LAUSR

Abstract The molecular mechanisms contributing to distant dissemination and local recurrence of medulloblastoma, the most common malignant brain tumor in childhood, are poorly understood and no targeted anti-invasion therapies exist till date. We explored regulators and effectors of MAP4K4, a pro-invasive kinase overexpressed in MB and associated with metastatic progression in different solid malignancies. MAP4K4 is upregulated both at mRNA and protein levels in primary pediatric brain tumors compared to normal cerebellum. MAP4K4 is required for growth factor- and irradiation-induced migration and invasion of medulloblastoma cells. It furthermore promotes turnover and activation of the receptor tyrosine kinase c-Met and of the ß1 integrin adhesion receptor 1. To characterize these clinically relevant consequences and to identify druggable targets of MAP4K4 function, we profiled the interactome of MAP4K4 in starved and growth factor stimulated medulloblastoma cells. To systematically address MAP4K4 impact on receptor expression and turnover, we determined the MAP4K4-dependent surface proteome in medulloblastoma cells. We found that MAP4K4 is part of the striatin-interacting phosphatase and kinase (STRIPAK) complex and that STRIPAK component striatin 4 is controlling cell motility and invasiveness in medulloblastoma cells. Invasiveness of medulloblastoma cells is abrogated by a truncation mutant of MAP4K4 lacking the striatin 4 interaction domain. We furthermore found that MAP4K4 mediates growth factor-induced surface expression of solute carriers and immunomodulatory proteins involved in chemoresistance and immune evasion. Thus, our study identified MAP4K4 as a missing link between pro-tumorigenic growth factor signaling and tumor cell functions relevant for disease progression. It may help identifying druggable vulnerabilities in medulloblastoma cells to restrict tumor growth and dissemination. 1. Tripolitsioti, D. et al., Oncotarget9, 23220–23236 (2018).