Chemotherapy‐Enriched THBS2‐Deficient Cancer Stem Cells Drive Hepatocarcinogenesis through Matrix Softness Induced Histone H3 Modifications

Abstract

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.

THBS2 is Closely Related to the Poor Prognosis and Immune Cell Infiltration of Gastric Cancer

“…THBS2, a member of the thrombospondin family of multidomain and secreted multicellular calcium-binding glycoproteins, mediates cell-to-cell and cell-to-matrix interactions (Ng et al, 2021). The expression level of THBS2 in colon cancer was significantly increased, and the higher the expression level of THBS2, the worse the OS of patients (Wang et al, 2016b).…”

Prognostic and Immunological Role of THBS2 in Colorectal cancer

“…THBS2 is a member of secreted calcium-binding glycoproteins mediating cell-cell and cell-matrix interactions. THBS2 is recognized as an ECM-modifying enzyme and functions as a suppressor of tumor growth and angiogenesis by interacting with matrix serine proteases and MMPs in numerous cancers [ 16 ]. On the other hand, the oncogenic role of THBS2 have also been observed [ 4 , 7 ].…”

The Role of Cancer-Associated Fibroblast as a Dynamic Player in Mediating Cancer Stemness in the Tumor Microenvironment

“…A fundamental function of activated fibroblast is its participation in ECM homeostasis by synthesizing ECM constituents, including collagen and fibronectin, and producing ECM-degrading proteases to aid communication and trafficking of inflammatory cells ( Kalluri, 2016 ). While the impact of matrix stiffness remains controversial as studies indicate both softer matrix ( Tan et al, 2014 ; Ng et al, 2021 ) and stiffer matrix ( Pang et al, 2016 ; Tao et al, 2021 ) can instigate cancer stemness, the role of CAF in mediating the stiffness of the ECM illustrates its ability to affect stemness. Indeed, collagen deposited by CAF functions as a mechano signal to escalate stem cell markers and spheroid formation ability ( Cazet et al, 2018 ).…”

“…The ability of CAF to mediate matrix stiffness via MMPs may be an area of interest. Given matrix stiffness regulates stemness and chemoresistance ( Ng et al, 2021 ); how a CAF-mediated ECM fosters a niche that endows chemoresistance warrants further investigations.…”