Figure 2.

Disorganized ECM modulate mechanical checkpoints in the liver TME

(A) A stiff ECM crosstalks with hepatocytes and HSCs, leading to increases in their rigidity, contractility, and geometrical confinement. Members of the disorganized ECM such as agrin, tenascin (TNCN), or osteopontin (OPN) activate their respective mechanosensory receptor integrins-lipoprotein related receptor-4 (Lrp4)-muscle-specific tyrosine kinase (MuSK), frizzled receptors (Fzds), or receptor tyrosine kinases (RTKs), respectively, to transmit biophysical signals. In response to stiff ECM, agrin stimulates integrin-FAK mechanosignaling and actomyosin-dependent RhoA activation, which potentiate the YAP/TAZ transcriptional program. TNCN induces nuclear β-catenin, and OPN via the integrin-EGFR pathway activates the MAPK-dependent transcription of genes that enhance tumorigenesis.

(B) Secreted proteins from the disorganized ECM also impact other cell types in the liver TME. For instance, agrin, perlecan, and OPN stimulate the VEGF-VEGFR2 pathway in liver endothelial cells, which increases shear stress and angiogenesis that favors tumor growth. These impacts transformed hepatocytes that further remodel the ECM. Therefore, a bidirectional network establishes a physical continuum between the extrinsic “disorganized ECM” and intrinsic “oncogenic behavior.”