Abstracts are provided in the language submitted.

"Introduction and Objectives: Brain metastases (BM) are the most common brain tumors in adults and a prominent cause of cancer-related mortality globally. Leading sources of BM in the clinic are cancers of the lung, breast and melanoma. Median survival times is 2 – 12 months in affected patients. Herein, we aimed to unravel the molecular mechanisms that promotes early-stage BM. We postulate that a better understanding of these mechanisms will enable the development of more effective therapeutic strategies. Materials and Methods: We utilized stem-like cells termed “brain metastasis-initiating cells” or BMICs from early- and late-stage lung-, breast- and melanoma-brain metastatic tumors, pre-clinical models of BM, RNA sequencing, flow cytometry analysis and several molecular techniques including western blot analysis. Results: Pre-metastatic BMICs displayed a unique genetic profile distinct from their macro-metastatic counterparts. Further analysis identified several genes commonly up-regulated in all pre-metastatic BMIC cohorts irrespective of their primary tumor of origin including the non-classical human leukocyte class I antigen-G or HLA-G gene. HLA-G depletion reduced the ability of BMICs to form mature brain lesions. Mechanistically, we discovered that high HLA-G levels increased the activation of STAT3 signaling in BMICs mediated in part via a novel HLA-G binding partner – SPAG9. Conclusion and Significance/Implication: This is the first study to reveal a role for a novel HLA-G-SPAG9-STAT3 axis in BM and highlights the potential of targeting this axis to inhibit BM, which will markedly extend patient survival."

Blessing Bassey-Archibong