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 threedimensional 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.

Automated summary

Hepatocellular carcinoma tissue exhibits mechanical heterogeneity, with increasing stiffness from the core to the invasion front. Liver cancer stem cells (LCSCs), which preferentially enrich the invasion front, also demonstrate the highest stiffness in the tumor. A stiffer matrix significantly enhances LCSC stemness, potentially mediated by Yes-associated protein signaling. Our findings reveal the relationship between matrix stiffness and LCSC stemness, contributing to the development of novel treatment approaches for liver cancer.