Rapid reprogramming of tumour cells into cancer stem cells on double-network hydrogels

• Published in: Nature biomedical engineering Vol. 5; no. 8; pp. 914 - 925
• Main Authors: Suzuka, Jun, Tsuda, Masumi, Wang, Lei, Kohsaka, Shinji, Kishida, Karin, Semba, Shingo, Sugino, Hirokazu, Aburatani, Sachiyo, Frauenlob, Martin, Kurokawa, Takayuki, Kojima, Shinya, Ueno, Toshihide, Ohmiya, Yoshihiro, Mano, Hiroyuki, Yasuda, Kazunori, Gong, Jian Ping, Tanaka, Shinya
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2021; Nature Publishing Group
• Subjects: 13/100; 13/89; 13/95; 14/5; 38/23; 38/39; 38/61; 38/70; 38/77; 631/1647/767/70; 631/67/71; 64/60; 692/4017; Animals; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedical materials; Biomedicine; Brain; Brain cancer; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain tumors; Cancer; Cell Differentiation; Cellular Reprogramming; ErbB Receptors - metabolism; Gene Expression Regulation, Neoplastic - drug effects; Glioblastoma; Glioblastoma - metabolism; Glioblastoma - pathology; Growth factors; Humans; Hydrogels; Hydrogels - chemistry; Hydrogels - pharmacology; Immunodeficiency; Kinases; Mice; Mice, SCID; Neoplastic Stem Cells - cytology; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - transplantation; Oct-4 protein; Osteopontin; Osteopontin - genetics; Osteopontin - metabolism; Phosphorylation; Phosphorylation - drug effects; Platelet-derived growth factor; Polymers - chemistry; Radiation therapy; Receptors; Signal Transduction - drug effects; Signal Transduction - genetics; Spheroids; Stem cell transplantation; Stem cells; Tumor cell lines; Tumor Cells, Cultured; Tumorigenicity; Tumors; Tyrosine
• ISSN: 2157-846X; 2157-846X
• DOI: 10.1038/s41551-021-00692-2

Cancer recurrence can arise owing to rare circulating cancer stem cells (CSCs) that are resistant to chemotherapies and radiotherapies. Here, we show that a double-network hydrogel can rapidly reprogramme differentiated cancer cells into CSCs. Spheroids expressing elevated levels of the stemness genes Sox2 , Oct3/4 and Nanog formed within 24 h of seeding the gel with cells from any of six human cancer cell lines or with brain cancer cells resected from patients with glioblastoma. Human brain cancer cells cultured on the double-network hydrogel and intracranially injected in immunodeficient mice led to higher tumorigenicity than brain cancer cells cultured on single-network gels. We also show that the double-network gel induced the phosphorylation of tyrosine kinases, that gel-induced CSCs from primary brain cancer cells were eradicated by an inhibitor of the platelet-derived growth factor receptor, and that calcium channel receptors and the protein osteopontin were essential for the regulation of gel-mediated induction of stemness in brain cancer cells. A double-network hydrogel can rapidly reprogramme differentiated tumour cells into cancer stem cells that display elevated tumorigenicity in vivo.