Tipping point and molecular mechanism of the transformation of lung adenocarcinoma in situ to invasive adenocarcinoma: A study based on dynamic network markers in systems biology

Abstract

Background

Lung adenocarcinoma in situ (AIS), characterised by ground-glass nodules as observed in computed tomography imaging, generally demonstrates a relatively inert biological behaviour and exhibits slow growth rates. Upon transitioning to invasive adenocarcinoma (IAC), the growth rate significantly increases. The molecular mechanisms governing this transformation remain poorly understood.

Methods

This study employed the dynamic network marker (DNB) approach grounded in systems biology to analyse transcriptomic sequencing data from 30 lung nodules including one case of atypical adenomatous hyperplasia, eight cases of AIS, 10 cases of minimally invasive adenocarcinoma (MIA) and 11 cases of IAC and their corresponding 30 adjacent normal tissues from 21 patients were analysed. The primary objective was to elucidate the tipping point and biological mechanisms involved in the progression of lung AIS to IAC.

Results

We successfully constructed a dynamic gene expression network linking lung AIS, MIA and IAC. A total of 144 key differential genes were identified, establishing MIA as the critical tipping point for transformation. Furthermore, our findings underscored the significance of pyruvate metabolism in relation to metabolic enzyme genes such as PKLR and LDHAL6A, the metabolic regulation of tumour cells reflecting the Warburg effect during the invasive transformation of lung AIS.

Conclusion

This study demonstrates that the DNB-based approach to identify the tipping point (MIA stage) and associated key genes and pathways in the invasive transformation of lung adenocarcinoma, providing a novel systems biology perspective for dynamic risk monitoring.