For several years, we have been interested in the anticoagulant factor Protein S and its TAM tyrosine kinase receptors (TYRO3, AXL and MERTK). We were among the first to reveal that Protein S, independently of its role as an inhibitor of blood coagulation, interacts with membrane receptors, exerts cellular effects, and can be produced by vascular cells [1]. This work contributed to the discovery of TAM tyrosine kinase receptors and served as a basis for the emergence of the important role of Protein S in several pathophysiological processes, including cancer [2]. We were also the first to demonstrate that the Protein S produced within the brain inhibits cell proliferation in the neurogenic niches of the brain [3]. Our work has enabled us to establish, both in vitro and in vivo, that the Protein S/MERTK system acts both as an angiogenesis inhibitor [4] and as a major regulator of phagocytosis [5]. The Protein S/TAM receptors system would be involved in other events of the metastatic cascade that we aim to identify and characterize.

The TAM receptors play an essential role in various tumoral processes such as cell migration, invasion, survival, and growth, as well as metastasis formation and maintenance of the stem state of cancer stem cells [6,7]. Recent research data distinctly indicate that TAM receptors, especially MERTK and its ligand PROS1, are highly involved in glioma cell invasion and survival [6,8]. Moreover, TYRO3 and MERTK receptors are newly identified therapeutic targets in colorectal cancer [9] and in the tumoral microenvironment [10]. Therefore, our current research project consists in studying the PROS1/TAM receptors system’s involvement in molecular mechanisms that allow some colorectal cancer cells to generate metastases in the brain.

[1] Benzakour O, Kanthou C. The anticoagulant factor, protein S, is produced by cultured human vascular smooth muscle cells and its expression is up-regulated by thrombin. Blood 2000; 95:2008.

[2] Benzakour O. Vitamin K-dependent proteins: functions in blood coagulation and beyond. Throm Haemost 2008; 100: 527-9

[3] Gely-Pernot A, Coronas V, Harnois T, Prestoz L, Mandairon N, Didier A, et al. An endogenous vitamin K-dependent mechanism regulates cell proliferation in the brain subventricular stem cell niche. Stem cells 2012; 30:719.

[4] Fraineau S, Monvoisin A, Clarhaut J, Talbot J, Simonneau C, Kanthou C, et al. The vitamin K-dependent anticoagulant factor, protein S, inhibits multiple VEGF-A-induced angiogenesis events in a Mer- and SHP2-dependent manner. Blood 2012; 120:5073.

[5] Yefimova MG, Messaddeq N, Harnois T, Meunier AC, Clarhaut J, Noblanc A, et al. A chimerical phagocytosis model reveals the recruitment by Sertoli cells of autophagy for the degradation of ingested illegitimate substrates. Autophagy 2013; 9:653.

[6] Wang Y, Moncayo G, Morin P Jr, Xue G, Grzmil M, Lino MM, et al. Mer receptor tyrosine kinase promotes invasion and survival in glioblastoma multiforme. Oncogene 2013. 32:872.

[7] Linger RM, Cohen RA, Cummings CT, Sather S, Migdall-Wilson J, Middleton DH, et al. Mer or Axl receptor tyrosine kinase inhibition promotes apoptosis, blocks growth and enhances chemosensitivity of human non-small cell lung cancer. Oncogene 2013. 32:3420.

[8] Che Mat MF, Abdul Murad NA, Ibrahim K, Mohd Mokhtar N, Wan Ngah WZ, Harun R, et al. Silencing of PROS1 induces apoptosis and inhibits migration and invasion of glioblastoma multiforme cells. International Journal of Oncology 2016. 49:2359.

[9] Schmitz R, Valls AF, Yerbes R, von Richter S, Kahlert C, Loges S, et al. TAM receptors Tyro3 and Mer as novel targets in colorectal cancer. Oncotarget 2016. 7:56355.

[10] Myers KV, Amend SR, Pienta KJ. Targeting Tyro3, Axl and MerTK (TAM receptors): implications for macrophages in the tumor microenvironment. Mol Cancer 2019. 18:94.