Metastatic Lung Cancer Research Articles

Brain Metastasis of Non-small Cell Lung Cancer After Disease-Free Survival of 5 years: Case Series and Comprehensive Literature Review

BackgroundIn the treatment of non-small cell lung cancer (NSCLC), a disease-free survival (DFS) of 5 years is a criterion for cure. This study aimed to evaluate the characteristics and outcomes of patients with brain metastases of NSCLC after a DFS of 5 years (late recurrent brain metastasis, LRBM). MethodsWe reviewed 1,281 consecutive patients with brain metastasis of lung cancer at a single institute between November 2014 and December 2022. Relevant articles were retrieved from PubMed. Only peer-reviewed journals published in English were included. ResultsSix patients (0.47%) showed LRBM. Three were male. The median age at lung cancer diagnosis was 45 years. The histological diagnosis of all patients was adenocarcinoma. Driver gene mutations were observed in five patients. The median latency period from lung cancer treatment to the development of brain metastasis was 13 years. All patients had no metastasis to any other organs and underwent craniotomies. The median follow-up duration after craniotomy was 3.5 years. No local intracranial recurrences were observed. Three patients had distant intracranial recurrences at 7, 2, and 0.6 years after craniotomy. Five patients survived for 8, 4, 3, 2, and 0.3 years after craniotomy. One patient experienced re-recurrence in the lung 4 years after craniotomy and died 3.7 years later. In our systematic review, only six studies described LRBM of NSCLC. ConclusionsLRBM is rare in patients with NSCLC. In our institution, many of these patients harbored driver gene mutations, and achieved long-term survival with aggressive local therapy. Multicenter analysis is mandatory.

LncRNA MIR100HG affects the proliferation and metastasis of lung cancer cells through mediating the microRNA-5590-3p/DCBLD2 axis.

The aim of this paper is to investigate the effect of long noncoding RNA (lncRNA) MIR100HG on the proliferation and metastasis of lung cancer cells by mediating the microRNA (miR)-5590-3p/DCBLD2 axis. RNA levels of MIR100HG, miR-5590-3p, and DCBLD2 in lung cancer tissues and cells were detected by quantitative reverse-transcription polymerase chain reaction, and protein level was assessed by Western blot. Effects of MIR100HG or miR-5590-3p on proliferation, migration, and invasion of lung cancer cells were detected by Cell Counting Kit-8, colony formation, and Transwell assays. Luciferase reporter assay and RNA-immunoprecipitation assay confirmed the target relationship between miR-5590-3p and MIR100HG or DCBLD2. MIR100HG and DCBLD2 were highly expressed, while miR-5590-3p was lowly expressed in lung cancer tissues and cells. Silencing MIR100HG or upregulating miR-5590-3p impeded lung cancer cell proliferation, migration, and invasion. MIR100HG could up-regulate DCBLD2 by sponging miR-5590-3p. Downregulation of miR-5590-3p partly overturned the suppressive effect of silencing MIR100HG on lung cancer cell proliferation and metastasis, and overexpression of DCBLD2 also reversed the effect of overexpression of miR-5590-3p on lung cancer cell proliferation and metastasis. LncRNA MIR100HG promotes lung cancer progression by targeting and negatively regulating DCBLD2 through binding with miR-5590-3p.

114 Non-dilated Obstructive Uropathy: A Cause of Rapidly Reversible AKI in a Patient with Metastatic Lung Cancer

114 Non-dilated Obstructive Uropathy: A Cause of Rapidly Reversible AKI in a Patient with Metastatic Lung Cancer

Total metabolic tumor volume on 18F-FDG PET/CT is a game-changer for patients with metastatic lung cancer treated with immunotherapy

PurposeBecause of atypical response imaging patterns in patients with metastatic non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICPIs), new biomarkers are needed for a better monitoring of...

Relationship Between Clozapine and Non-Hematological Malignant Tumors: A Pharmacovigilance Analysis Using the FDA Adverse Event Reporting System Database.

Clozapine shows higher efficacy against treatment-resistant schizophrenia than other antipsychotics. This study aimed to investigate whether clozapine is associated with the risk of non-hematological malignant tumors, utilizing the US Food and Drug Administration (FDA) Adverse Event Report System (FAERS) database. The records from the first quarter of 2004 to the third quarter of 2012 were used for disproportionality analysis, and patients who developed non-hematological malignant tumors were identified by the Standardized Medical Dictionary for Regulatory Activities Queries (SMQ). Of the 3,641,281 patients with 12,401,586 reports of adverse drug events, 151,904 reports belonged to non-hematological malignant tumors (SMQ). We identified 1668 reports of non-hematological malignant tumors (SMQ) in clozapine users, and the reporting odds ratio (ROR) was calculated to be 1.28 (95% confidence interval (CI): 1.22-1.34). ROR (95% CI) for the relationship between clozapine and the risk of testis cancer was calculated as 10.94 (6.99-17.12), 9.87 (7.42-13.15) for gastrointestinal carcinoma, 7.48 (5.57-10.05) for metastatic lung cancer, 6.71 (4.52-9.97) for throat cancer, 6.12 (4.56-8.21) for metastases to the spine, 5.97 (5.30-6.72) for lung malignant neoplasm, 5.07 (3.69-6.95) for esophageal carcinoma, 1.88 (1.43-2.47) for colon cancer, and 1.65 (1.24-2.21) for metastases to the liver. Colon cancer, esophageal carcinoma, and throat cancer were predominantly reported in males, and metastases to the spine and liver were in females. This study detected signals indicating a relationship between clozapine and certain non-hematological malignant tumors, utilizing the FAERS database. Despite the database relying on spontaneous reporting, the current results justify further investigation.

CT-based intratumoral and peritumoral deep transfer learning features prediction of lymph node metastasis in non-small cell lung cancer.

The main metastatic route for lung cancer is lymph node metastasis, and studies have shown that non-small cell lung cancer (NSCLC) has a high risk of lymph node infiltration. This study aimed to compare the performance of handcrafted radiomics (HR) features and deep transfer learning (DTL) features in Computed Tomography (CT) of intratumoral and peritumoral regions in predicting the metastatic status of NSCLC lymph nodes in different machine learning classifier models. We retrospectively collected data of 199 patients with pathologically confirmed NSCLC. All patients were divided into training (n = 159) and validation (n = 40) cohorts, respectively. The best HR and DTL features in the intratumoral and peritumoral regions were extracted and selected, respectively. Support Vector Machine (SVM), k-Nearest Neighbors (KNN), Light Gradient Boosting Machine (Light GBM), Multilayer Perceptron (MLP), and Logistic Regression (LR) models were constructed, and the performance of the models was evaluated. Among the five models in the training and validation cohorts, the LR classifier model performed best in terms of HR and DTL features. The AUCs of the training cohort were 0.841 (95% CI: 0.776-0.907) and 0.955 (95% CI: 0.926-0.983), and the AUCs of the validation cohort were 0.812 (95% CI: 0.677-0.948) and 0.893 (95% CI: 0.795-0.991), respectively. The DTL signature was superior to the handcrafted radiomics signature. Compared with the radiomics signature, the DTL signature constructed based on intratumoral and peritumoral areas in CT can better predict NSCLC lymph node metastasis.

ADCY4 promotes brain metastasis in small cell lung cancer and is associated with energy metabolism

Brain metastasis (BMs) in small cell lung cancer (SCLC) has a very poor prognosis. This study combined WGCNA with the mfuzz algorithm to identify potential biomarkers in the peripheral blood of patients with BMs. By comparing the significantly differentially expressed genes present in BMs samples, we identified ADCY4 as a target for further study. Expression of ADCY4 was used to cluster mfuzz expression pattern, and 28 hub genes for functional enrichment. PPI network analysis were obtained by comparing with differentially expressed genes in BMs. GABRE, NFE4 and LMOD2 are highly expressed in patients with BMs and have a good diagnostic effect. Immunoinfiltration analysis showed that SCLC patients with BMs may be associated with memory B cells, Tregs, NK cell activation, macrophage M0 and dendritic cell activation. prophytic was used to investigate the ADCY4-mediated anti-tumor drug response. In conclusion, ADCY4 can be used as a promising candidate biomarker for predicting BMs, molecular and immune features in SCLC. PCR showed that ADCY4 expression was increased in NCI–H209 and NCI–H526 SCLC cell lines. In vitro experiments confirmed that the expression of ADCY4 was significantly decreased after anti-PD1 antibody treatment, while the expression of energy metabolism factors were significantly different. This study reveals a potential mechanism by which ADCY4 mediates poor prognosis through energy metabolism -related pathways in SCLC.

Contemporary Strategies: Incorporating Immunotherapy into Stage 3 Non-small Cell Lung Cancer Treatment.

Stage 3 non-small cell lung cancer (NSCLC) exhibits significant diversity, making it challenging to define an optimal treatment. A collaborative multidisciplinary approach is essential in crafting individualized treatments. Previously, targeted therapies and immunotherapies were commonly used to treat patients with advanced and metastatic lung cancer. Such treatments are now being extended to individuals considered surgery, as well as patients once considered unsuitable for surgery. These changes have increased surgical success and substantially reduced postoperative recurrence. However, the possibility of severe adverse effects from immunotherapy can deter some patients from performing surgery. It is essential to carefully explore the clinical traits and biomarkers of patients who may benefit the most from immunotherapy, and patients for whom immunotherapy should not be prescribed. In summary, it's crucial to effectively integrate the latest immunotherapy in treating stage 3 NSCLC patients, thereby increasing their opportunities for surgical intervention, and ensuring they receive the best possible care.

Mechanically stimulated osteocytes maintain tumor dormancy in bone metastasis of non-small cell lung cancer by releasing small extracellular vesicles

Although preclinical and clinical studies have shown that exercise can inhibit bone metastasis progression, the mechanism remains poorly understood. Here, we found that non-small cell lung cancer (NSCLC) cells adjacent to bone tissue had a much lower proliferative capacity than the surrounding tumor cells in patients and mice. Subsequently, it was demonstrated that osteocytes, sensing mechanical stimulation generated by exercise, inhibit NSCLC cell proliferation and sustain the dormancy thereof by releasing small extracellular vesicles with tumor suppressor micro-RNAs, such as miR-99b-3p. Furthermore, we evaluated the effects of mechanical loading and treadmill exercise on the bone metastasis progression of NSCLC in mice. As expected, mechanical loading of the tibia inhibited the bone metastasis progression of NSCLC. Notably, bone metastasis progression of NSCLC was inhibited by moderate exercise, and combinations with zoledronic acid had additive effects. Moreover, exercise preconditioning effectively suppressed bone metastasis progression. This study significantly advances the understanding of the mechanism underlying exercise-afforded protection against bone metastasis progression.

Mechanically stimulated osteocytes maintain tumor dormancy in bone metastasis of non-small cell lung cancer by releasing small extracellular vesicles.

Although preclinical and clinical studies have shown that exercise can inhibit bone metastasis progression, the mechanism remains poorly understood. Here, we found that non-small cell lung cancer (NSCLC) cells adjacent to bone tissue had a much lower proliferative capacity than the surrounding tumor cells in patients and mice. Subsequently, it was demonstrated that osteocytes, sensing mechanical stimulation generated by exercise, inhibit NSCLC cell proliferation and sustain the dormancy thereof by releasing small extracellular vesicles with tumor suppressor micro-RNAs, such as miR-99b-3p. Furthermore, we evaluated the effects of mechanical loading and treadmill exercise on the bone metastasis progression of NSCLC in mice. As expected, mechanical loading of the tibia inhibited the bone metastasis progression of NSCLC. Notably, bone metastasis progression of NSCLC was inhibited by moderate exercise, and combinations with zoledronic acid had additive effects. Moreover, exercise preconditioning effectively suppressed bone metastasis progression. This study significantly advances the understanding of the mechanism underlying exercise-afforded protection against bone metastasis progression.

Uniportal video-assisted thoracic surgery: segmentectomy versus lobectomy-early outcomes.

To assess the feasibility and safety of uniportal video-assisted thoracoscopic pulmonary segmentectomy compared with lobectomy by studying early postoperative outcomes. We included all patients who underwent uniportal segmentectomy and lobectomy between 2017 and 2022 at Karolinska University Hospital. Early clinical outcomes were compared between the uniportal segmentectomy and lobectomy groups. Differences in baseline characteristics were addressed using inverse probability of treatment weighting. A total of 833 patients (232 segmentectomy, 601 lobectomy) were included. The number of uniportal operations increased during the study period. Patients in the segmentectomy and lobectomy groups, respectively, had stage I lung cancer in 65% and 43% of the cases; 97% and 94% had no postoperative complications, the median number of lymph node stations sampled was 4 vs 5, and non-radical microscopic resection occurred in 1.7% vs 1.8%. The drains were removed on postoperative day 1 in 75% vs 72% of the patients following segmentectomy and lobectomy, respectively, and 90% vs 89% were discharged directly home. Uniportal video-assisted segmentectomy was performed with similar early postoperative clinical results compared with uniportal lobectomy in patients with benign, metastatic or early-stage lung cancer.

Comprehensive Analysis of Lung Adenocarcinoma and Brain Metastasis through Integrated Single-Cell Transcriptomics.

Lung adenocarcinoma (LUAD) is a highly prevalent and lethal form of lung cancer, comprising approximately half of all cases. It is often diagnosed at advanced stages with brain metastasis (BM), resulting in high mortality rates. Current BM management involves complex interventions and conventional therapies that offer limited survival benefits with neurotoxic side effects. The tumor microenvironment (TME) is a complex system where cancer cells interact with various elements, significantly influencing tumor behavior. Immunotherapies, particularly immune checkpoint inhibitors, target the TME for cancer treatment. Despite their effectiveness, it is crucial to understand metastatic lung cancer and the specific characteristics of the TME, including cell-cell communication mechanisms, to refine treatments. Herein, we investigated the tumor microenvironment of brain metastasis from lung adenocarcinoma (LUAD-BM) and primary tumors across various stages (I, II, III, and IV) using single-cell RNA sequencing (scRNA-seq) from publicly available datasets. Our analysis included exploring the immune and non-immune cell composition and the expression profiles and functions of cell type-specific genes, and investigating the interactions between different cells within the TME. Our results showed that T cells constitute the majority of immune cells present in primary tumors, whereas microglia represent the most dominant immune cell type in BM. Interestingly, microglia exhibit a significant increase in the COX pathway. Moreover, we have shown that microglia primarily interact with oligodendrocytes and endothelial cells. One significant interaction was identified between DLL4 and NOTCH4, which demonstrated a relevant association between endothelial cells and microglia and between microglia and oligodendrocytes. Finally, we observed that several genes within the HLA complex are suppressed in BM tissue. Our study reveals the complex molecular and cellular dynamics of BM-LUAD, providing a path for improved patient outcomes with personalized treatments and immunotherapies.

Coexistent sarcoidosis mimics metastasis in a patient with early-stage non-small cell lung cancer: a case report.

Sarcoidosis is a granulomatous disease. Malignant tumors are accompanied rarely by granuloma reactions that mimic metastasis. We present the case of a patient with possible advanced lung cancer with metastases to the mediastinal lymph nodes and bilateral ilia. Ilium biopsy revealed the presence of sarcoid-like reaction. Bronchoscopy and endobronchial ultrasound revealed an adenocarcinoma in the right upper lung lobe, with a negative mediastinal lymph node. The correct staging of lung cancer was achieved through pathological examination of the surgically removed lung tissues. Two years later, the lung cancer metastasized, and the patient underwent systemic treatment. Coexistent sarcoid-like reaction may mimic metastatic lung cancer. A multidisciplinary approach and sequential diagnostic biopsies can prevent unnecessary surgery or inadequate treatment by distinguishing between coexistent sarcoidosis and metastatic lung cancer.

Atezolizumab-induced encephalitis in a patient with metastatic small cell lung cancer: A clinical case and literature review

The emergence of immunotherapeutic drugs for the treatment of cancer has become a breakthrough in the clinical practice of oncologists. Immunotherapeutic drugs include checkpoint inhibitors, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor. However, their widespread use directly correlates not only with the rate of positive responses to therapy, but also with the rate of immune-mediated adverse events. The main mechanism of which is hyperactivation of T lymphocytes.

Microcomputed tomography as a diagnostic tool for detection of lymph node metastasis in non-small cell lung cancer: A decision-support approach for pathological examination “A pilot study for method validation”

BackgroundNon-small cell lung cancer (NSCLC) patients without lymph node (LN) metastases (pN0) may exhibit different survival rates, even when their T stage is similar. This divergence could be attributed to the current pathology practice, wherein LNs are examined solely in two-dimensional (2D). Unfortunately, adhering to the protocols of 2D pathological examination does not ensure the exhaustive sampling of all excised LNs, thereby leaving room for undetected metastatic foci in the unexplored depths of tissues. The employment of micro-computed tomography (micro-CT) facilitates a three-dimensional (3D) evaluation of all LNs without compromising sample integrity. In our study, we utilized quantitative micro-CT parameters to appraise the metastatic status of formalin-fixed paraffin-embedded (FFPE) LNs. MethodsMicro-CT scans were conducted on 12 FFPEs obtained from 8 NSCLC patients with histologically confirmed mediastinal LN metastases. Simultaneously, whole-slide images from these FFPEs underwent scanning, and 47 regions of interest (ROIs) (17 metastatic foci, 11 normal lymphoid tissues, 10 adipose tissues, and 9 anthracofibrosis) were marked on scanned images. Quantitative structural variables obtained via micro-CT analysis from tumoral and non-tumoral ROIs, were analyzed. ResultSignificant distinctions were observed in linear density, connectivity, connectivity density, and closed porosity between tumoral and non-tumoral ROIs, as indicated by kappa coefficients of 1, 0.90, 1, and 1, respectively. Receiver operating characteristic analysis substantiated the differentiation between tumoral and non-tumoral ROIs based on thickness, linear density, connectivity, connectivity density, and the percentage of closed porosity. ConclusionsQuantitative micro-CT parameters demonstrate the ability to distinguish between tumoral and non-tumoral regions of LNs in FFPEs. The discriminatory characteristics of these quantitative micro-CT parameters imply their potential usefulness in developing an artificial intelligence algorithm specifically designed for the 3D identification of LN metastases while preserving the FFPE tissue.

Bioactive solanidane steroidal alkaloids from Solanum lyratum

Six previously unreported solanidane steroidal alkaloids, namely lyrasolanosides A–F, were isolated from Solanum lyratum. In addition, five known steroidal alkaloids were also identified. The structures of these compounds were determined through the use of NMR, HRESIMS,UV, IR and ECD analysis. To assess their bioactivities, the cytotoxic effects of the six previously unreported compounds were evaluated on A549 cells. The results revealed that lyrasolanoside B (2) exhibited the highest potency among them. Lyrasolanoside B (2) exhibited significant inhibition of cell migration, invasion, and adhesion dramatically. Mechanistically, it was found to suppress the activity of JAK2/STAT3 signaling pathway by downregulating the expression of phosphorylated JAK2/STAT3 in an exosome-dependent manner. In addition, lyrasolanoside B (2) was found to significantly upregulate the expression of E-cadherin and downregulate the expression of N-cadherin and vimentin. These findings indicate that lyrasolanoside B (2) inhibits the metastasis of A549 cells by suppressing exosome-mediated EMT. These findings suggest that lyrasolanoside B (2) may inhibit the metastasis of lung cancer by regulating A549-derived exosomes.

Abstract 5422: Identification of ZEB1-regulated circular RNAs in lung cancer cells

Abstract ZEB1 is a master transcription factor playing a crucial role in promoting epithelial-mesenchymal transition (EMT), as well as the progression and metastasis of lung cancer. The progression of lung cancer is regulated by non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs (circRNAs). In this study, we aimed to identify circRNAs under the regulation of ZEB1 and elucidate their functions within lung cancer cells. Through RNA sequencing and subsequent CIRI-full analysis in ZEB1-overexpressing lung cancer cells, we identified 25 circRNAs displaying differential expression compared to control cells. Among these circRNAs, we targeted circDennd1b, which showed down-regulation in ZEB1-overexpressing cells. We used siRNAs to target the back-splicing junction of circDennd1b, resulting in its knockdown and consequently promoting the invasion of lung cancer cells. Now, we are studying how circDennd1b affects the progression and metastasis of lung cancer. In summary, the circRNAs modulated by ZEB1 are anticipated to play a key role in the invasion, progression, and metastasis of lung cancer. Citation Format: Seongran Cho, Jin-A Choi, Young-Ho Ahn. Identification of ZEB1-regulated circular RNAs in lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5422.

Abstract 2992: miR-200-mediated inactivation of cancer-associated fibroblasts attenuates lung cancer invasion and metastasis

Abstract Cancer-associated fibroblasts (CAFs) play a crucial role in the tumor microenvironment and contribute to the development and progression of lung cancer. We aimed to elucidate whether miRNA-200 (miR-200), which is recognized for its ability to suppress EMT, prevents CAFs from promoting cancer progression. Inactivation of CAFs mediated by miR-200 suppressed lung cancer cell invasion, migration, tumorigenesis, and metastasis. Additionally, miR-200 attenuated the ability of CAFs to facilitate the aggressiveness of lung cancer cells, encourage M2 polarization of macrophages, and increase the angiogenic sprouting of vascular endothelial cells. NRP2, known as a co-receptor of VEGFR, was identified as a target of miR-200, mediating the functional activity of miR-200 in CAFs. NRP2-VEGFR signaling promoted the secretion of VEGFD and PTN from CAFs to activate cancer cell migration and invasion. Based on these findings, we suggest that miR-200 impedes cancer progression and metastasis by remodeling CAFs, and that miR-200 and NRP2 are potential therapeutic targets in the treatment of lung cancer. Citation Format: Inyoung Cheon, Sieun Lee, Young-Ho Ahn. miR-200-mediated inactivation of cancer-associated fibroblasts attenuates lung cancer invasion and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2992.

Abstract 7019: Identifying cell free DNA methylation signatures in cerebrospinal fluids for the early detection of brain metastasis in non-small cell lung cancer

Abstract Brain metastasis (BM) is major complication for adult cancer patients. Up to 2% of all cancer patients develop BM. Non-small cell lung cancer (NSCLC) contributes up to 55% of all BM. Approximately 15-20% of NSCLC patients show metastases at diagnosis, and approximately half will develop BM during their clinical course. Even after treatments like surgery, radiation and immunotherapy, the prognosis is dismal with median overall survival less than 13 months. No standard screening or early diagnostic testing exists for BM now. There is an urgent need to identify genomic features that predispose towards brain metastasis - these biomarkers could be used for early detection and disease monitoring. The cfDNA methylation and fragmentation patterns provide potential epigenetic biomarkers for detecting cancer. These patterns are specific to cell/tissue origin and cancer types. DNA methylation refers to a chemical modification of a specific carbon with an added methyl group in the cytosine. Hypomethylation in the gene body and hypermethylation in the promoter region lead to cancer development. We hypothesize that there are specific cfDNA methylation and fragmentation signatures in CSF that reflect the epigenetic states of BMs, and cancer predisposition for brain metastasis. We applied a novel single molecule sequencing approach to study CSF cfDNA methylation of BM from NSCLC. Our cohort consisted of ten patients with NSCLC-BM (samples N=14) and eleven healthy controls (N=11). Briefly, extracted cfDNA was obtained from CSF samples. Multiplexed sequencing libraries were prepared following an optimized protocol, and sequenced on PromethION flow cell for 72hr by Oxford nanopore technologies. Data were processed with the onboard base and methylation calling, followed by our bioinformatic pipelines for cfDNA size and methylation analysis. Distinct methylation patterns were found on significant CpG sites (fdr-corrected p<0.01) between cancer patients and controls, in both gene-body and promoter region. Biological pathway analysis showed enrichment in essential functions involving PI3K, ERBB2, TNF-α signaling (p<0.03), all of which play a role in NSCLC. Enriched mono-nucleosome levels (p = 1.07e-03) and differentiated mono-/tri- nucleosome ratios (p = 1.34e-03) were found in cancer vs. controls. Overall, our results suggest that a combination of cfDNA methylation and fragmentation can detect NSCLC-BM. This study will benefit BM patients with early detection and better prognosis, and extend our understanding in brain metastases in NSCLC. Citation Format: Tianqi (Kiki) Chen, Billy T. Lau, Xiangqi Bai, Melanie Hayden Gephart, Hanlee P. Ji. Identifying cell free DNA methylation signatures in cerebrospinal fluids for the early detection of brain metastasis in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7019.

Abstract 7581: Nicotine promotes the proliferation and metastasis of non-small cell lung cancer through c-Myc/EZH2 pathway

Abstract Objective: Lung cancer, particularly non-small cell lung cancer (NSCLC), continues to be a predominant contributor to global cancer-related mortality, with smoking emerging as a significant risk factor. Nicotine, which is one of the main chemicals from the tobacco smoke, is identified as carcinogen for lung cancer, especially for squamous carcinoma (LUSC). This study aims to investigates the intricate molecular mechanisms by which nicotine facilitates proliferation and migration in NSCLC through the c-Myc/EZH2 signaling pathway. Methods: Clinical tissue specimens were procured from surgical patients with lung cancer for immunohistochemical staining. Additionally, public databases were scrutinized to compare EZH2 expression between smokers and non-smokers. NSCLC cell lines underwent treatment with nicotine in a time- and concentration-dependent manner, and the impact on EZH2 was corroborated through Western Blot, Real-time PCR, and immunofluorescence staining. Proliferation and migration assays, encompassing CCK8 experiments, colony formation assays, EdU staining, and Transwell assays, were conducted to discern the effects of nicotine on NSCLC. Experimental techniques such as si-RNA and CHIP were deployed to investigate changes in c-Myc-mediated regulation of EZH2, elucidating the intricate role of the c-Myc/EZH2 pathway in nicotine-induced NSCLC proliferation and migration. Results: Smokers exhibited heightened EZH2 expression in tumor tissue compared to non-smokers. Nicotine treatment induced a concentration- and time-dependent upregulation of EZH2 in NSCLC cell lines. In 10 μM nicotine-treated NSCLC cells, concurrent treatment with 10 μM DZNep (EZH2 inhibitor) or si-EZH2 significantly augmented proliferation and migration. Moreover, the upregulation of EZH2 correlated with increased c-Myc expression, and siRNA-mediated c-Myc inhibition resulted in a corresponding reduction in EZH2 expression. Nicotine was identified as a promoter of NSCLC proliferation and migration through the c-Myc/EZH2 signaling pathway. This study establishes a robust association between nicotine and EZH2 in NSCLC cells, unveiling the novel regulatory axis of c-Myc/EZH2. Combined treatment with c-Myc and EZH2 inhibitors demonstrated efficacy in suppressing nicotine-induced promotion of NSCLC proliferation and migration. Conclusion: In summary, this study elucidates the mechanisms through which nicotine propels NSCLC development via the c-Myc/EZH2 pathway, providing a theoretical underpinning for future NSCLC treatment paradigms. The combined use of c-Myc and EZH2 inhibitors emerges as a promising therapeutic strategy, poised to inhibit nicotine-induced NSCLC proliferation and migration, offering enhanced treatment modalities for patients. Citation Format: Chen Ding, Hua Huang, Chen Chen, Yongwen Li, Hongyu Liu, Jun Chen. Nicotine promotes the proliferation and metastasis of non-small cell lung cancer through c-Myc/EZH2 pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7581.