Evolutionary metabolic landscape from preneoplasia to invasive lung adenocarcinoma


Nie MengORCID,Yao KeORCID,Zhu XinshengORCID,Chen NaORCID,Xiao NanORCID,Wang Yi,Peng BoORCID,Yao LiAngORCID,Li Peng,Zhang PengORCID,Hu ZepingORCID


AbstractMetabolic reprogramming evolves during cancer initiation and progression. However, thorough understanding of metabolic evolution from preneoplasia to lung adenocarcinoma (LUAD) is still limited. Here, we perform large-scale targeted metabolomics on resected lesions and plasma obtained from invasive LUAD and its precursors, and decipher the metabolic trajectories from atypical adenomatous hyperplasia (AAH) to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC), revealing that perturbed metabolic pathways emerge early in premalignant lesions. Furthermore, three panels of plasma metabolites are identified as non-invasive predictive biomarkers to distinguish IAC and its precursors with benign diseases. Strikingly, metabolomics clustering defines three metabolic subtypes of IAC patients with distinct clinical characteristics. We identify correlation between aberrant bile acid metabolism in subtype III with poor clinical features and demonstrate dysregulated bile acid metabolism promotes migration of LUAD, which could be exploited as potential targetable vulnerability and for stratifying patients. Collectively, the comprehensive landscape of the metabolic evolution along the development of LUAD will improve early detection and provide impactful therapeutic strategies.


National Natural Science Foundation of China


Springer Science and Business Media LLC


General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry








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