Endothelial Calcineurin Signaling Restrains Metastatic Outgrowth by Regulating Bmp2
Stefanie Hendrikx,
Sanja Coso,
Borja Prat-Luri,
Laureline Wetterwald,
Amélie Sabine,
Claudio A. Franco,
Sina Nassiri,
Nadine Zangger,
Holger Gerhardt,
Mauro Delorenzi,
Tatiana V. Petrova
Affiliations
Stefanie Hendrikx
Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland; Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland; Division of Experimental Pathology, CHUV, Epalinges 1066, Switzerland
Sanja Coso
Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland; Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland; Division of Experimental Pathology, CHUV, Epalinges 1066, Switzerland
Borja Prat-Luri
Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland; Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland; Division of Experimental Pathology, CHUV, Epalinges 1066, Switzerland
Laureline Wetterwald
Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland; Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland; Division of Experimental Pathology, CHUV, Epalinges 1066, Switzerland
Amélie Sabine
Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland; Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland; Division of Experimental Pathology, CHUV, Epalinges 1066, Switzerland
Claudio A. Franco
Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
Sina Nassiri
Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland; Translational Bioinformatics and Statistics, Swiss Cancer Center Lausanne, Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland
Nadine Zangger
Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland; Translational Bioinformatics and Statistics, Swiss Cancer Center Lausanne, Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland
Holger Gerhardt
Vascular Patterning Laboratory, Department of Oncology, KU Leuven, Leuven, Belgium; Integrative Vascular Biology Laboratory, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Berlin Institute of Health (BIH), German Center for Cardiovascular Research (DZHK) Partner Site, Berlin, Germany
Mauro Delorenzi
Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland; Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland; Translational Bioinformatics and Statistics, Swiss Cancer Center Lausanne, Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland
Tatiana V. Petrova
Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland; Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland; Division of Experimental Pathology, CHUV, Epalinges 1066, Switzerland; Swiss Institute for Cancer Research, École Polytechnique Fédérale de Lausanne, Lausanne 1015, Switzerland; Corresponding author
Summary: Calcineurin/NFAT signaling is active in endothelial cells and is proposed to be an essential component of the tumor angiogenic response. Here, we investigated the role of endothelial calcineurin signaling in vivo in physiological and pathological angiogenesis and tumor metastasis. We show that this pathway is dispensable for retinal and tumor angiogenesis, but it is implicated in vessel stabilization. While ablation of endothelial calcineurin does not affect the progression of primary tumors or tumor cell extravasation, it does potentiate the outgrowth of lung metastases. We identify Bmp2 as a downstream target of the calcineurin/NFAT pathway in lung endothelium, potently inhibiting cancer cell growth by stimulating differentiation. We reveal a dual role of calcineurin/NFAT signaling in vascular regression or stabilization and in the tissue-specific production of an angiocrine factor restraining cancer cell outgrowth. Our results suggest that, besides targeting the immune system, post-transplantation immunosuppressive therapy with calcineurin inhibitors directly targets the endothelium, contributing to aggressive cancer progression. : Hendrikx et al. show that endothelial calcineurin signaling is dispensable for physiological and tumor angiogenesis. Instead, it promotes vascular stabilization and, in cancer, restrains metastatic outgrowth. Immunosuppressive therapy with calcineurin inhibitors thus also directly affects the endothelium, which may contribute to aggressive cancer progression in organ transplant recipients. Keywords: angiogenesis, calcineurin, NFAT, BMP2, endothelial, metastasis, melanoma
