Bioengineered Hydrogels Recapitulate Fibroblast Heterogeneity in Cancer

• Published in: Advanced science 2024-05, Vol.11 (20), p.e2307129-n/a
• Main Authors: Ho, Nicholas Ching Wei, Yap, Josephine Yu Yan, Zhao, Zixuan, Wang, Yunyun, Fernando, Kanishka, Li, Constance H, Kwang, Xue Lin, Quah, Hong Sheng, Arcinas, Camille, Iyer, N. Gopalakrishna, Fong, Eliza Li Shan
• Format: Article
• Language: English
• Subjects: Antigens; Bioengineering - methods; CAF heterogeneity; Cancer-Associated Fibroblasts - metabolism; Cancer-Associated Fibroblasts - pathology; cancer‐associated fibroblasts; Chemokines; Cytokines; Extracellular matrix; Fibroblasts; Genes; Genetic engineering; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; Humans; hydrogel; Hydrogels; Hydrogels - chemistry; Immunotherapy; inflammatory CAF; Ligands; Medical prognosis; Metabolism; myofibroblastic CAF; Pancreatic cancer; Patients; Transcription factors; Tumor Microenvironment - genetics; Tumors
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202307129

Recently mapped transcriptomic landscapes reveal the extent of heterogeneity in cancer‐associated fibroblasts (CAFs) beyond previously established single‐gene markers. Functional analyses of individual CAF subsets within the tumor microenvironment are critical to develop more accurate CAF‐targeting therapeutic strategies. However, there is a lack of robust preclinical models that reflect this heterogeneity in vitro. In this study, single‐cell RNA sequencing datasets acquired from head and neck squamous cell carcinoma tissues to predict microenvironmental and cellular features governing individual CAF subsets are leveraged. Some of these features are then incorporated into a tunable hyaluronan‐based hydrogel system to culture patient‐derived CAFs. Control over hydrogel degradability and integrin adhesiveness enabled derivation of the predominant myofibroblastic and inflammatory CAF subsets, as shown through changes in cell morphology and transcriptomic profiles. Last, using these hydrogel‐cultured CAFs, microtubule dynamics are identified, but not actomyosin contractility, as a key mediator of CAF plasticity. The recapitulation of CAF heterogeneity in vitro using defined hydrogels presents unique opportunities for advancing the understanding of CAF biology and evaluation of CAF‐targeting therapeutics. In this study, Ho and co‐workers leveraged the use of bioengineered hyaluronan hydrogels to recapitulate cancer‐associated fibroblast (CAF) heterogeneity in vitro in head and neck squamous cell carcinoma. Tuning hydrogel degradation alters microtubule dynamics in CAFs, which plays a key role in the plasticity between myofibroblastic and inflammatory CAF subsets.