Deciphering the transcriptional regulatory network driving lung adenocarcinoma progression

Normal type II alveolar epithelial cells transform into lung adenocarcinoma through intermediate stages of adenocarcinoma in situ and minimally invasive adenocarcinoma, eventually becoming invasive adenocarcinoma. Transcription factors (TFs) are pivotal in tumorigenesis and development, etc. In this study, we modeled the malignant transformation of AT2 cells into lung adenocarcinoma using single-cell profiling, focusing on TF-mediated transcriptional repression or activation as a key mechanism. We analyzed data from 29 motifs database, including Jaspar, Bergman, Transfac and cisBP, compiling a collection of 18,422 motifs. By integrating Motif analysis to deduce the target genes regulated by transcription factors exhibiting activity alterations across various progression stages of lung adenocarcinoma, and subsequently determining the intersection between these target genes and the differentially expressed genes at each stage, we can pinpoint the target genes that are both differentially expressed and under the regulation of key transcription factors at each stage. Consequently, the regulatory mechanism of TFs on target genes in lung adenocarcinoma was speculated. Furthermore, the transcriptional regulatory network reveals that TFs modulate signaling pathways, cellular metabolism, and biological processes during the transformation process. In addition, leveraging six transcription factors (REBF2, CEBPB, TFCP2, IRF6, ETV4, and BHLHE40) that exhibit progressively increasing activity during the progression of lung adenocarcinoma, we developed a pivotal progression model score, termed the "Lung Adenocarcinoma Transformation TFs Upregulation" (LUAD-TTFs-UP) score, to predict both the progression and prognosis of this disease.