FNDC4 Drives Metastasis and Immune Evasion in Pancreatic Cancer

作者：Li JingWei, Renfei Wu, Xiaohan Jin, Yuntao Yang, Ke Jiang, Yilin Wang, Shenghui Huang, Serena Tondi, Chu-Hu Lai, Shuang Lin Dong, Berina Šabanović, Miriam Roberto, Chenlei Wen, Yu Jiang, Da Fu, Alexandra Aicher, Baiyong Shen, Christopher Heeschen · 发表于：Cancer Research · 年份：2025 · DOI：10.1158/0008-5472.can-25-1001 · 被引用次数：4 · 研究领域：Cell Adhesion Molecules Research、Immune cells in cancer、Ferroptosis and cancer prognosis

Pancreatic ductal adenocarcinoma (PDAC) is highly metastatic and largely refractory to current therapies, underscoring the need to uncover the molecular drivers of progression to identify targetable vulnerabilities. In this study, we found that fibronectin type III domain-containing 4 (FNDC4), known for its role in macrophage polarization and metabolic regulation, was elevated in metastatic PDAC cells and correlated with poor patient outcomes. FNDC4 knockdown reduced tumor growth and metastasis in a diverse set of aggressive PDAC models. Mechanistically, FNDC4 enhanced cell cycle and apoptosis regulator 1 (CCAR1) stability, thereby sustaining CCAR1/β-catenin signaling. FNDC4 deficiency led to reduced CCAR1 and β-catenin expression and consequently impaired invasion and colony formation. Moreover, FNDC4 promoted immune evasion by driving macrophage polarization toward a protumorigenic M2 phenotype. FNDC4 loss shifted macrophage polarization toward an antitumor profile and increased CD4+ and CD8+ T-cell infiltration. Together, the effects of FNDC4 targeting resulted in reduced tumor burden, suppression of metastasis, and improved survival in immunocompetent murine PDAC models. Unexpectedly, FNDC4 localized to the nucleus, pointing to potential intranuclear activity. Transcriptomic and functional analyses further identified CCL5 as a critical downstream effector, required for recruiting CCR5+ T cells and mediating the immune effects of FNDC4 inhibition. Upstream, BHLHE40 directl...