Immobilized Transforming Growth Factor-Beta 1 in a Stiffness-Tunable Artificial Extracellular Matrix Enhances Mechanotransduction in the Epithelial Mesenchymal Transition of Hepatocellular Carcinoma

• Published in: ACS applied materials & interfaces Vol. 11; no. 16; pp. 14660 - 14671
• Main Authors: Tang, Rui-Zhi, Gu, Sai-Sai, Chen, Xin-Ting, He, Li-Jie, Wang, Kai-Ping, Liu, Xi-Qiu
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 24.04.2019
• Subjects: growth factor presentation; epithelial−mesenchymal transition; mechanotransduction; ECM mimicking; hepatocellular carcinoma
• ISSN: 1944-8244; 1944-8252
• DOI: 10.1021/acsami.9b03572

Cancer progression is regulated by multiple factors of extracellular matrix (ECM). Understanding how cancer cells integrate multiple signaling pathways to achieve specific behaviors remains a challenge because of the lack of appropriate models to copresent and modulate ECM properties. Here we proposed a strategy to build a thin biomaterial matrix by poly­(l-lysine) and hyaluronan as an artificial stiffness-tunable ECM. Transforming growth factor-beta 1 (TGF-β1) was used as a biochemical cue to present in an immobilized and spatially controlled manner, with a high loading efficiency of 90%. Either soft matrix with immobilized TGF-β1 (i-TGF) or bare stiff matrix could only promote HCC cells to form the epithelial phenotype, whereas stiff matrix with i-TGF was the only condition to induce the mesenchymal phenotype. Further investigation revealed that i-TGF increased the specific TGF-β1 receptor (TβRI) expression to activate PI3K pathway. i-TGF-TβRI interactions also promoted HCC cell adhesion to enlarge contact area for stiffness sensing, resulting in the raising expression of the mechano-sensor (β1 integrin). Mechanotransduction would then be enhanced by the β1 integrin/vinculin/p-FAK pathway, leading to a noble PI3K activation. Using our model, a novel mechanism was discovered to elucidate regulation of cell fates by coupling mechanotransduction and biochemical signaling.