Up-regulated SPP1 increases the risk from IPF to lung cancer via activating the pro-tumor macrophages

Abstract

The incidence of lung cancer (LC) in Idiopathic Pulmonary Fibrosis (IPF) patients is more than twice that in non-IPF. This study aims to investigate IPF-to-LC pathogenesis and to develop a predictor for detecting IPF predisposing patients to LC. We conducted unsupervised clustering to detect high-risk subtypes from IPF to LC. Subsequently, we performed single-cell RNA-seq analysis to characterize high-risk IPF by examining the immune microenvironment. We identified 42 common immune function-related pathogenic genes between IPF and LC. We developed an LC risk classifier for IPF patients, comprising five genes: <i>SPP1</i>, <i>MMP9</i>, <i>MMP12</i>, <i>FABP4</i>, and <i>IL1B</i>. The five-gene classifier can successfully distinguish the high-risk population from IPF patients. High-risk IPF patients exhibited an immunosuppressive microenvironment with higher oncogene expression than low-risk patients. Single-cell analysis revealed that <i>SPP1</i>⁺ macrophages at the terminal of macrophages' developmental trajectory may promote the progression from IPF to LC. The strong crosstalk between <i>SPP1</i>⁺ macrophages and inflammation-related cancer-associated fibroblasts promoted the tumorigenic process in IPF. In vitro, assays showed that co-culturing macrophages overexpressing <i>SPP1</i> with MRC-5 cells induced the transition of fibroblasts into cancer-associated fibroblasts. <i>SPP1</i> produced by macrophages promoted epithelial-mesenchymal transition in alveolar epithelial cells via stimulating the upregulation of N-cadherin and Vimentin in MLE-12 cells. This study provided a novel method to identify the LC risk population from IPF, revealing the cellular interactions involved in the transition from IPF to LC. Our findings highlighted <i>SPP1</i> as a critical driver in IPF progression, offering a potential target for therapy in fibrosis.