Acquired resistance represents a bottleneck for effective molecular targeted therapy in lung cancer. Metabolic adaptation is a distinct hallmark of human lung cancer that might contribute to acquired resistance. In this study, we discovered a novel mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (TKI) mediated by IGF2BP3-dependent cross-talk between epigenetic modifications and metabolic reprogramming through the IGF2BP3–COX6B2 axis. IGF2BP3 was upregulated in patients with TKI-resistant non–small cell lung cancer, and high IGF2BP3 expression correlated with reduced overall survival. Upregulated expression of the RNA binding protein IGF2BP3 in lung cancer cells reduced sensitivity to TKI treatment and exacerbated the development of drug resistance via promoting oxidative phosphorylation (OXPHOS). COX6B2 mRNA bound IGF2BP3, and COX6B2 was required for increased OXPHOS and acquired EGFR-TKI resistance mediated by IGF2BP3. Mechanistically, IGF2BP3 bound to the 3′-untranslated region of COX6B2 in an m6A-dependent manner to increase COX6B2 mRNA stability. Moreover, the IGF2BP3–COX6B2 axis regulated nicotinamide metabolism, which can alter OXPHOS and promote EGFR-TKI acquired resistance. Inhibition of OXPHOS with IACS-010759, a small-molecule inhibitor, resulted in strong growth suppression in vitro and in vivo in a gefitinib-resistant patient-derived xenograft model. Collectively, these findings suggest that metabolic reprogramming by the IGF2BP3–COX6B2 axis plays a critical role in TKI resistance and confers a targetable metabolic vulnerability to overcome acquired resistance to EGFR-TKIs in lung cancer. Significance: IGF2BP3 stabilizes COX6B2 to increase oxidative phosphorylation and to drive resistance to EGFR inhibitors in lung cancer, which provides a therapeutic strategy to overcome acquired resistance by targeting metabolic transitions.

Non-intubated video-assisted thoracoscopic surgery (NIVATS) has been increasingly used in lobectomy, bullectomy, wedge resection, lung volume reduction, sympathectomy and talc pleurodesis, which may reduce postoperative complications. However, the benefits of non-intubated and intubated methods of VATS remain controversial. We comprehensively searched PubMed, Web of Science, Embase and the Cochrane Library, and performed a systematic review to assess the two techniques. Random and fixed-effects meta-analytical models were used based on the low between-study heterogeneity. Study quality, publication bias, and heterogeneity were assessed. Compared to intubated methods, NIVATS had a lower postoperative complications rate [odds ratio (OR): 0.63; 95% confidence interval (CI), 0.46-0.86; P<0.01], shorter global in-operating time [weighted mean difference (WMD): -35.96 min; 95% CI, -48.00 to -23.91; P<0.01], shorter hospital stay (WMD: -1.35 days; 95% CI, -1.72 to -0.98; P<0.01), shorter anesthesia time (WMD: -7.29 min; 95% CI, -13.30 to -1.29; P<0.01), shorter chest-tube placement time (WMD: -1.04 days; 95% CI, -1.75 to -0.33; P<0.01), less chest pain (WMD: -1.31; 95% CI, -2.45 to -0.17; P<0.05) and lower perioperative mortality rate (OR: 0.13; 95% CI, 0.02-0.99; P=0.05). NIVATS is a safe, efficient and feasible technique for thoracic surgery and may be a better alternative procedure owing to its advantage in reducing postoperative complications rate, hospital stay, and chest pain.

Aging is a global challenge, marked in the lungs by function decline and structural disorders, which affects the health of the elderly population. To explore anti-aging strategies, we develop a dynamic atlas covering 45 cell types in human lungs, spanning from embryonic development to aging. We aim to apply the discoveries of lung’s development to address aging-related issues. We observe that both epithelial and immune cells undergo a process of acquisition and loss of essential function as they transition from development to aging. During aging, we identify cellular phenotypic alternations that result in reduced pulmonary compliance and compromised immune homeostasis. Furthermore, we find a distinctive expression pattern of the ferritin light chain (FTL) gene, which increases during development but decreases in various types of lung cells during the aging process.

Background: Metastasis is the primary cause of mortality in small cell lung cancer (SCLC), with the liver being a predominant site for distal metastasis. Despite this clinical significance, mechanisms underlying the interaction between SCLC and liver microenvironment, fostering metastasis, remain unclear. Methods: SCLC patient tissue array, bioinformatics analysis were performed to demonstrate the role of periostin (POSTN) in SCLC progression, metastasis, and prognosis. Cell migration, invasion and sphere formation assay were performed to determine the oncogenic role of POSTN. RNA sequencing analysis was utilized to identify the key signaling pathway regulated by POSTN. Immunoprecipitation, immunofluorescence and co-culture system were used to clarify the mechanism of POSTN-NOTCH1 axis in tumor cells-hepatic stellate cells (HSCs) crosstalk. Subcutaneous xenograft model and liver metastasis model were established to examine the anti-tumor growth and metastases effect of targeting POSTN-NOTCH1 signaling axis. Results: Elevated expression of POSTN in SCLC is correlated with accelerated tumor progression and metastasis. Conditioned medium rich in POSTN derived from SCLC tumors demonstrates the ability to activate HSCs in the liver microenvironment. Mechanistically, POSTN emerges as a binding partner for the membrane receptor NOTCH1 and transducing the extracellular signals to intracellular fibroblasts. Furthermore, targeting the POSTN-NOTCH1 signaling axis proves effective in suppressing SCLC tumor growth and inhibiting liver metastasis. This study elucidates that the SCLC-derived secreted protein POSTN interacts with NOTCH1 on HSCs to promote the activation of HSCs, thereby providing a favorable microenvironment for liver metastasis. Conclusion: These findings uncover the intricate communications between primary SCLC cells and HSCs in the tumor microenvironment mediated by the secreted protein POSTN in the context of liver metastasis. Consequently, targeting the POSTN-NOTCH1 signaling axis emerges as a promising therapeutic strategy for metastatic SCLC.

Recent studies recommend sublobectomy as a surgical approach for non-small cell lung cancer (NSCLC) tumors that are 2 cm or smaller. However, it remains unclear whether NSCLC patients with squamous cell carcinoma (SCC) have comparable outcomes to those with adenocarcinoma (ADC) following sublobectomy. To that end, this study aims to compare the survival outcomes between SCC and ADC in patients with stage IA NSCLC (≤ 2 cm) who have undergone sublobectomy. We identified stage IA (≤ 2 cm) NSCLC patients diagnosed with lung squamous cell carcinoma or adenocarcinoma pathology and underwent sublobectomy from the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2020. Overall survival (OS) was determined using the Kaplan–Meier method, and Cox proportional hazards regression was employed to identify risk factors for OS. A total of 9,831 patients diagnosed with stage IA NSCLC (≤ 2 cm) were evaluated. Of these, 2,078 patients met the inclusion criteria, including 1,565 with adenocarcinoma (ADC) and 513 with squamous cell carcinoma (SCC). Notably, SCC was associated with worse overall survival compared to ADC (HR: 2.02, 95% CI: 1.34–3.05, P = 0.03). Subgroup analyses revealed that SCC was comparable to ADC in terms of OS for tumors ≤ 1 cm (HR: 1.22, 95% CI: 0.47–3.18, P = 0.83), while patients with SCC displayed worse OS compared to ADC for tumors > 1 to 2 cm (HR: 2.05, 95% CI: 1.31–3.23, P = 0.002). Cox proportional hazards regression analysis identified female sex (HR: 1.53, 95% CI: 1.08–2.19, P = 0.017), high tumor grade (HR: 1.76, 95% CI: 1.02–3.03, P = 0.011), and SCC (HR: 1.58, 95% CI: 1.08–2.30, P = 0.017) as independent risk factors for OS. In patients with stage IA (≤ 2 cm) NSCLC who underwent sublobectomy, SCC is associated with worse overall survival compared to ADC. Furthermore, being female, having a high tumor grade, and SCC pathology are independent risk factors for OS in these patients.