Connexins orchestrate progression of breast cancer metastasis to the brain by promoting FAK activation.

Autor: Lorusso G; Experimental and Translational Oncology, Pathology Unit, Department of Oncology Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg 1700, Switzerland.; Division of Experimental Oncology, Multidisciplinary Oncology Center (CePO), Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne (UNIL), Faculty of Biology and Medicine, Epalinges 1066, Switzerland.; National Center for Competence in Research (NCCR) Molecular Oncology, Swiss Institute of Experimental Cancer Research, Ecole Polytechnique Fédérale de Lausanne (ISREC-EPFL), Lausanne 1015, Switzerland., Wyss CB; Experimental and Translational Oncology, Pathology Unit, Department of Oncology Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg 1700, Switzerland., Kuonen F; Division of Experimental Oncology, Multidisciplinary Oncology Center (CePO), Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne (UNIL), Faculty of Biology and Medicine, Epalinges 1066, Switzerland.; National Center for Competence in Research (NCCR) Molecular Oncology, Swiss Institute of Experimental Cancer Research, Ecole Polytechnique Fédérale de Lausanne (ISREC-EPFL), Lausanne 1015, Switzerland., Vannini N; Ludwig Institute for Cancer Research (LICR), Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne (UNIL), Epalinges 1066, Switzerland., Billottet C; INSERM U1029 and University of Bordeaux, Pessac Cedex 33615, France., Duffey N; Experimental and Translational Oncology, Pathology Unit, Department of Oncology Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg 1700, Switzerland., Pineau R; INSERM U1029 and University of Bordeaux, Pessac Cedex 33615, France., Lan Q; Experimental and Translational Oncology, Pathology Unit, Department of Oncology Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg 1700, Switzerland.; Division of Experimental Oncology, Multidisciplinary Oncology Center (CePO), Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne (UNIL), Faculty of Biology and Medicine, Epalinges 1066, Switzerland.; National Center for Competence in Research (NCCR) Molecular Oncology, Swiss Institute of Experimental Cancer Research, Ecole Polytechnique Fédérale de Lausanne (ISREC-EPFL), Lausanne 1015, Switzerland., Wirapati P; Bioinformatics Core Facility, Swiss Institute for Bioinformatics (SIB), Lausanne 1015, Switzerland., Barras D; Bioinformatics Core Facility, Swiss Institute for Bioinformatics (SIB), Lausanne 1015, Switzerland., Tancredi A; Experimental and Translational Oncology, Pathology Unit, Department of Oncology Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg 1700, Switzerland., Lyck R; Theodor Kocher Institute, University of Bern (UNIBE), Bern 3012, Switzerland., Lehr HA; Institute of Pathology, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne (UNIL), Lausanne 1011, Switzerland., Engelhardt B; Theodor Kocher Institute, University of Bern (UNIBE), Bern 3012, Switzerland., Delorenzi M; Bioinformatics Core Facility, Swiss Institute for Bioinformatics (SIB), Lausanne 1015, Switzerland., Bikfalvi A; INSERM U1029 and University of Bordeaux, Pessac Cedex 33615, France., Rüegg C; Experimental and Translational Oncology, Pathology Unit, Department of Oncology Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg 1700, Switzerland.; Division of Experimental Oncology, Multidisciplinary Oncology Center (CePO), Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne (UNIL), Faculty of Biology and Medicine, Epalinges 1066, Switzerland.; National Center for Competence in Research (NCCR) Molecular Oncology, Swiss Institute of Experimental Cancer Research, Ecole Polytechnique Fédérale de Lausanne (ISREC-EPFL), Lausanne 1015, Switzerland.
Jazyk: angličtina
Zdroj: Science translational medicine [Sci Transl Med] 2022 Sep 07; Vol. 14 (661), pp. eaax8933. Date of Electronic Publication: 2022 Sep 07.
DOI: 10.1126/scitranslmed.aax8933
Abstrakt: Brain metastasis is a complication of increasing incidence in patients with breast cancer at advanced disease stage. It is a severe condition characterized by a rapid decline in quality of life and poor prognosis. There is a critical clinical need to develop effective therapies to prevent and treat brain metastases. Here, we describe a unique and robust spontaneous preclinical model of breast cancer metastasis to the brain (4T1-BM 2 ) in mice that has been instrumental in uncovering molecular mechanisms guiding metastatic dissemination and colonization of the brain. Key experimental findings were validated in the additional murine D2A1-BM 2 model and in human MDA231-BrM 2 model. Gene expression analyses and functional studies, coupled with clinical transcriptomic and histopathological investigations, identified connexins (Cxs) and focal adhesion kinase (FAK) as master molecules orchestrating breast cancer colonization of the brain. Cx31 promoted homotypic tumor cell adhesion, heterotypic tumor-astrocyte interaction, and FAK phosphorylation. FAK signaling prompted NF-κB activation inducing Lamc2 expression and laminin 332 (laminin 5) deposition, α6 integrin-mediated adhesion, and sustained survival and growth within brain parenchyma. In the MDA231-BrM 2 model, the human homologous molecules CX43, LAMA4, and α3 integrin were involved. Systemic treatment with FAK inhibitors reduced brain metastasis progression. In conclusion, we report a spontaneous model of breast cancer metastasis to the brain and identified Cx-mediated FAK-NF-κB signaling as a mechanism promoting cell-autonomous and microenvironmentally controlled cell survival for brain colonization. Considering the limited therapeutic options for brain metastatic disease in cancer patients, we propose FAK as a therapeutic candidate to further pursue in the clinic.
Databáze: MEDLINE
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