Identification of cancer-associated fibrolast subtypes and distinctive role of MFAP5 in CT-detected extramural venous invasion in gastric cancer

Abstract

Extramural venous invasion (EMVI) detected by computed tomography has been identified as an independent risk factor for distant metastasis in patients with advanced gastric cancer (GC). Cancer-associated fibroblasts (CAFs) are critical for remodeling the tumor microenvironment in GCs. Here, we report that MFAP5+ CAFs promote the formation of EMVI imaging in GC. We detected gene expression in pathological samples from 13 advanced GC patients with EMVI. Radiogenomics results showed the degree of CAFs infiltration was directly proportional to the EMVI score and EMT pathway in GC patients. Single-cell sequencing data analysis results showed that MFAP5+CAFs subtypes in GC were negatively correlated with patient prognosis and were enriched in tumor lactylation modification and EMT pathways. Immunohistochemistry results showed that the expression of MFAP5, L-lactyl and EMT markers in GC tissues was proportional to the EMVI score. CAF from gastric cancer tissue was extracted using collagenase method and co-cultured with GC cell line in vitro. After lentivirus knockdown of MFAP5 in CAFs, the levels of L-lactoyl and histone lactylation modifications were significantly reduced, and the sphere-forming and vascularization abilities of CAFs were significantly inhibited. Cell function experiments showed that MFAP5+ CAFs can affect the EMT, metastasis and invasion capabilities of GC cells. In vivo experimental results of the nude mouse in situ EMVI model suggest that MFAP5+ CAF may promote the formation of EMVI imaging features in GC by regulating lactylation modification. This innovative work may provide important new references for the diagnosis and treatment of GC.