ANT

Lung cancer remains the leading cause of cancer-related mortality worldwide, with increasing evidence suggesting that tumor-associated inflammatory cells influence tumor progression. This study investigates the role of neutrophil elastase (NE), encoded by Elane, in lung adenocarcinoma using the loxP-Stop-loxP K-ras(G12D) (LSL-K-ras) mouse model. Deletion of Elane significantly reduced tumor burden and improved survival, with all LSL-K-ras-Elane(+/+) mice succumbing to disease while none of the Elane-deficient mice died. Mechanistically, NE directly promotes tumor cell proliferation by entering the endosomal compartment of lung adenocarcinoma cells, where it degrades insulin receptor substrate-1 (IRS-1). This degradation enhances phosphatidylinositol 3-kinase (PI3K) association with platelet-derived growth factor receptor (PDGFR), driving tumor growth. The inverse relationship between NE and IRS-1 observed in the mouse model was also confirmed in human lung adenocarcinomas, underscoring the translational relevance of these findings. This study not only identifies IRS-1 as a key regulator of PI3K signaling in malignant cells but also provides the first evidence of a secreted proteinase penetrating intracellular compartments to modulate signaling pathways, offering new therapeutic insights into lung cancer progression.