date: Mar 13, 2025
• Journal: Advanced Healthcare Materials
• Print ISSN: 2192-2640
• Electronic ISSN: 2192-2659
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Article Number: 2301941
• DOI: https://doi.org/10.1002/adhm.202301941
• Keywords: 3D disease model; drug resistance; pancreatic cancer; peptide amphiphile; self-assembling hydrogels; tumor microenvironment; tunable stiffness
• Public URL: https://nottingham-repository.worktribe.com/output/32470432
• Additional Information: Received: 2023-08-17; Published: 2024-03-12