PAI-1-Dependent Inactivation of SMAD4-Modulated Junction and Adhesion Complex in Obese Endometrial Cancer

• Published in: Cell reports (Cambridge) 2020-10, Vol.33 (2), p.108253-108253, Article 108253
• Main Authors: Lin, Li-Ling, Kost, Edward R., Lin, Chun-Lin, Valente, Philip, Wang, Chiou-Miin, Kolonin, Mikhail G., Daquinag, Alexes C., Tan, Xi, Lucio, Nicholas, Hung, Chia-Nung, Wang, Chen-Pin, Kirma, Nameer B., Huang, Tim H.-M.
• Format: Article
• Language: English
• Subjects: adipose stromal cells; cell-cell communication; cytometry by time-of-flight; endometrial cancer; LRP1; obesity; PAI-1; single-cell analysis; SMAD4
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108253

While plasminogen activator inhibitor-1 (PAI-1) is known to potentiate cellular migration via proteolytic regulation, this adipokine is implicated as an oncogenic ligand in the tumor microenvironment. To understand the underlying paracrine mechanism, here, we conduct transcriptomic analysis of 1,898 endometrial epithelial cells (EECs) exposed and unexposed to PAI-1-secreting adipose stromal cells. The PAI-1-dependent action deregulates crosstalk among tumor-promoting and tumor-repressing pathways, including transforming growth factor β (TGF-β). When PAI-1 is tethered to lipoprotein receptor-related protein 1 (LRP1), the internalized signaling causes downregulation of SMAD4 at the transcriptional and post-translational levels that attenuates TGF-β-related transcription programs. Repression of genes encoding the junction and adhesion complex preferentially occurs in SMAD4-underexpressed EECs of persons with obesity. The findings highlight a role of PAI-1 signaling that renders ineffective intercellular communication for the development of adiposity-associated endometrial cancer. [Display omitted] •ASC infiltration in endometrial tumor microenvironments positively correlates with BMI•ASC-secreted PAI-1 influences heterogeneous endometrial epithelial cell subpopulations•PAI-1-LRP1-modulated SMAD4 downregulation leads to JAC repression in vitro•Repressive JAC is present in cancer cell subpopulations of persons with obesity Lin et al. demonstrate that PAI-1 secreted by adipose stromal cells interacts with LRP1 to repress TGF-β/SMAD4-regulated genes linked to cellular junction and adhesion complexes. This action disrupts cell-cell communication and facilitates the development of obesity-driven endometrial cancer.