Neuropeptide Precursor VGF Promotes Neuroendocrine Differentiation and Cancer-Associated Fibroblast Activation in Small Cell Lung Cancer

Small cell lung cancer (SCLC) is a highly aggressive malignancy with limited therapeutic options. Neuroendocrine differentiation is a prominent feature of SCLC. This study identified VGF, a secreted neuropeptide precursor, as a critical regulator of neuroendocrine differentiation in SCLC, particularly the achaete-scute homolog 1 (ASCL1)+ subtype. VGF orchestrated upregulation of the transcription factor ASCL1 through a cAMP-responsive element-binding protein-dependent mechanism, thereby promoting neuroendocrine differentiation. Furthermore, VGF mediated the transformation of fibroblasts into cancer-associated fibroblasts (CAF), establishing metabolic coupling between SCLC cells and CAFs via lactate exchange. A therapeutic strategy targeting VGF and monocarboxylate transporter 1 disrupted neuroendocrine differentiation and SCLC-CAF metabolic coupling, demonstrating significant efficacy in both in vitro and in vivo models. Together, this study provides insights into the mechanisms underlying SCLC neuroendocrine differentiation and reveals targets and therapeutic strategies for advanced SCLC. SIGNIFICANCE: VGF is a therapeutic target in small cell lung cancer that promotes expression of ASCL1 to drive neuroendocrine differentiation and mediates lactate exchange between cancer cells and fibroblasts in the tumor microenvironment.