A common signature of brain metastases among patients with breast cancer, melanoma and lymphoma

A common signature of brain metastases among patients with breast cancer, melanoma and lymphoma Thuy Thi Nguyen1,2,3, Duc M Hoang1,2,3, Tai V Nguyen1,2,3, Frédéric Pamoukdjian2,4, Li Wang5,6, Maxime Battistella7,8, Catherine Miquel7, Céleste Lebbé7,9, Quang V Le1,3, Wei-Li Zhao5,6, Anne Janin7, Jean-Paul Feugeas10*, Guilhem Bousquet2,11*& 1National Cancer Hospital, Ha Noi, Viet Nam 2Université Sorbonne Paris Nord, SynKoMIC research unit, F-93430, Villetaneuse, France 3Hanoi Medical University, Ha Noi, Viet Nam 4APHP, Hôpital Avicenne, Médecine Gériatrique, Bobigny, France 5Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China 6Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Shanghai, China 7Université Paris Cité, INSERM, Paris, France 8Pathology Department, APHP, Hôpital Saint Louis, Paris, France 9APHP, Dermatolo-Oncology, Hôpital Saint Louis, Paris, France 10Université Marie et Louis Pasteur, CHU Besançon, Inserm UMR 1098, CIC 1431, F-25000, Besançon, France 11Assistance Publique Hôpitaux de Paris, Hôpital Avicenne, Service d'Oncologie Médicale, 93000 Bobigny, France *Co-senior author &Corresponding author Prof. Guilhem Bousquet, Université Sorbonne Paris Nord, UFR SMBH, 1 rue Chablis, 93000 Bobigny, France, Email: guilhem.bousquet@aphp.fr, Tel: +(33) 1 42 38 54 28 Abstract Background Despite considerable improvement in cancer treatments, brain metastases are still challenging daily practice in oncology. Their biology remains largely unknown with limited data obtained from brain metastatic samples. Here, using metastatic samples of three different cancer types – breast cancer, melanoma and lymphoma – we aimed to identify a common genomic signature related to metastatic localizations in the brain. Methods Using samples from 133 patients with metastatic breast cancer, melanoma or lymphoma, laser-microdissection of cancer cells and transciptomic analyses were performed on 18 brain metastatic samples, and compared to data from 115 extra-cerebral metastases. To obtain murine models of the common brain metastatic signature observed in patients with these three cancer types, in vivo experiments were performed after intra-cardiac injections of cancer cell lines. Results Among patients, we identified 23 common genes up-regulated in brain metastases from breast cancer, melanoma and lymphoma, including KLK6, a serine protease with trypsin-like properties and physiological expression in oligodendrocytes and normal brain endothelial cells. At protein level, KLK6 expression was significantly higher in brain metastases than in extra-cerebral metastases. In particular, KLK6 was not overexpressed in extra-cerebral metastases of patients who developed brain metastases. In murine models of breast cancer, melanoma and lymphoma brain metastases, we confirmed that KLK6 overexpression was linked to the implantation of cancer cells in the brain. Conclusion KLK6 overexpression is linked to brain localizations whatever the cancer type, which provides new perspectives for the development of anti-KLK6 therapeutic strategies, pending specific cancer cell targeting to avoid cytotoxicity on normal brain cells.