Lung cancer stem cells have the ability to self-renew and are resistant to conventional chemotherapy. MicroRNAs (miRNAs) regulate and control the expression and function of many target genes; therefore, miRNA disorders are involved in the pathogenesis of human diseases, such as cancer. However, the effects of miRNA dysregulation on tumour stemness and drug resistance have not been fully elucidated. miR-181b has been reported to be a tumour suppressor miRNA and is associated with drug-resistant non-small cell lung cancer. Cancer stem cell (CSC)-like properties were tested by a cell proliferation assay and flow cytometry; miR-181b expression was measured by real-time PCR; and Notch2 and related proteins were detected by Western blotting and immunohistochemistry. A mouse xenograft model was also established. In this study, we found that ectopic miR-181b expression suppressed cancer stem cell properties and enhanced sensitivity to cisplatin (DDP) treatment by directly targeting Notch2. miR-181b could inactivate the Notch2/Hes1 signalling pathway. In addition, tumours from nude mice treated with miR-181b were significantly smaller than tumours from mice treated with control agomir. Decreased miR-181b expression and increased Notch2 expression were observed to have a significant relationship with overall survival (OS) and CSC-like properties in non-small cell lung cancer (NSCLC) patients. This study elucidates an important role of miR-181b in the regulation of CSC-like properties, suggesting a potential therapeutic target for overcoming drug resistance in NSCLC.

14-3-3/TGFR1 promotes tumor metastasis in lung squamous cell carcinoma

Autophagy plays a complicated role in tumorigenesis, and the effects of autophagy in drug resistance have not been fully known. The aim of this study was to evaluate autophagy activity in lung cancer cells derived from different origins and explore the mechanism regulating autophagy in tyrosine kinase inhibitor (TKI) resistance. We found basal level of autophagy had no significant increase in resistant H1650 and H1975 cells compared with sensitive HCC827 and PC9 cells. After erlotinib treatment, the autophagy activity enhanced threefold in H1650 cells but a little in H1975 cells. Inhibiting autophagy with 3-MA increased apoptosis in H1650 rather than H1975 cells. Combined with transmission microscope, results showed PC9 cells tended to be apoptotic and more autophagosomes formed in H1650 cells, which may be correlated with cell viability. GATA6 expression was found markedly elevated in H1650 cells after erlotinib and knocking down GATA6 led to significantly reduced autophagy activity and cell viability. Furthermore, a significant increase of GATA6 and LC3-II expression was observed in insensitive tissues compared with sensitive ones by immunostaining in nonsmall cell lung cancer (NSCLC) patients. With chi-square test, we found GATA6 was positively correlated with LC3-II. The Kaplan-Meier curve analyses further showed patients with high GATA6 had lower overall survival and progression-free survival rates than those with low GATA6 after EGFR-TKI treatment. Our results suggest that GATA6 could enhance autophagy activity contributing to TKI resistance. Targeting GATA6 and autophagy together with TKI may be promising to overcome drug resistance in NSCLC.

Small cell lung cancer (SCLC) remains a lethal malignancy. Although immunochemotherapy regimens have improved patient survival rates, drug resistance still occurs in a significant subset of patients, highlighting the importance of elucidating the mechanisms within the tumor microenvironment. Here, we applied spatial single-cell transcriptomics to investigate the spatial characteristics of SCLC and their associations with immunochemotherapy resistance. By analyzing samples from 18 patients with extensive-stage SCLC, we identified two distinct epithelial cell subtypes: Epi-I and Epi-II. Epi-I exhibited high proliferative activity and was associated with treatment resistance and poor survival outcomes. In contrast, Epi-II showed more spatial contact with immune cells and was associated with treatment sensitivity. Further analysis uncovered a fascinating cellular transition paradigm, wherein Epi-I may be derived from Epi-II, with myeloid cells playing a facilitatory role in this transformation cascade. Specifically, within the spatial zone that was enriched with the Epi-II, epithelial cells may secrete MIF gene, which promoted the polarization of myeloid cells towards the M2 macrophages. The M2-polarized myeloid cells subsequently upregulated the expression of SPP1 that in turn triggered the activation of the PI3K-AKT signaling pathway in the adjacent epithelial cells, driving the conversion of Epi-II to Epi-I cells. Our findings revealed that the intricate crosstalk between epithelial and myeloid cells constitutes a pivotal resistance mechanism in SCLC, and targeting the SPP1/MIF pathway emerged as a promising strategy with the potential to enhance the treatment efficacy.

The therapeutic efficacy and prognosis of various tumors can be assessed using the systemic immune-inflammatory index (SII) and prognostic nutritional index (PNI). Despite their potential, no studies have investigated the prognostic value of the combined SII-PNI score for outcomes in patients with extensive small cell lung cancer (ES-SCLC) treated with chemotherapy and immune checkpoint inhibitors (ICIs). Our study retrospectively examined 213 ES-SCLC patients treated with chemotherapy and ICIs across two institutions. The patients were divided into three groups based on their SII-PNI scores. Cox regression analysis was employed to identify independent prognostic factors. A nomogram was constructed based on these independent factors. With 1000 repeated samples, the bootstrap method was used to validate the nomogram model internally. The model’s performance was assessed using calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). Before and after chemotherapy with immune checkpoint inhibitors (ICIs), SII was significantly higher in the PD group compared with the PR group (both p < 0.05). In the meantime, PNI was considerably lower in the PD group than in the PR group (both p < 0.01). Kaplan-Meier curves demonstrated that patients with a low SII-PNI had prolonged progression-free survival (PFS) and overall survival (OS) compared to those with a high SII-PNI (all p < 0.01). Multivariate Cox analysis showed that PS = 1, bone metastasis, brain metastasis, and SII-PNI = 1,2 after four treatment cycles were independent risk factors for shorter OS and were included in the nomogram model. The ROC curves, C-index, and DCA curves confirm that the SII-PNI scores-based nomograms have strong predictive accuracy for OS. There was a significant correlation between pre- and post-treatment SII-PNI and treatment effect in ES-SCLC. The SII-PNI score after four treatment cycles is a useful prognostic indicator for ES-SCLC patients receiving chemotherapy combined with immune checkpoint inhibitors (ICIs).