PAI-1 uncouples integrin-β1 from restrain by membrane-bound β-catenin to promote collagen fibril remodeling in obesity-related neoplasms

• Published in: Cell reports (Cambridge) 2024-08, Vol.43 (8), p.114527, Article 114527
• Main Authors: Lin, Li-Ling, Nayak, Bijaya, Osmulski, Pawel A., Wang, Exing, Wang, Chen-Pin, Valente, Philip T., Wang, Chiou-Miin, Tan, Xi, Santanam, Nalini, Wang, Tian-Li, Gaczynska, Maria E., Kost, Edward R., Huang, Tim H.-M., Kirma, Nameer B.
• Format: Article
• Language: English
• Subjects: Animals; beta Catenin - metabolism; Cell Membrane - metabolism; Collagen - metabolism; collagen fibrils; Collagen Type I - metabolism; DKK1; ECM remodeling; endometrial cancer; Endometrial Neoplasms - metabolism; Endometrial Neoplasms - pathology; Endometrium - metabolism; Endometrium - pathology; Epithelial Cells - metabolism; Epithelial Cells - pathology; Extracellular Matrix - metabolism; Female; Humans; Integrin beta1 - metabolism; integrin inside-out signaling; Intercellular Signaling Peptides and Proteins; obesity; Obesity - metabolism; Obesity - pathology; Osteonectin - genetics; Osteonectin - metabolism; PAI-1; Plasminogen Activator Inhibitor 1 - metabolism; Tissue Inhibitor of Metalloproteinase-2 - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114527

The paracrine actions of adipokine plasminogen activator inhibitor-1 (PAI-1) are implicated in obesity-associated tumorigenesis. Here, we show that PAI-1 mediates extracellular matrix (ECM) signaling via epigenetic repression of DKK1 in endometrial epithelial cells (EECs). While the loss of DKK1 is known to increase β-catenin accumulation for WNT signaling activation, this epigenetic repression causes β-catenin release from transmembrane integrins. Furthermore, PAI-1 elicits the disengagement of TIMP2 and SPARC from integrin-β1 on the cell surface, lifting an integrin-β1-ECM signaling constraint. The heightened interaction of integrin-β1 with type 1 collagen (COL1) remodels extracellular fibrillar structures in the ECM. Consequently, the enhanced nanomechanical stiffness of this microenvironment is conducive to EEC motility and neoplastic transformation. The formation of extensively branched COL1 fibrils is also observed in endometrial tumors of patients with obesity. The findings highlight PAI-1 as a contributor to enhanced integrin-COL1 engagement and extensive ECM remodeling during obesity-associated neoplastic development. [Display omitted] •DKK1/SPARC/TIMP2 is epigenetically repressed in obesity-driven endometrial cancer•PAI-1 repression of DKK1/SPARC/TIMP2 promotes endometrial epithelial neoplasia•PAI-1 suppressive actions elicit integrin-α3/β1-mediated inside-out signaling•PAI-1 promotes integrin-β1-induced extracellular COL1 branching and ECM stiffness Lin et al. demonstrate that PAI-1-suppressed genes DKK1, SPARC, and TIMP2 exhibit increased promoter methylation in obesity-driven endometrial cancer. This suppression event induces β-catenin uncoupling from transmembrane integrins, which triggers inside-out signaling. Consequently, integrin engagement with epithelial-deposited ECM leads to extensive COL1 fibril branching conducive to neoplastic transformation.