Liver tumor-initiating cells initiate the formation of a stiff cancer stem cell microenvironment niche by secreting LOX

This study identified crosslinked collagen mediated by LOX as an essential microenvironment niche for liver tumor-initiating cells through ITGA7-FAK-ERK1/2 signaling pathway by an autocrine mechanism. Accumulating evidence has shown that the traits of tumor-initiating cells (TICs) are controlled by the microenvironment niches (MENs), but the composition and remodeling mechanisms of the MENs of TICs are poorly defined. Here, we report that the voltage-gated calcium channel alpha 2 delta 1 subunit-positive TICs of hepatocellular carcinoma (HCC) specifically secret lysyl oxidase (LOX), which leads to the cross-linking of collagen, forming a stiff extracellular matrix (ECM) that is sufficient to drive the formation of TICs with a stiff mechanical trait and is subsequently required for the maintenance the properties of HCC TICs. Furthermore, the cross-linked collagen results in the upregulation of integrin alpha 7 (ITGA7), increased phosphorylation of FAK and extracellular signal-regulated kinase 1/2 (ERK1/2). Inhibition of ITGA7 abolishes all the effects of cross-linked collagen mediated by LOX. Hence, the alpha 2 delta 1(+) HCC TICs initiate ECM remodeling by secreting LOX to create a stiff MEN of TIC with cross-linked collagen, which drives the acquisition and subsequent maintenance of the properties of HCC TICs through ITGA7-FAK-ERK1/2 signaling pathway.

Automated summary

This study identifies crosslinked collagen mediated by LOX as a crucial component of the microenvironment niche for liver tumor-initiating cells. Through the ITGA7-FAK-ERK1/2 signaling pathway, LOX is involved in regulating the traits of tumor-initiating cells. These findings provide insights into the composition and remodeling mechanisms of the microenvironment niches of tumor-initiating cells.