Identification of key molecules in micropapillary progression of lung adenocarcinoma: A comprehensive gene expression analysis study using the spatial gene expression solution methodology

The micropapillary histological subtype is a high-grade element and a poor prognostic marker in lung adenocarcinoma (LUAD). This subtype develops through the lepidic-filigree micropapillary (filigree)-conventional/overt micropapillary (mPAP) pathway. The present study aimed to identify key molecules that promote this progression. To this end, gene expression profiles specific to lepidic, filigree and mPAP elements were investigated in histological sections obtained from 4 different LUAD cases. The 10× Genomics Visium Spatial Gene Expression Solution was used due to its superior resolution compared with conventional microdissection techniques. Cellular retinoic acid binding protein 2 (CRABP2), carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and mucin 21 (MUC21) were identified as common molecules with significantly elevated levels along the lepidic-filigree-mPAP pathway. Furthermore, the present findings indicated that CRABP2 may serve an important role in the early stage of this process, as its level significantly increases during the transition from the lepidic to the filigree substage. Immunohistochemical analysis of the expression of CRABP2, CEACAM5 and MUC21 proteins in 207 surgically resected LUAD samples (expanded sample size) was performed. The present study revealed an increase in the expression levels of CRABP2 between the lepidic and filigree elements, and between filigree and mPAP for CEACAM5 and MUC21. Thus, these three proteins were demonstrated to serve roles in the lepidic-filigree-mPAP pathway at different stages. Notably, these molecules were associated with poor prognosis, characterized by an elevated recurrence rate and poor survival rate. In conclusion, crucial molecules that promote the lepidic-filigree-mPAP pathway, and exhibit potential clinical utility as prognostic markers and molecular therapeutic targets, were identified.