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

Tingting Chen; Jiayu Guo; Liqiang Ai; Yuquan Wang; Yan Wang; Bo Chen; Mingyue Liu; Shuping Zhuang; Kaidong Liu; Zhangxiang Zhao; Haihai Liang; Yunyan Gu

doi:10.1016/j.csbj.2023.11.018

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

Comput Struct Biotechnol J. 2023 Nov 14:21:5751-5764. doi: 10.1016/j.csbj.2023.11.018. eCollection 2023.

Authors

Tingting Chen^{1

2}, Jiayu Guo³, Liqiang Ai^{1

4}, Yuquan Wang³, Yan Wang³, Bo Chen¹, Mingyue Liu¹, Shuping Zhuang³, Kaidong Liu¹, Zhangxiang Zhao⁵, Haihai Liang³, Yunyan Gu¹

Affiliations

¹ Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China.
² Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region of China.
³ Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China.
⁴ Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
⁵ The Sino-Russian Medical Research Center of Jinan University, The Institute of Chronic Disease of Jinan University, The First Affiliated Hospital of Jinan University, Guangzhou, China.

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: SPP1, MMP9, MMP12, FABP4, and IL1B. 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 SPP1⁺ macrophages at the terminal of macrophages' developmental trajectory may promote the progression from IPF to LC. The strong crosstalk between SPP1⁺ macrophages and inflammation-related cancer-associated fibroblasts promoted the tumorigenic process in IPF. In vitro, assays showed that co-culturing macrophages overexpressing SPP1 with MRC-5 cells induced the transition of fibroblasts into cancer-associated fibroblasts. SPP1 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 SPP1 as a critical driver in IPF progression, offering a potential target for therapy in fibrosis.

Keywords: Idiopathic pulmonary fibrosis; Lung cancer; SPP1+ macrophages; Single-cell RNA-seq.