Abstract 2553: Hypoxia-associated lncRNA-induced glycolysis and lactylation-driven senescence-associated secretory phenotype in cancer-associated fibroblasts enhances peritoneal dissemination

Abstract Peritoneal Dissemination is the main site of diffuse gastric cancer (DGC) distant metastasis and indicates an extremely poor prognosis and survival. Our previous research revealed that HIF-1a can initiate the expression of LINC01355, promoting the progression of DGC. Here, in DGC orthotopic transplantation model, we observed that overexpression of LINC01355 could accelerate peritoneal dissemination. We found that LINC01355 could directly bind to Pyruvate Kinase M1/2 (PKM), inhibiting its degradation, thereby facilitating glycolysis in GC and creating a microenvironment with accumulated lactate. Single-cell analysis reveals the presence of a hypoxia-associated subtype of cancer-associated fibroblasts (hypoxiaCAF) within TME of DGC. This distinct subtype is independent of myoCAF, iCAF, and apCAF, representing a novel CAF population. HypoxiaCAFs exhibit a slow proliferation rate and display a senescence-associated secretory phenotype (SASP). Mass spectrometry and related experimental data suggest that lactate accumulation in the TME downregulates the specific histone lysine delactylase HDAC3, promoting histone H4 lysine 12 lactylation (H4K12la). H4K12la is enriched in the promoters of SASP-related genes, driving SASP transcription and exacerbating the senescence of CAFs. Inhibition of HDAC3 blocks the increased viability of DGC cells induced by senescent CAFs and peritoneal tumor formation. Single-cell mass cytometry reveals the presence of fibroblasts in the ascites of patients with peritoneally disseminated DGC, with fibroblast populations displaying high levels of p16 expression and SASP factors. These findings provide insights into the role of histone lactylation in sustaining inflammation-related SASP and the involvement of senescent CAFs in DGC peritoneal dissemination. Citation Format: Jun Zhang. Hypoxia-associated lncRNA-induced glycolysis and lactylation-driven senescence-associated secretory phenotype in cancer-associated fibroblasts enhances peritoneal dissemination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2553.