In conclusion, this unbiased proteomic screen of the profibrogenic endothelial secretome revealed DKK3 acting as an agonist of the Wnt pathway, enhancing formation of myofibroblasts and endothelial-mesenchymal transition and impairing angiogenesis. A potent inhibitor of the Wnt pathway, sulindac sulfide, suppressed nephropathy-induced DKK3 expression and renal fibrosis.
The secretome, defined as a portion of proteins secreted by specific cells to the extracellular space, secures a proper microenvironmental niche not only to the donor cells, but equally to the neighboring cells, thus maintaining tissue homeostasis. Communication via secretory products exists between endothelial cells and fibroblasts and this local mechanism maintains the viability and density of each compartment. Endothelial dysfunction, apart from obvious cell-autonomous defects, leads to the aberrant secretome which predisposes fibroblasts to acquire myofibroblastic fibrogenic phenotype. In our recent profiling of the secretome of such dysfunctional pro-fibrogenic renal microvascular endothelial cells we identified unique pro-fibrogenic signatures among which we detected ligands of Notch and Wnt/beta-catenin pathways. Here, we stress the role of reprogramming cues in the immediate microenvironment of (myo)fibroblasts and the contribution of endothelial secretome to the panoply of instructive signals in the vicinity of fibroblasts. We hope that this brief overview of endothelial-fibroblast communication in health and disease will lead to eventual unbiased proteomic mapping of individual secretomes of glomerular and tubular epithelial cells, pericytes and podocytes through reductionist approaches to allow for the synthetic creation of a complex network of secretomic signals acting as reprogramming factors on individual cell types in the kidney. Knowledge of pro- and anti-fibrogenic signatures in the secretome may garner future therapeutic efforts.
Thyroid cancer is the most prevalent endocrine malignancy in the United States with greater than 53,000 new cases in 2020. There is a significant gender disparity in disease incidence as well, with women developing thyroid cancer three times more often than men; however, the underlying cause of this disparity is poorly understood. Using RNA-sequencing, we profiled the immune landscape of papillary thyroid cancer (PTC) and identified a significant inverse correlation between androgen receptor (AR) levels and the immune checkpoint molecule PD-L1. The expression of PD-L1 was then measured in an androgen responsive-thyroid cancer cell line. Dihydrotestosterone (DHT) treatment resulted in significant reduction in surface PD-L1 expression in a time and dose-dependent manner. To determine if androgen-mediated PD-L1 downregulation was AR-dependent, we treated cells with flutamide, a selective AR antagonist, and prior to DHT treatment to pharmacologically inhibit AR-induced signaling. This resulted in a > 90% restoration of cell surface PD-L1 expression, suggesting a potential role for AR activity in PD-L1 regulation. Investigation into the AR binding sites showed AR activation impacts NF-kB signaling by increasing IkBα and by possibly preventing NF-kB translocation into the nucleus, reducing PD-L1 promoter activation. This study provides evidence of sex-hormone mediated regulation of immune checkpoint molecules in vitro with potential ramification for immunotherapies.
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