Identified new biomarker crucial for brain metastasis in breast cancer

Authors and affiliations:
Rita Carvalho ^1,2,8, Liliana Santos ^3,4,5, Inês Conde^1,2,8, Ricardo Leitão^3,4,5, Hugo R. S. Ferreira^3,4,5, Célia Gomes ^3,4,5, Ana Paula Silva^3,4,5, Fernando Schmitt^2,6,10, Carina Carvalho-Maia⁷, João Lobo^7,8,9, Carmen Jerónimo^7,8, Joana Paredes^1,2,10, Ana Sofia Ribeiro^1,2

¹ Cancer Metastasis group, i3S – Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal.

² IPATIMUP – Institute of Molecular Pathology and Immunology of the University of Porto, 4200-465 Porto, Portugal.

³ Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

⁴ iCBR – Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal

⁵ CIBB - Center for Innovation in Biomedicine and Biotechnology, University of Coimbra, 3000-548 Coimbra, Portugal.

⁶ CINTESIS@RISE, 4200-450 Porto, Portugal

⁷ Cancer Biology and Epigenetics Group, IPO Porto Research Center (GEBC CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center Raquel Seruca (P.CCC) & CI-IPOP@RISE (Health Research Network), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal

⁸ Department of Pathology and Molecular Immunology, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Rua Jorge Viterbo Ferreira 228, 4050-513, Porto, Portugal

⁹ Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center Raquel Seruca (P.CCC), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal

¹⁰ FMUP – Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal.

Abstract:
Brain metastases are one of the most serious clinical problems in breast cancer (BC) progression, associated with lower survival rates and a lack of effective therapies. Thus, to dissect the early stages of the brain metastatic process, we studied the impact of brain organotropic BC cells’ secretomes on the establishment of the brain pre-metastatic niche (PMN). We found that BC cells with specific tropism to the brain caused significant blood–brain barrier (BBB) disruption, as well as microglial activation, in both in vitro and in vivo models. Further, we searched for a brain-organotropic metastatic signature, as a promising source for the discovery of new biomarkers involved in brain metastatic progression. Of relevance, we identified VGF (nerve growth factor inducible) as a key mediator in this process, also impacting the BBB and microglial functions both in vitro and in vivo. In a series of human breast tumors, VGF was found to be expressed in both cancer cells and the adjacent stroma. Importantly, VGF-positive tumors showed a significantly worse prognosis and were associated with HER2 (human epidermal growth factor receptor 2) overexpression and triple-negative molecular signatures. Further clinical validation in primary tumors from metastatic BC cases showed a significant association between VGF and the brain metastatic location, clearly and significantly impacting on the prognosis of BC patients with brain metastasis. In conclusion, our study reveals a unique secretome signature for BC with a tropism for the brain, highlighting VGF as a crucial mediator in this process. Furthermore, its specific impact as a poor prognostic predictor for BC patients with brain metastasis opens new avenues to target VGF to control the progression of brain metastatic disease.

Journal: The Journal of Pathology

Link: https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/path.6319