The NK killer receptor Ncr1 shapes tumor architecture to prevent metastasis (TUM10P.1034)

Abstract Natural killer (NK) cells were so-named because of their excellent ability to kill tumors and pathogens. NKp46 (Ncr1 in mice) is a prominent NK killer receptor, critically involved in controlling various pathogens as well as tumors and tumor metastases. We and others and have demonstrated the ability of the NK killer receptor Ncr1 to contain tumor growth, however, the mechanisms underlying the ability of Ncr1 to control tumor growth and metastases in vivo are yet undetermined Metastatic melanoma is an extremely aggressive disease and the leading cause of death from skin cancers. Here, we used two melanoma spontaneous metastases models: B16F10.9 (B16) and RET, the Ncr1 knockout mice (Ncr1gfp/gfp), Ifnγ-/- and Tnfα-/- knockout mice to visualize the tumors’ architecture in-vivo, using Reflectance Confocal Microscopy (RCM). We demonstrate that Ncr1, through Ifnγ prevents tumor metastasis by modulating the structural properties of the developing tumors, at the level of the tissue organization. Using RNAseq we have analyzed the transcriptome of Ifnγ treated B16 cells and reveled a 24 fold increase in the integrin binding ECM protein Fibronictin1 (FN1), the absence of which was reported to correlate with increased metastases. The finding that Ncr1, through Ifnγ, shapes the tumors’ structures and thus controls metastasis may lead to generation of new drugs aimed at targeting specifically the tumors’ architecture and new treatment options for melanoma patients.