A niche-mimicking polymer hydrogel-based approach to identify molecular targets for tackling human pancreatic cancer stem cells

Inflammation and Regeneration

Research Article

Shinji Tanaka¹  Mariko Nagane²  Kouichi Tabu²  Yoshitaka Murota²  Tetsuya Taga²  Mei Wu³  Mark Bradley³  Mithun Santra³  Seshasailam Venkateswaran³ 

[1] Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-Ku, 113-8519, Tokyo, Japan;Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45, Yushima, Bunkyo-Ku, 113-8510, Tokyo, Japan;School of Chemistry, University of Edinburgh, Joseph Black Building, West Mains Road, EH9 3FJ, Edinburgh, UK;

关键词: Cancer stem cells (CSCs);    Niche mimicry;    Synthetic polymer;    Polymer microarray;    Hydrogel;    Biomaterial;   

DOI  :  10.1186/s41232-023-00296-0

 received in 2023-06-19, accepted in 2023-09-10,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundPancreatic adenocarcinoma (PAAD) is one of the most fatal human cancers, but effective therapies remain to be established. Cancer stem cells (CSCs) are highly resistant to anti-cancer drugs and a deeper understanding of their microenvironmental niche has been considered important to provide understanding and solutions to cancer eradication. However, as the CSC niche is composed of a wide variety of biological and physicochemical factors, the development of multidisciplinary tools that recapitulate their complex features is indispensable. Synthetic polymers have been studied as attractive biomaterials due to their tunable biofunctionalities, while hydrogelation technique further renders upon them a diversity of physical properties, making them an attractive tool for analysis of the CSC niche.MethodsTo develop innovative materials that recapitulate the CSC niche in pancreatic cancers, we performed polymer microarray analysis to identify niche-mimicking scaffolds that preferentially supported the growth of CSCs. The niche-mimicking activity of the identified polymers was further optimized by polyethylene glycol (PEG)-based hydrogelation. To reveal the biological mechanisms behind the activity of the optimized hydrogels towards CSCs, proteins binding onto the hydrogel were analyzed by liquid chromatography with tandem mass spectrometry (LC–MS/MS), and the potential therapeutic targets were validated by looking at gene expression and patients’ outcome in the TCGA database.ResultsPA531, a heteropolymer composed of 2-methoxyethyl methacrylate (MEMA) and 2-(diethylamino)ethyl methacrylate (DEAEMA) (5.5:4.5) that specifically supports the growth and maintenance of CSCs was identified by polymer microarray screening using the human PAAD cell line KLM1. The polymer PA531 was converted into five hydrogels (PA531-HG1 to HG5) and developed to give an optimized scaffold with the highest CSC niche-mimicking activities. From this polymer that recapitulated CSC binding and control, the proteins fetuin-B and angiotensinogen were identified as candidate target molecules with clinical significance due to the correlation between gene expression levels and prognosis in PAAD patients and the proteins associated with the niche-mimicking polymer.ConclusionThis study screened for biofunctional polymers suitable for recapitulation of the pancreatic CSC niche and one hydrogel with high niche-mimicking abilities was successfully fabricated. Two soluble factors with clinical significance were identified as potential candidates for biomarkers and therapeutic targets in pancreatic cancers. Such a biomaterial-based approach could be a new platform in drug discovery and therapy development against CSCs, via targeting of their niche.

【 授权许可】

CC BY   
© Japanese Society of Inflammation and Regeneration 2023

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