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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\u2013SCs 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\u2013coupled receptor 37(GPR37) on SCs, initiating RAC1-dependent cytoskeletal remodeling. This activation also induces secretion of transforming growth factor-\u03b2-1(TGF\u03b21) by SCs, which, in turn, binds transforming growth factor-\u03b2 receptor-II (TGF\u03b2RII) on GC cells and activates a TGF\u03b21\/Smad4\/Sortilin signaling cascade. This pathway amplifies PSAP production and reinforces tumor\u2013nerve 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, TGF\u03b21, and SCs marker S100\u03b2 correlates with PNI incidence and improve PNI discrimination. Collectively, these findings define a novel PSAP\u2013TGF\u03b21\u2013Sortilin axis that mediates SCs\u2013tumor crosstalk and sustains PNI in GC. Disrupting this paracrine loop may provide a therapeutic avenue to limit PNI and improve outcomes.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>\n                  <jats:p>This schematic model illustrates a self-amplifying tumor\u2013nerve 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-\u03b21 secretion. SC-derived TGF-\u03b21 signals back to GC cells via the TGF-\u03b21\/Smad4 pathway to repress Sortilin expression, reducing PSAP\u2013Sortilin 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\u2013nerve crosstalk and accelerates PNI.<\/jats:p>","DOI":"10.1186\/s13046-026-03652-3","type":"journal-article","created":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T11:24:30Z","timestamp":1769253870000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Prosaposin orchestrates a TGF\u03b21-driven paracrine loop between Schwann cells and gastric cancer to accelerate perineural invasion"],"prefix":"10.1186","volume":"45","author":[{"given":"Shijie","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Xi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"LinFan","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ZiJian","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangming","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shixun","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,24]]},"reference":[{"issue":"3","key":"3652_CR1","first-page":"209","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. 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