Endotrophin and CD44-Mediated Heterotypic Signaling Mediates Tumor-Stroma Crosstalk and Facilitates Malignant Progression in Hepatocellular Carcinoma - PubMed
3 months ago
- #Tumor-Stroma Crosstalk
- #STAT3 Signaling
- #Hepatocellular Carcinoma
- Endotrophin (ETP) is a cleavage fragment of collagen VI α3 (COL6A3) and acts as a fibrotic and pro-tumorigenic factor in hepatocellular carcinoma (HCC).
- ETP serves as a diagnostic and prognostic biomarker in HCC, increasing throughout tumor development and promoting progression.
- CD44 was identified as an ETP receptor through peroxidase-catalyzed proximity labeling.
- ETP binding to CD44 activates STAT3 signaling, leading to epithelial-mesenchymal transition (EMT), proliferation, and sorafenib resistance.
- Hepatic stellate cell-derived ETP targets pericentral CD44+ tumor cells, inducing COL6A3 expression and sustaining ETP production via a STAT3-dependent feedback loop.
- Disruption of the ETP-CD44-STAT3 axis by CD44 knockout, STAT3 inhibition, or CD44-binding-deficient ETP mutants suppresses malignant phenotypes in vitro.
- In metabolic dysfunction-associated HCC, dual knockout of Col6a3 and Cd44 in mice reduced tumor burden, restored sorafenib sensitivity, and attenuated EMT, fibrosis, and steatotic-fibrotic niche formation.
- The ETP-CD44-STAT3 axis is a key driver of tumor-stroma crosstalk, linking fibro-inflammation to malignancy, and represents a therapeutic target in obesity-associated liver cancer.