SMARCA1-NPFF axis inhibits colorectal cancer metastasis by blocking epithelial-mesenchymal transition and macrophage-dependent immune reprogramming.

Dysregulation of chromatin remodeling represents an essential driving factor for cancer development and progression. Our previous work demonstrated that increased inclusion of exon 13 during alternative splicing functionally inactivates SMARCA1, the catalytic subunit of the ISWI chromatin remodeling complex, to promote colorectal cancer (CRC) metastasis, but the precise mechanism underlying SMARCA1-mediated metastasis suppression remains elusive. In this study, through ATAC-seq and RNA-seq analyses, we established an inverse correlation between SMARCA1 activity and neuropeptide FF (NPFF) transcriptional output in CRC cell lines and clinical specimens. Ectopic NPFF expression significantly enhanced CRC cell migration, invasion and metastatic potential, effectively counteracting the antimetastatic function mediated by SMARCA1. Mechanistically, SMARCA1 attenuates NPFF transcription by impairing the DNA-binding capacity of the ETS-family transcription factor SPIB at the NPFF promoter. SMARCA1-deficient CRC cells exhibit increased NPFF secretion, which drives epithelial‒mesenchymal transition (EMT) through autocrine activation of the JAK2/STAT5 signaling axis, subsequently increasing the expression of EMT-related transcription factors. Notably, the oncogenic activity of NPFF was also dependent on immune microenvironment modulation, as NPFF orchestrated the polarization of tumor-associated macrophages toward the M2-like phenotype while upregulating protumorigenic genes, which encode growth factors, chemokines, and matrix metalloproteinases, in macrophages. Our study reveals the SMARCA1-NPFF axis as a dual regulator of metastatic progression and immune microenvironment reprogramming in CRC, identifying the NPFF as a novel therapeutic vulnerability factor for the management of metastatic CRC.