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- Title
Connexins orchestrate progression of breast cancer metastasis to the brain by promoting FAK activation.
- Authors
Lorusso, Girieca; Wyss, Christof B.; Kuonen, François; Vannini, Nicola; Billottet, Clotilde; Duffey, Nathalie; Pineau, Raphael; Lan, Qiang; Wirapati, Pratyaksha; Barras, David; Tancredi, Alessandro; Lyck, Ruth; Lehr, Hans-Anton; Engelhardt, Britta; Delorenzi, Mauro; Bikfalvi, Andreas; Rüegg, Curzio
- Abstract
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-BM2) 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-BM2 model and in human MDA231-BrM2 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-BrM2 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. Breast-brain ConneXion: Development of brain metastases in patients with breast cancer markedly worsens disease prognosis. Preventing or slowing the development of brain metastasis could ameliorate disease outcome. Here, Lorusso et al. used in vitro and in vivo models to show that connexins (Cxs) and focal adhesion kinase (FAK) likely play a major role in cancer brain invasion. Cx-mediated FAK activation promoted cell adhesion, tumor-astrocyte interaction, and tumor survival within the brain parenchyma. In vivo, in a spontaneous model of breast cancer–induced brain metastases, FAK inhibitors reduced brain metastasis progression, suggesting that targeting the Cx-FAK signaling might help prevention and treatment of breast cancer–associated brain metastasis.
- Subjects
METASTATIC breast cancer; BRAIN metastasis; BREAST; FOCAL adhesion kinase; CONNEXINS; CANCER invasiveness
- Publication
Science Translational Medicine, 2022, Vol 14, Issue 661, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.aax8933