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

doi:10.3390/cancers15051531

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)

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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 language	English
Article number	1531
Number of pages	15
Journal	Cancers
Volume	15
Issue number	5
DOIs	https://doi.org/10.3390/cancers15051531
Publication status	Published - 28 Feb 2023

Bibliographical note

Funding Information:
We are grateful to the CHU Amiens Picardie and Université de Picardie Jules Verne for supporting research in our laboratory.

Funding Information:
We thank Amiens University Hospital and Université de Picardie Jules Verne for financial support. The authors gratefully acknowledge the contribution of the patients and researchers involved in TCGA. S.P. and W.Z. are supported by KWF grant #12128 and The Oncode Institute.

Publisher Copyright:
© 2023 by the authors.

Keywords

glucocorticoids
tumor coagulome
tumor microenvironment

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "The Tumor Coagulome as a Transcriptional Target and a Potential Effector of Glucocorticoids in Human Cancers",

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.",

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author = "Floriane Racine and Christophe Louandre and Corinne Godin and Baptiste Chatelain and Stefan Prekovic and Wilbert Zwart and Antoine Galmiche and Zuzana Saidak",

note = "Funding Information: We are grateful to the CHU Amiens Picardie and Universit{\'e} de Picardie Jules Verne for supporting research in our laboratory. Funding Information: We thank Amiens University Hospital and Universit{\'e} de Picardie Jules Verne for financial support. The authors gratefully acknowledge the contribution of the patients and researchers involved in TCGA. S.P. and W.Z. are supported by KWF grant #12128 and The Oncode Institute. Publisher Copyright: {\textcopyright} 2023 by the authors.",

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day = "28",

doi = "10.3390/cancers15051531",

language = "English",

volume = "15",

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T1 - The Tumor Coagulome as a Transcriptional Target and a Potential Effector of Glucocorticoids in Human Cancers

AU - Racine, Floriane

AU - Louandre, Christophe

AU - Godin, Corinne

AU - Chatelain, Baptiste

AU - Prekovic, Stefan

AU - Zwart, Wilbert

AU - Galmiche, Antoine

AU - Saidak, Zuzana

N1 - Funding Information: We are grateful to the CHU Amiens Picardie and Université de Picardie Jules Verne for supporting research in our laboratory. Funding Information: We thank Amiens University Hospital and Université de Picardie Jules Verne for financial support. The authors gratefully acknowledge the contribution of the patients and researchers involved in TCGA. S.P. and W.Z. are supported by KWF grant #12128 and The Oncode Institute. Publisher Copyright: © 2023 by the authors.

PY - 2023/2/28

Y1 - 2023/2/28

N2 - 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.

AB - 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.

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KW - tumor coagulome

KW - tumor microenvironment

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DO - 10.3390/cancers15051531

M3 - Article

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AN - SCOPUS:85149862631

SN - 2072-6694

VL - 15

JO - Cancers

JF - Cancers

IS - 5

M1 - 1531

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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