PAK1 overexpression promotes myxofibrosarcoma angiogenesis through STAT5B-mediated transactivation: clinical and therapeutic relevance of amplification and nuclear entry.

Myxofibrosarcoma is genetically complex without established nonsurgical therapies. In public datasets, was recurrently gained with mRNA upregulation. Using myxofibrosarcoma cells, we explored the oncogenic underpinning of PAK1 with genetic manipulation and a pan-PAK inhibitor (PF3758309). Myxofibrosarcoma specimens were analyzed for the levels of PAK1, phospho-PAK, CSF2 and microvascular density (MVD) and those of gene and mRNA. PAK1-expressing xenografts were assessed for the effects of PF3758309 and silencing. Besides pro-proliferative and pro-migrator/pro-invasive attributes, PAK1 strongly enhanced angiogenesis in vitro, which, not phenocopied by PAK2-4, was identified as CSF2-mediated using antibody arrays. PAK1 underwent phosphorylation at tyrosines and threonine to facilitate nuclear entry, whereby nuclear PAK1 bound STAT5B to co-transactivate the promoter, increasing CSF2 secretion needed for angiogenesis. Angiogenesis driven by PAK1-upregulated CSF2 was negated by silencing, anti-CSF2, and PF3758309. Clinically, overexpressed whole-cell phospho-PAK, related to amplification, was associated with increased grades, stages, and mRNA, higher MVD, and CSF2 overexpression. Overexpressed whole-cell phospho-PAK and CSF2 independently portended shorter metastasis-free survival and disease-specific survival, respectively. In vivo, both CSF2 silencing and PF3758309 suppressed PAK1-driven tumor proliferation and angiogenesis. Conclusively, the nuclear entry of overexpressed/activated PAK1 endows myxofibrosarcomas with pro-angiogenic function, highlighting the vulnerable PAK1/STAT5B/CSF2 regulatory axis.