Polysulfides contribute to persulfidation of FSCN-1 to accelerate development of pancreatic ductal adenocarcinoma

We previously reported polysulfides (PS) are overgenerated in ovarian and breast cancers that contribute to worsening prognosis and chemoresistance (1, 2), while molecular mechanisms remain unknown. In this study, expression of PS-generating enzymes in post-operative pancreatic ductal adenocarcinoma (PDAC) tissues were examined immunohistochemically using FFPE samples from 120 Japanese patients. Analyses revealed that cystathionine gamma-lyase (CSE) expressed in cancer-associated fibroblasts (CAF) serves as an independent factor worsening post-operative disease-free and overall survivals. CSE-positive CAF predominantly occurs in regions adjacent to cancer cells and activated glycolysis to deliver C1 units towards transsulfudation as judged by elevated methylation of PFKFB3 and PKM2 that activates the carbon delivery for serine-cysteine synthesis. Gold nanoparticle-based surface-enhanced Raman spectroscopy (SERS) imaging (3) using frozen PDAC tissues unveiled PS generation over the cancer tissues. PS renders cancer cells to induce site-specific persulfidation of fascin-actin-bundling protein (FSCN)-1 to stimulate the ability of cancer cells to migrate, while PS-degrading ambroxol or gemcitabine canceled the effects through their action to scavenge PS in vitro. These results suggest that PS serves as a marker inducing CAF-mediated cancer invasiveness.References (1) Yamamoto T, et al. Cancer Res (2024)(2) Honda K, et al. Redox Biol (2021)(3) Shiota M, et al. Nature Commun (2018)