Matrix Stiffness Potentiates Stemness of Liver Cancer Stem Cells Possibly via the Yes-Associated Protein Signal

A hepatocellular carcinoma tissue has mechanical heterogeneity, where the stiffness gradually increases from the core to the invasion front. Furthermore, there is evidence that stem cells from liver cancer (LCSCs) preferentially enrich the invasion front, exhibiting the stiffest modulus in the tumor. LCSCs have the features of stem/progenitor cells and play a vital part in liver cancer development. However, whether matrix stiffness affects LCSC stemness remains unclear. Here, we established a three-dimensional hydrogel for culturing LCSCs to simulate the stiffness of the core and the invasion front of a liver cancer tissue. The results showed that a stiffer matrix (72.2 ± 0.90 kPa) significantly potentiated LCSC stemness as compared with a soft matrix (7.7 ± 0.41 kPa). Moreover, Yes-associated protein signaling might mediate this promotion. Together, our findings illustrate the relationship between matrix stiffness and LCSC stemness, which may aid the production of novel treatment approaches against liver cancer.