Single cell RNA-seq and bulk RNA-seq analysis identifies MUC1 as a key gene for lung adenocarcinoma to neuroendocrine transformation

Tyrosine kinase inhibitors (TKIs) have demonstrated significant effectiveness in treating advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Despite initial success, resistance to EGFR-TKIs inevitably occurs. One observed phenomenon in resistant lung cancers is the histological transformation from NSCLC to neuroendocrine carcinoma (NEC). The objective of this study is to explore and delineate the genetic and immune features linked to the transition from lung adenocarcinoma (LUAD) to NEC. Bulk RNA-sequencing and Mendelian randomization (MR) analysis were utilized to identify candidate genes associated with the progression from LUAD to NEC. Expression quantitative trait locus data from publicly available databases were leveraged to pinpoint key genes in relevant tissues. Furthermore, the immune microenvironment was explored using weighted gene co-expression network analysis (WGCNA) and cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) databases. Single-cell RNA sequencing data from 16,765 cells across six tissue biopsy samples of LUAD and NEC were scrutinized to investigate cell interaction networks during histological transformation. The molecular pathways involved in dynamic cellular processes were elucidated through the analysis of cellular communication and pseudotime trajectory. Through the use of RNA-sequencing and MR analysis, it was determined that mucin-1 (MUC1) displayed a negative correlation with the progression of LUAD to NEC, as evidenced by its downregulation in clinical specimens. Additionally, MUC1 expression was found to be significantly correlated with the infiltration of diverse immune cell populations, notably CD8+ T cells. These results suggest a notable enrichment of neuron-related signaling pathways in the context of transformed NEC. Examination of immune cell infiltration in NEC indicated a reduction in the proportion of CD8+ central memory T cells, which has implications for the immune microenvironment and may point to potential therapeutic targets. Further investigation into cell-cell interactions among subpopulations identified the MIF-CD74 axis as the principal signaling pathway facilitating intercellular communication between immune cells and epithelial cells. In conclusion, our study provides insights into the molecular landscape governing the LUAD-to-NEC transition, highlighting MUC1 as a potential biomarker. The immune microenvironment is believed to exert a substantial influence on histological transformation, particularly with regards to T cells.