Polyphosphate functions as a filopodial scaffold to promote cell adhesion and oppose cancer cell invasion

Its role at the plasma membrane, however, where it reaches peak concentrations in many primary mammalian cells, was unknown. Here we identify polyP as a stabilizer of filopodia, actin-based membrane protrusions that drive cell adhesion, migration, and environmental sensing.

Genetically elevating cellular polyP stabilizes filopodia, which increases filopodia number and length and impairs migration. Mechanistically, polyP acts post-translationally by scaffolding the I-BAR protein IRSp53 into phase-separated condensates, recruiting it to vesicle membranes and, in the presence of other filopodial proteins, supporting filopodia formation in vitro. Translationally, we find that metastatic fibroblasts and breast cancer organoids markedly downregulate and reorganize endogenous polyP, which contributes to their migratory and invasive behavior.