The Tumor Coagulome as a Transcriptional Target and a Potential Effector of Glucocorticoids in Human Cancers

Simple Summary Human tumors often establish a local hypercoagulant state that promotes vascular complications, such as venous thromboembolism. The concept of the tumor << coagulome >> refers to the repertoire of tumor-expressed genes that locally regulate coagulation and fibrinolysis. Recent systems studies have helped to define the landscape of the coagulome across the spectrum of human tumors, unveiling its link with the tumor microenvironment. Understanding the key elements that regulate the expression of the coagulome is therefore essential. In this study, we explored the dynamic regulation of the tumor coagulome by glucocorticoids. We found that glucocorticoids regulate the coagulome through a combination of direct transcriptional and indirect effects. We show that this transcriptional regulation applies to human tumors, and we suggest that the direct transcriptional regulation of PAI-1 expression by the glucocorticoid receptor may regulate the tumor microenvironment. The transcriptional regulation of the coagulome by glucocorticoids that we report here may have vascular consequences and may account for some of the effects of glucocorticoids on the tumor microenvironment. Background: The coagulome, defined as the repertoire of genes that locally regulate coagulation and fibrinolysis, is a key determinant of vascular thromboembolic complications of cancer. In addition to vascular complications, the coagulome may also regulate the tumor microenvironment (TME). Glucocorticoids are key hormones that mediate cellular responses to various stresses and exert anti-inflammatory effects. We addressed the effects of glucocorticoids on the coagulome of human tumors by investigating interactions with Oral Squamous Cell Carcinoma, Lung Adenocarcinoma, and Pancreatic Adenocarcinoma tumor types. Methods: We analyzed the regulation of three essential coagulome components, i.e., the tissue factor (TF), urokinase-type plasminogen activator (uPA), and plasminogen activator inhibitor-1 (PAI-1) in cancer cell lines exposed to specific agonists of the glucocorticoid receptor (GR) (dexamethasone and hydrocortisone). We used QPCR, immunoblots, small-interfering RNA, Chromatin immunoprecipitation sequencing (ChIPseq) and genomic data from whole tumor and single-cell analyses. Results: Glucocorticoids modulate the coagulome of cancer cells through a combination of indirect and direct transcriptional effects. Dexamethasone directly increased PAI-1 expression in a GR-dependent manner. We confirmed the relevance of these findings in human tumors, where high GR activity/high SERPINE1 expression corresponded to a TME enriched in active fibroblasts and with a high TGF-beta response. Conclusion: The transcriptional regulation of the coagulome by glucocorticoids that we report may have vascular consequences and account for some of the effects of glucocorticoids on the TME.

Automated summary

Human tumors often exhibit a hypercoagulant state that promotes vascular complications. The tumor coagulome, a repertoire of tumor-expressed genes that regulates coagulation and fibrinolysis, has been found to be linked with the tumor microenvironment. Glucocorticoids were discovered to regulate the coagulome through direct transcriptional and indirect effects, which have potential vascular consequences and impact on the tumor microenvironment.