The physical microenvironment is a critical mediator of
tumor behavior. However, detailed biological and mechanistic insight is lacking. The present study reveals the role of
chemotherapy-enriched CD133+
liver cancer stem cells (CSCs) with THBS2 deficiency. This subpopulation of cells contributes to a more aggressive
cancer and functional stemness phenotype in
hepatocellular carcinoma (HCC) by remodeling the extracellular matrix (ECM) through the regulation of
matrix metalloproteinase (
MMP) activity,
collagen degradation, and matrix stiffness. The local soft spots created by these liver CSCs can enhance stemness and drug resistance and provide a route of escape to facilitate HCC
metastasis. Interestingly, a positive feed-forward loop is identified where a local soft spot microenvironment in the HCC
tumor is enriched with CD133 expressing cells that secrete markedly less ECM-modifying THBS2 upon
histone H3 modification at its promoter region, allowing the maintenance of a localized soft spot matrix. Clinically, THBS2 deficiency is also correlated with low HCC survival, where high levels of CSCs with low THBS2 expression in HCC are associated with decreased
collagen fiber deposits and an invasive
tumor front. The findings have implications for the treatment of
cancer stemness and for the prevention of
tumor outgrowth through disseminated
tumor cells.