Prosaposin orchestrates a TGFβ1-driven paracrine loop between Schwann cells and gastric cancer to accelerate perineural invasion.

Perineural invasion (PNI) is an established adverse prognostic factor in gastric cancer (GC), yet the molecular events initiating this process remain poorly defined. In this study, we identify Schwann cells (SCs) as active facilitators of PNI and elucidate a reciprocal signaling axis between GC cells and SCs that promotes PNI. Using a GC–SCs co-culture model, we show that SCs enhance PNI potential in GC cells, accompanied by increased expression of prosaposin (PSAP), a lysosomal secretory protein, in both co-cultured cells and PNI-positive tumor specimens. Mechanistic studies reveal that PSAP forms a complex with cathepsin D (CTSD) and galactocerebrosidase (GALC) to inhibit autophagy and to promote PNI progression. GC-derived PSAP activates the G protein–coupled receptor 37(GPR37) on SCs, initiating RAC1-dependent cytoskeletal remodeling. This activation also induces secretion of transforming growth factor-β-1(TGFβ1) by SCs, which, in turn, binds transforming growth factor-β receptor-II (TGFβRII) on GC cells and activates a TGFβ1/Smad4/Sortilin signaling cascade. This pathway amplifies PSAP production and reinforces tumor–nerve interactions, establishing a feedforward paracrine loop that drives PNI. Functionally, enforced PSAP expression in GC cells significantly enhances PNI both in vitro and in vivo. Clinically, co-expression of PSAP, TGFβ1, and SCs marker S100β correlates with PNI incidence and improve PNI discrimination. Collectively, these findings define a novel PSAP–TGFβ1–Sortilin axis that mediates SCs–tumor crosstalk and sustains PNI in GC. Disrupting this paracrine loop may provide a therapeutic avenue to limit PNI and improve outcomes.