Metastatic Lung Cancer Research Articles

Abstract A012: Aging drives TNBC lung metastasis dependency on FGFR-triggered metabolic reprogramming exposing an age-induced liability with therapeutic potential

Abstract The clinical manifestation of metastasis in a vital organ is the final stage of breast cancer progression and the main culprit of breast cancer related mortality. This remain especially problematic in the case of triple negative breast cancer (TNBC), the most aggressive type of breast cancer, often diagnosed in its metastatic form and for which chemotherapies are still the major therapeutic option. Typically, TNBC is seen as a disease of younger women, however, 20% of TNBCs occur in patients aged 65 and older, whose prognosis is equally staggering. Unfortunately, due to co-morbidities, tolerability of chemotherapies, as well as severe reduction in quality of life, majority of women above age 65 can’t or decide not to receive chemotherapy ultimately cutting their lives short. Metastatic outgrowth is largely dictated by the ability of TNBC disseminated cancer cells (DCCs) to thrive distal organs and is largely dependent on the physiology of the specific organs. However, how the aging process, a major driver of changes in organismal physiology, affects the interaction between the host organ and TNBC DCCs remains unknown. Here, we adapted several traditional syngeneic models of TNBC metastasis to old mice of different strains and coupled with RNA-seq to unveil molecular adaptations of TNBC DCCs to the aging lung. We show that the changes that occur in the lung with aging drives an increase in mitochondrial fitness in TNBC DCCs, an adaptation that is necessary for metastasis to thrive in the old lung environment. Mechanistically, our data show that the expression of FGF19, a gut hormone not normally expressed in TNBC DCCs, drives this increase in mitochondrial fitness in the old lung through an autocrine signaling axis impinging on activation of FGF-19 cognate receptor family, FGFRs. Inhibition of FGF19-FGFR signaling using an FDA- approved FGFR inhibitor not only blocks the age-induced increase in mitochondrial fitness but also effectively abolishes lung metastasis in old, but not in young, immune competent and immune compromised mice. We traced this to age-specific metastatic adaptation of TNBC lung metastasis to the increase in bile acids, the canonical regulators of FGF19 expression, in the old lung environment. Together, our work demonstrates an important contribution of age-driven metabolic reprogramming of the host to the traits that enable metastasis to thrive in the lung and provides rationale for the use of FDA-approved FGFR inhibitors for the treatment of breast cancer lung metastasis in the most vulnerable of stage IV metastatic TNBC patients, the elderly. Citation Format: Stanislav Drapela, Shiun Chang, Rojan Chimeh Rad, Vanessa Rubio, Didem Ilter, Paulo Rodriguez, Ana P. Gomes. Aging drives TNBC lung metastasis dependency on FGFR-triggered metabolic reprogramming exposing an age-induced liability with therapeutic potential [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A012.

Abstract PR017: Anti-metastatic immunotherapy discovery using ex vivo lung tissue cultures and high-throughput single-cell chemical transcriptomics

Abstract Introduction: Tumors systemically remodel the immune system during metastasis. Developing anti-metastatic immunotherapies that target these tumor-immune interactions to make the metastatic niche hostile colonization would represent a paradigm shift in cancer treatment. However, traditional high-throughput screening (HTS) platforms that use simple read-outs and contrived in vitro systems are ill-suited to identify such therapies. In contrast, HTS platforms that accurately model the metastatic niche and use high-dimensional read-outs such as multiplexed single-cell RNA-sequencing (scRNA-seq) can accurately profile nuanced perturbation responses in individual immune cell types and therefore have the potential to discover anti-metastatic immunotherapies. In this study, we describe the development of an ex vivo lung tissue culture HTS platform that preserves immune gene expression signatures observed in the in vivo metastatic niche and is amenable to single-cell chemical transcriptomic analysis using MULTI- seq (McGinnis et al., Nature Methods, 2019). Inspired by our recent description of myeloid cell TLR-NFκB inflammation during breast cancer lung metastasis (McGinnis et al., Cancer Cell, 2024), we then performed the first anti-metastatic immunotherapy drug screen and identified TLR-NFκB inhibitors that effectively operate on all desired myeloid cell types in the lung metastatic niche. Methods and Results: Building upon existing techniques for culturing precision-cut lung slices (Wu et al., Journal of Experimental Medicine, 2024) and patient- derived tumor fragments (Voabil et al., Nature Medicine, 2021), we established and optimized an ex vivo lung tissue culture system that enables 48-hour culturing of lung slices isolated from 4T1 tumor-bearing mice. scRNA-seq profiling revealed successful capture of all relevant immune cell types and retention of metastasis-associated gene expression programs (e.g., myeloid TLR-NFκB inflammation and neutrophil degranulation) following culture. We then scaled our platform to address how myeloid cells in the lung metastatic niche respond to perturbations targeting every component of the canonical TLR-NFκB signaling cascade. Cell-type-specific perturbation modeling and quantification of TLR-NFκB signaling inhibition identified compounds that optimally perturb all intended myeloid cell types (e.g., tissue-resident macrophages, neutrophils, and monocytes) and represent prioritized candidates for future in vivo validation studies to assess impact on metastatic disease progression. Conclusions: In this study, we describe the development and application of a novel HTS platform that couples ex vivo lung tissue cultures with single-cell chemical transcriptomics to identify anti-metastatic immunotherapy candidates. We demonstrate how our platform can identify TLR-NFκB signaling inhibitors that optimally operate in the lung metastatic niche, paving the way for future interrogation of additional metastasis-associated immune cell signaling pathways in different disease and tissue backgrounds. Citation Format: Chris McGinnis, Winnie Yao, Ansuman Satpathy. Anti-metastatic immunotherapy discovery using ex vivo lung tissue cultures and high-throughput single-cell chemical transcriptomics [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR017.

Abstract A023: RNA secondary structures mediate circular RNA stability and function

Abstract Our group recently discovered that the circular RNA (circRNA), CDR1as, promotes lung cancer metastasis in part through the stabilization of the coding gene, CDR1. The purpose of this study was to identify intramolecular RNA secondary structures of CDR1as and determine whether there is a functional relationship between the CDR1as secondary structure and non-small cell lung cancer (NSCLC) metastasis. We employed the chemical probing approach selective 2’- hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE-MaP) to experimentally inform structure predictions of CDR1as. The SHAPE-MaP profiling experiments revealed that CDR1as is remarkably unstructured overall, with an exception of a highly probable and consistent stem-loop structure embedding the CDR1as backsplice junction (BSJ). Additionally, BSJ-embedding secondary structures were identified in all other mammalian circRNAs studied in a similar chemical probing experiment. To evaluate the role of the BSJ structure on CDR1as expression, we sterically disrupted the BSJ structure using a chemically modified, inert antisense oligonucleotide (BSJ-ASO) lacking a gapmer in order to block RNAse H activity. After transfection of the structure disrupting BSJ-ASO into several cell lines, we observed a 90-95% reduction of CDR1as expression by the BSJ-ASO by 24 hours. Furthermore, the BSJ-ASO significantly inhibited cancer cell proliferation and spheroid formation in several NSCLC models. Strikingly, using RNA stability assays we observed that the BSJ-ASO caused dramatic reductions in CDR1as levels within 5 minutes of transfection, suggesting a possibly hydrolytic process. A functional screen of silencing curated CDR1as RNA-binding proteins failed to rescue the loss of CDR1as expression following BSJ-ASO treatment. We next tested whether an RNA-catalyzed mechanism of action is possible. By incubating total RNA with the BSJ-ASO in buffers of varying magnesium chloride concentrations in vitro, we observed a dramatic decrease in CDR1as levels similar to that of the BSJ-ASO cellular transfection experiments, suggestive of ribozyme-like activity. Interestingly, use of a primer mapping approach indicated two putative cut sites within CDR1as. Further chemical probing following treatment with the BSJ-ASO revealed a new, highly probable secondary structure upstream of the BSJ, which appears similar to a hairpin ribozyme when modeled two-dimensionally. Taken together, our work reveals that intramolecular RNA secondary structures can have critical roles in maintaining circRNA cellular stability and function, and strategic steric disruption of these structures may induce circRNA self-cleavage. Citation Format: Aaron C Chack, Emily B Harrison, Caroline J Aufgebauer, Mark A Boerneke, Patrick S Irving, Edgar M Faison, Jingyu Zhao, Qi Zhang, Kevin M Weeks, Chad V Pecot. RNA secondary structures mediate circular RNA stability and function [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A023.

Multi-omics with dynamic network biomarker algorithm prefigures organ-specific metastasis of lung adenocarcinoma.

Efficacious strategies for early detection of lung cancer metastasis are of significance for improving the survival of lung cancer patients. Here we show the marker genes and serum secretome foreshadowing the lung cancer site-specific metastasis through dynamic network biomarker (DNB) algorithm, utilizing two clinical cohorts of four major types of lung cancer distant metastases, with single-cell RNA sequencing (scRNA-seq) of primary lesions and liquid chromatography-mass spectrometry data of sera. Also, we locate the intermediate status of cancer cells, along with its gene signatures, in each metastatic state trajectory that cancer cells at this stage still have no specific organotropism. Furthermore, an integrated neural network model based on the filtered scRNA-seq data is successfully constructed and validated to predict the metastatic state trajectory of cancer cells. Overall, our study provides an insight to locate the pre-metastasis status of lung cancer and primarily examines its clinical application value, contributing to the early detection of lung cancer metastasis in a more feasible and efficacious way.

EXPRESS: Radiation therapy in combination with immune checkpoint inhibitors in metastatic lung cancer: Effect of fractionation.

Immunotherapy with checkpoint inhibitors has improved the outcomes of patients with metastatic lung cancer in recent years. Despite improved prognosis, not all patients respond to treatment. Therapeutic interventions to build on the success of immune checkpoint inhibitors are needed. A retrospective review of patient records for patients who had received immune checkpoint inhibitors in a single cancer center over four years was undertaken. Demographic and disease characteristics of patients with metastatic non-small cell lung cancer were recorded. Data on other treatments including chemotherapy and radiation therapy were extracted, and survival outcomes were calculated. Most (81.8%) of the 77 metastatic lung cancer patients examined had received palliative radiation therapy within three months of starting immune checkpoint inhibitors. While the survival outcomes of these patients did not differ from patients who had not received radiotherapy, patients who had undergone hypofractionated radiotherapy (defined as one or more fractions of 700 cGy or higher) displayed a better overall survival (OS) than the rest of the cohort. Palliative radiation therapy administered in proximity with immune checkpoint inhibitors immunotherapy had no effect on the OS of metastatic lung cancer patients. However, patients receiving palliative radiotherapy with fractions above 700 cGy showed better OS. Further studies are needed to optimize a combination strategy.

Retraction: Differential Expression of the RANKL/RANK/OPG System Is Associated with Bone Metastasis in Human Non-Small Cell Lung Cancer.

Retraction: Differential Expression of the RANKL/RANK/OPG System Is Associated with Bone Metastasis in Human Non-Small Cell Lung Cancer.

Abstract A038: Investigating PD-L1 status in circulating tumor cells isolated from blood samples of lung cancer patients

Abstract Background: This research study aimed to assess the performance of a research use only (RUO) immunofluorescence (IF) assay targeting programmed death-ligand 1 (PD-L1) evolution in epithelial and/or mesenchymal circulating tumor cells (CTCs) isolated from blood using Parsortix® microfluidic technology. Upregulation of PD-L1 enables cancer cells to evade the host immune response. Assessment of PD-L1 status in the tumor, as determined by traditional tissue biopsy, can indicate if immunotherapy has the potential to be an effective treatment. However, PD-L1 expression in tumor biopsies may not reflect metastatic sites in their entirety and can become outdated during tumor evolution, as the process cannot be repeated due its invasive nature. Liquid biopsy offers a minimally invasive option for dynamic testing of PD-L1 in CTCs as patients undergo treatment. Methods: Analytical linearity, and specificity and sensitivity were assessed by spiking HCC1954 and Hs 578T cancer cell lines into the blood samples of 34 healthy volunteers. The assay was then evaluated in samples from 47 metastatic lung cancer patients, among which 32 had a known PD-L1 tissue status (19 positive, 13 negative). Up to six successive draws were taken for each patient, collected into Streck Cell-Free DNA blood collection tubes. ANGLE’s Parsortix® instruments were used to isolate spiked cancer cells or CTCs from blood samples based on their size and deformability. The CTC- enriched harvests were processed onto ANGLE’s CellKeepTM slides and IF stained with ANGLE’s Portrait® PD-L1 RUO assay for PD-L1 identification on CTCs. Slides were imaged on a BioView automated imaging system. Results: Analytical specificity of PD-L1 was 98% and analytical sensitivity was 81%. Analytical linearity (R2=0.91) was shown over a 0–500 cells range. In metastatic lung cancer patients, ≥1 CTC was identified in at least one draw for 91% of donors, with 55% of those donors exhibiting ≥1 PD-L1 positive CTC. A majority (81%) of donors exhibited a positive correlation between PD-L1 tissue status and CTC expression. However, the remaining 19% of donors exhibited discordance with a PD-L1 negative tissue status but PD-L1 positivity identified in ≥1 CTC. Of the PD-L1 positive CTCs identified, 98% expressed mesenchymal markers. Dynamic change was shown in all but one donor, with PD-L1 status of the CTCs changing over time. Conclusions: This study demonstrated the ability to determine PD-L1 status in CTCs from the blood of metastatic lung cancer patients and, subject to further study, the future potential to develop dynamic PD-L1 testing for advancement of more personalized cancer treatments. Patients with a PD-L1 negative tissue status exhibited PD-L1 positive CTCs, demonstrating the feasibility of a more repeatable and accurate assessment of PD-L1 status than can be achieved through a traditional tissue biopsy. Citation Format: Morgan Spode, Chloe Goodwin, Aarabhi Varatharajah, Aaron Cottingham, Elisha Duhig, Laura Kaja, David Greaves, Mariacristina Ciccioli, Anne-Sophie Pailhes-Jimenez. Investigating PD-L1 status in circulating tumor cells isolated from blood samples of lung cancer patients [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A038.

2D Nano-Photosensitizer Facilitates Proximity Labeling for Living Cells Surfaceome Deciphering.

Photocatalytic proximity labeling has shown great promise for mapping the spatiotemporal dynamics of surfaceome. Although cell-surface targeting photosensitizers relying on antibodies, lipid molecules, and metabolic labeling have gained effects, the development of simpler and stable methods that avoid complex chemical synthesis and biosynthesis steps is still a huge challenge. Here, the study has introduced 2D nanomaterials with the ability of cell surface engineering to perform the in situ anchoring of photosensitizer on living cell surface. Photosensitizer can be stabilized on nanomaterials by coordination after one-step mixing, resulting in the nano-photosensitizer combining cell surface targeting ability and photosensitivity that allowing surface-specific proximity labeling. Nano-photosensitizer can be dispersed stably in aqueous solution, avoiding the defects of poor water solubility and aggregation of traditional organic photosensitizers. Singlet oxygen is generated locally under light irradiation, enabling spatiotemporally-resolved activating and labeling of cell surface proteome. Further application in the brain metastatic lung cancer has been found effective with numerous quantified differential cell surfaces proteins highly correlated with cancer metastasis and three potential players have been validated via immunoblotting and immunofluorescence, providing important insights for metastasis supported molecular mechanism.

LSD1 deficiency in breast cancer cells promotes the formation of pre-metastatic niches.

Lysine-specific demethylase 1 (LSD1), a histone demethylating enzyme, plays a crucial role in cancer metastasis. Studies show LSD1 knockout promotes breast cancer lung metastasis, but it's unknown if it alters the lung microenvironment for metastasis. In this study, we investigated the effects of exosomes from LSD1-knockdown (LSD1 KD) breast cancer cells on pre-metastatic niche formation. Injecting exosomes from LSD1 KD cells in mice resulted in a substantial increase in lung colonization by breast cancer cells, while treatment with exosomes derived from LSD1 KD cells decreased the expression of the ZO-1 and occludin, leading to increased vascular permeability. The LSD1 KD reduced the expression of circDOCK1, which augmented the levels of miR-1270 in exosomes. And miR-1270 inhibited ZO-1 expression in human endothelial cells, which enhanced their permeability. Our study uncovered a novel mechanism in which the LSD1 promotes the formation of pre-metastatic niches via the regulation of exosomal miRNA.

BIOM-06. NOGGIN CONTRIBUTES TO BRAIN METASTATIC COLONIZATION OF LUNG CANCER CELLS

Abstract Brain metastasis is a common complication among patients with lung cancer, yet the underlying mechanisms remain unclear. In this study, we aimed to investigate the pathogenesis of brain metastasis in lung cancer. We established highly colonizing metastatic lung cancer cells, A549-M2, through multiple implantations of A549 human lung cancer cells in the carotid artery of athymic nude mice. Compared to parental cells (M0), M2 cells demonstrated slower growth in culture plates and soft agar, as well as lower motility and higher adhesion, key characteristics of mesenchymal-epithelial transition (MET). Further analysis revealed that M2 cells exhibited decreased expression of epithelial-mesenchymal transition markers, including ZEB1 and Vimentin. M2 cells also demonstrated reduced invasiveness in co-culture systems. RNA sequencing and gene set enrichment analysis confirmed that M2 cells underwent MET. Intriguingly, depletion of Noggin, a BMP antagonist, was observed in M2 cells, and replenishment of Noggin restored suppressed migration and invasion of M2 cells. In addition, Noggin knockdown in control M0 cells promoted cell attachment and suppressed cell migration, suggesting that Noggin reduction during brain colonization causes inhibition of migration and invasion of metastatic lung cancer cells. Our results suggest that lung cancer cells undergo MET and lose their motility and invasiveness during brain metastatic colonization, which is dependent on Noggin.

Unusual Cutaneous Reaction with Erlotinib: A Brief Report with Current Review of Management of Tyrosine Kinase Inhibitor-associated Cutaneous Toxicity

ABSTRACT Tyrosine kinase inhibitors (TKIs) have emerged as the preferred choice of treatment for various tumors as a result of better outcomes and quality of life without the debilitating side effects of cytotoxic chemotherapy. Erlotinib is a TKI against epidermal growth factor receptor that is commonly used in lung cancer and pancreatic cancer. The most common adverse effect expected is cutaneous toxicity, which occurs as acneiform rash. Here, we present a case of 71-year-old man with metastatic lung cancer who had an atypical squamous-crusted eruption with intense itching and pain on his forehead that resolved spontaneously after withholding erlotinib along with supportive care. The present case depicts unusual cutaneous toxicity with the use of TKI.

EXTH-13. COMBINED ANTI-ANGIOGENIC TREATMENT TO INCREASE INTRATUMORAL PERSISTENCE OF CAR T-CELLS IN LUNG CANCER BRAIN METASTASES

Abstract BACKGROUND Metastatic lung cancer, especially when it spreads to the brain, shows a devastating prognosis. Immunotherapeutic approaches including CAR T-cells show promise in hematologic malignancies. However, the presence of immunosuppressive factors within the tumor microenvironment and physical barriers like elevated interstitial pressure due to dysfunctional tumor vessels are one of the main obstacles especially in solid tumors. Evaluation of the potential synergy between anti-angiogenetic drugs and CAR T-cells in this context are an ongoing investigation. METHODS Here, we set up an immunocompetent syngeneic orthotopic cerebral metastasis model in mice by combining a chronic cranial window with repetitive intracerebral two-photon laser scanning microscopy (TPLSM). This model allows in vivo characterization of fluorescent tumor cells and CAR T-cells on a single cell level over time. Intraparenchymal injection of red fluorescent EpCAM-transduced Lewis Lung carcinoma cells (EpCAM/tdtLL/2 cells) followed by injection of EpCAM-directed or undirected CAR T-cells into the adjacent brain tissue was performed. Additionally, aVEGF-A combined with aVEGF-R2 and the respective isotype control were injected intraperitoneally. RESULTS Compared to undirected CAR T-cells, mice receiving EpCAM-directed CAR T-cells showed higher intratumoral CAR T-cell densities after intraparenchymal injection. This finding was accompanied with reduced tumor growth and eventually translates into a survival benefit. However, intratumoral CAR T-cell numbers diminish over time indicating insufficient persistence inside of the tumor microenvironment. Additional anti-VEGF-A/VEGF-R2 treatment results in reduced tumor growth after EpCAM/GFPCAR T-cell and GFPT-cell treatment, respectively. Interestingly, in vivo imaging reveals higher intratumoral CAR T-cell numbers after anti-angiogenic treatment compared to isotype controls pointing towards enhanced CAR T-cell persistence resulting in a survival benefit. CONCLUSION Collectively, our findings indicate that locally injected CAR T-cells may safely induce relevant anti-tumor effects in brain metastases from lung cancer. Additional anti-angiogenic treatment provides a mechanism to enhance intratumoral CAR T-cell persistence and reduce tumor growth.

Retraction Note: LncRNA LINC00261 overexpression suppresses the growth and metastasis of lung cancer via regulating miR-1269a/FOXO1 axis

Retraction Note: LncRNA LINC00261 overexpression suppresses the growth and metastasis of lung cancer via regulating miR-1269a/FOXO1 axis

Advances in the Management of Lung Cancer Brain Metastases

Lung cancer, both non-small cell and small cell, harbors a high propensity for spreading to the central nervous system. Radiation therapy remains the backbone of the management of brain metastases. Recent advances in stereotactic radiosurgery have expanded its indications and ongoing studies seek to elucidate optimal fractionation and coordination with systemic therapies, especially targeted inhibitors with intracranial efficacy. Efforts in whole-brain radiotherapy aim to preserve neurocognition and to investigate the need for prophylactic cranial irradiation. As novel combinatorial strategies are tested and prognostic/predictive biomarkers are identified and tested, the management of brain metastases in lung cancer will become increasingly personalized to optimally balance intracranial efficacy with preserving neurocognitive function and patient values.

RIPK2 and lysosomal pathway: Unveiling a new mechanism for lung cancer metastasis

BackgroundThis study aims to explore the role of RIPK2 in lung cancer metastasis and its potential mechanisms. MethodsThe expression levels of RIPK2 in lung cancer patients and cell lines were detected by immunohistochemistry, qRT-PCR, and Western blot. RIPK2 expression was knocked down using siRNA technology, and its effects on the proliferation, migration, and invasion capabilities of lung cancer cells were assessed through CCK-8, EdU, colony formation, and Transwell assays. Furthermore, by overexpressing RIPK2 and LAMP2, the regulatory effect of RIPK2 on the lysosomal pathway and its mechanism of action in lung cancer metastasis were investigated. ResultsThe results showed that the expression of RIPK2 was significantly increased in lung cancer patients and cell lines. Knockdown of RIPK2 significantly inhibited the migration, invasion, and proliferation capabilities of lung cancer cells, while overexpression of RIPK2 promoted these malignant behaviors. Further studies found that RIPK2 promoted lung cancer metastasis by inhibiting LAMP2 expression, thereby suppressing the lysosomal pathway and altering the tumor microenvironment. Additionally, overexpression of LAMP2 could reverse the promotive effects of RIPK2 overexpression on the malignant behaviors of lung cancer cells. ConclusionThis study reveals for the first time that RIPK2 promotes lung cancer metastasis by inhibiting LAMP2 expression, thereby suppressing the lysosomal pathway and altering the tumor microenvironment. In the future, targeted therapy against RIPK2 and LAMP2 may become an effective means to inhibit lung cancer metastasis.

The Role of Anesthetic Management in Lung Cancer Recurrence and Metastasis: A Comprehensive Review

The Role of Anesthetic Management in Lung Cancer Recurrence and Metastasis: A Comprehensive Review

Mechanisms of microRNA Regulation of the Epithelial–Mesenchymal Transition (EMT) in Lung Cancer

Lung cancer remains the cancer with the highest mortality worldwide, largely due to a limited understanding of the precise molecular mechanisms that drive its progression. microRNAs (miRNAs) have emerged as crucial regulators of lung cancer progression by influencing key cellular processes, notably the epithelial–mesenchymal transition (EMT). EMT is a complex and potentially reversible process where epithelial cells lose their polarity and adhesion, reorganize their cytoskeleton, and transition to a mesenchymal phenotype, enhancing their migratory and invasive capacities. While EMT plays an essential role in normal physiological contexts such as tissue development and wound healing, it is also a critical mechanism underlying the progression and metastasis of lung cancer. This review aims to summarize the latest research findings on the role of endogenous and exosome-derived microRNAs in regulating EMT in lung cancer, focusing on studies conducted over the past five years. It also provides an overview of EMT’s essential molecular mechanisms to better understand how miRNAs regulate EMT in lung cancer.

Preoperative prediction of occult lymph node metastasis in patients with non-small cell lung cancer: a simple and widely applicable model.

Lymph node metastasis (LNM) is one of the most common pathways of metastasis in non-small cell lung cancer (NSCLC). Preoperative assessment of occult lymph node metastasis (OLNM) in NSCLC patients is beneficial for selecting appropriate treatment plans and improving patient prognosis. A total of 370 NSCLC patients were included in the study. Univariate and multivariate logistic regression analysis were used to screen potential risk factors for OLNM in preoperative NSCLC patients. And establish a nomogram for OLNM in NSCLC patients before surgery. Receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were used to evaluate the established nomogram. Both univariate and multivariate logistic regression analyses suggested that multiple tumors, ERBB2 missense mutation, CA125 levels, CA153 levels, tumor site, tumor length, and serum ferritin are potential risk factors for OLNM in NSCLC patients. The constructed nomogram was evaluated, and the consistency index (C-index) and area under the ROC curve of the model were both 0.846. The calibration curve showed that the predicted values of the model had a high degree of fit with the actual observed values, and DCA suggested that the above indicators had good utility. The personalized scoring prediction model constructed based on multiple tumors, ERBB2 miss mutation, CA125 levels, CA153 levels, tumor site, tumor length, and serum ferritin can screen NSCLC patients who may have OLNM.

KRAS inhibitors in drug resistance and potential for combination therapy.

Kirsten Rat Sarcoma (KRAS) is a potent target for cancer therapy because it acts as a signaling hub, engaging in various signaling pathways and regulating a number of cellular functions like cell differentiation, proliferation, and survival. Recently, an emergency approval from the US-FDA has been issued for KRASG12C inhibitors (sotorasib and adagrasib) for metastatic lung cancer treatment. However, clinical studies on covalent KRASG12C inhibitors have rapidly confronted resistance in patients. Many methods are being assessed to overcome this resistance, along with various combinatorial clinical studies that are in process. Moreover, because KRASG12D and KRASG12V are more common than KRASG12C, focus must be placed on the therapeutic strategies for this type of patient, along with sustained efforts in research on these targets. In the present review, we try to focus on various strategies to overcome rapid resistance through the use of combinational treatments to improve the activity of KRASG12C inhibitors.

4‑Methoxydalbergione inhibits the tumorigenesis and metastasis of lung cancer through promoting ferroptosis via the DNMT1/system Xc‑/GPX4 pathway.

Lung cancer is responsible for the highest number of tumor‑related deaths worldwide. A flavonoid extracted from the heartwood of Dalbergia sissoo Roxb., 4‑methoxydalbergione (4‑MD), exhibits potent anticancer activity in multiple malignancies; however, the potential anticancer activity of 4‑MD in lung cancer has not yet been elucidated. In the present study, A549 cells were treated with increasing concentrations of 4‑MD, and cell viability was assessed using a Cell Counting Kit‑8 assay. In addition, colony formation, 5‑ethynyl‑2'‑deoxyuridine, wound healing and Transwell assays were conducted to evaluate cell proliferation, migration and invasion, respectively. Cell morphology was observed using transmission electron microscopy, and ferroptosis was determined using thiobarbituric acid reactive substance, lipid reactive oxygen species (ROS) and iron assays. Moreover, molecular docking was used to verify the potential interaction between 4‑MD and DNA methyltransferase 1 (DNMT1). Tumor‑bearing mice were established and treated with 10 or 30 mg/kg 4‑MD, and tumor volume and weight were recorded. Immunohistochemistry and Prussian blue staining were conducted to examine Ki‑67 expression and iron deposition in tumor tissues, and protein expression was further explored using western blot analysis. The results of the present study revealed that 4‑MD significantly inhibited cell proliferation, migration, invasion and epithelial‑mesenchymal transition in a concentration‑dependent manner. Notably, 4‑MD induced ferroptosis via increased lipid peroxidation, lipid ROS and Fe2+ levels. In addition, it was revealed that 4‑MD can directly bind to DNMT1 to inhibit expression, and inhibit solute carrier family 7 member 11 (SLC7A11; also known as cystine‑glutamate antiporter) and glutathione peroxidase 4 expression. Following DNMT1 overexpression, the observed antitumor activity and ferroptosis‑promoting effects of 4‑MD were partially reversed. Furthermore, 4‑MD significantly inhibited tumor growth in vivo, and reduced tumor volume and weight. In addition, Ki‑67 expression was reduced while iron deposition was increased in the tumor tissues of mice following treatment with 4‑MD. In conclusion, 4‑MD may exhibit anticancer activity through the promotion of DNMT1‑mediated cell ferroptosis. Thus, 4‑MD may have potential as a novel therapeutic agent in the treatment of lung cancer.