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. GRAPHICAL ABSTRACT: This schematic model illustrates a self-amplifying tumor–nerve signaling circuit between GC cells and SCs that promotes PNI by coupling intracellular PSAP sorting to paracrine communication. PSAP is overexpressed in GC cells. The 65 kDa PSAP synthesized in the endoplasmic reticulum (ER) is transported to the Golgi and sorted into two trafficking routes. A fraction binds Sortilin in the trans-Golgi network (TGN) and is delivered to lysosomes, during which PSAP forms a complex with CTSD/GALC to inhibit autophagy and potentiate malignant traits. In parallel, another fraction is processed and secreted as a 75 kDa form, which engages GPR37 on SCs, activates RAC1-dependent cytoskeletal remodeling, and induces TGF-β1 secretion. SC-derived TGF-β1 signals back to GC cells via the TGF-β1/Smad4 pathway to repress Sortilin expression, reducing PSAP–Sortilin interaction and limiting lysosomal targeting, which in turn increases PSAP abundance and secretion. Collectively, these events establish a feed-forward paracrine amplification loop that sustains tumor–nerve crosstalk and accelerates PNI. [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-026-03652-3.