Lung squamous cell carcinoma (LUSC) is associated with poor clinical prognosis and lacks available targeted therapy. Novel molecules are urgently required for the diagnosis and prognosis of LUSC. Here, we conducted our data mining analysis for LUSC by integrating the differentially expressed genes acquired from Gene Expression Omnibus (GEO) database by comparing tumor tissues versus normal tissues (GSE8569, GSE21933, GSE33479, GSE33532, GSE40275, GSE62113, GSE74706) into The Cancer Genome Atlas (TCGA) database which includes 502 tumors and 49 adjacent non-tumor lung tissues. We identified intersections of 129 genes (91 up-regulated and 38 down-regulated) between GEO data and TCGA data. Based on these genes, we conducted our downstream analysis including functional enrichment analysis, protein-protein interaction, competing endogenous RNA (ceRNA) network and survival analysis. This study may provide more insight into the transcriptomic and functional features of LUSC through integrative analysis of GEO and TCGA data and suggests therapeutic targets and biomarkers for LUSC.

The complexity of the tumor microenvironment (TME) is a crucial factor in lung adenocarcinoma (LUAD) progression. To gain deeper insights into molecular mechanisms of LUAD, we perform an integrative single-cell RNA sequencing (scRNA-seq) data analysis of 377,574 cells from 117 LUAD patient samples. By linking scRNA-seq data with bulk gene expression data, we identify a cluster of prognostic-related UPP1^high tumor cells. These cells, primarily situated at the invasive front of tumors, display a stronger association with the immunosuppressive components in the TME. Our cytokine array analysis reveals that the upregulation of UPP1 in tumor cells leads to the increased release of various immunosuppressive cytokines, with TGF-β1 being particularly prominent. Furthermore, this UPP1 upregulation also elevates the expression of PD-L1 through the PI3K/AKT/mTOR pathway, which contributes to the suppression of CD8 + T cells. Cytometry by time-of-flight (CyTOF) analysis provides additional evidence of the role of UPP1 in shaping the immunosuppressive nature of the TME. Using patient-derived organoids (PDOs), we discover that UPP1^high tumors exhibit relatively increased sensitivity to Bosutinib and Dasatinib. Collectively, our study highlights the immunosuppressive role of UPP1 in LUAD, and these findings may provide insights into the molecular features of LUAD and facilitate the development of personalized treatment strategies.

To evaluate the clinical features and radiomics nomograms of tumors and peritumoral regions for the preoperative prediction of the presence of spread through air spaces (STAS) in patients with lung adenocarcinoma. A total of 107 STAS-positive lung adenocarcinomas were selected and matched to 105 STAS-negative lung adenocarcinomas. Thin-slice CT imaging annotation and region of interest (ROI) segmentation were performed with semi-automatic in-house software. Radiomics features were extracted from all nodules and incremental distances of 5, 10, and 15 mm outside the lesion segmentation. A radiomics nomogram was established with multivariable logistic regression based on clinical and radiomics features. The maximum diameter of the solid component and mediastinal lymphadenectasis were selected as independent predictors of STAS. The radiomics nomogram of lung nodules showed especially good prediction in the training set [area under the curve (AUC), 0.98; 95% confidence interval (CI), 0.97–1.00] and test set (AUC, 0.99; 95% CI, 0.97–1.00). The radiomics nomogram of peritumoral regions also showed good prediction, but the fitting degrees of the calibration curves were not good. Our study may provide guidance for surgical methods in patients with lung adenocarcinoma.

FoxM1 has been reported to be important in initiation and progression of various tumors. However, whether FoxM1 has any indication for prognosis in non-small cell lung cancer patients remains unclear. In this study, FoxM1 expression in tumor cells was examined first by immunohistochemistry in 175 NSCLC specimens, the result of which showed that FoxM1 overexpression was significantly associated with positive smoking status (P = 0.001), poorer tissue differentiation (P = 0.0052), higher TNM stage (P<0.0001), lymph node metastasis (P<0.0001), advanced tumor stage (P<0.0001), and poorer prognosis (P<0.0001). Multivariable analysis showed that FoxM1 expression increased the hazard of death (hazard ratio, 1.899; 95% CI, 1.016–3.551). Furthermore, by various in vitro and in vivo experiments, we showed that targeted knockdown of FoxM1 expression could inhibit the migratory and invasive abilities of NSCLC cells, whereas enforced expression of FoxM1 could increased the invasion and migration of NSCLC cells. Finally, we found that one of the cellular mechanisms by which FoxM1 promotes tumor metastasis is through inducing epithelial-mesenchymal transition (EMT) program. These results suggested that FoxM1 overexpression in tumor tissues is significantly associated with the poor prognosis of NSCLC patients through promoting tumor metastasis.

Ferroptosis, an iron-dependent non-apoptotic cell death, has been shown to play a vital role in tumor proliferation and chemotherapy resistance. Here, we report that KLF11 inhibits lung adenocarcinoma (LUAD) cell proliferation and promotes chemotherapy sensitivity by participating in the GPX4-related ferroptosis pathway. Through an RNA-sequence screen from LUAD cells pretreatment with ferroptosis inducers (FINs), we discovered that KLF11 expression was significantly higher in FINs-treated cells, suggesting that KLF11 may be involved in ferroptosis. Overexpression of KLF11 promoted LUAD cells to undergo ferroptosis alterations. Meanwhile, upregulation of KLF11 expression also inhibited cell proliferation and increased chemosensitivity, whereas knockout of KLF11 did the opposite. With ChIP-Seq and RNA-Seq, we identified GPX4 as a downstream target of KLF11. Through ChIP-qPCR and dual luciferase assay, we clarified that KLF11 binds to the promoter region of GPX4 and represses its transcription. Restored GPX4 expression antagonized the ability of KLF11 to promote ferroptosis, increase chemotherapy sensitivity and inhibit cell proliferation in vitro and in vivo. Clinically, KLF11 declined in LUAD and its low expression was associated with reduced patient survival. Our findings established the function of KLF11 to promote ferroptosis in LUAD, thereby inhibiting cell proliferation and enhancing the efficacy of chemotherapy.