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

Floriane Racine, Christophe Louandre, Corinne Godin, Baptiste Chatelain, Stefan Prekovic, Wilbert Zwart, Antoine Galmiche, Zuzana Saidak*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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-β 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.

Original languageEnglish
Article number1531
Number of pages15
JournalCancers
Volume15
Issue number5
DOIs
Publication statusPublished - Mar 2023

Keywords

  • glucocorticoids
  • tumor coagulome
  • tumor microenvironment

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