COPD basal cells are primed towards secretory to multiciliated cell imbalance driving increased resilience to environmental stressors.

INTRODUCTION: Environmental pollutants injure the mucociliary elevator, thereby provoking disease progression in chronic obstructive pulmonary disease (COPD). Epithelial resilience mechanisms to environmental nanoparticles in health and disease are poorly characterised. METHODS: We delineated the impact of prevalent pollutants such as carbon and zinc oxide nanoparticles, on cellular function and progeny in primary human bronchial epithelial cells (pHBECs) from end-stage COPD (COPD-IV, n=4), early disease (COPD-II, n=3) and pulmonary healthy individuals (n=4). After nanoparticle exposure of pHBECs at air-liquid interface, cell cultures were characterised by functional assays, transcriptome and protein analysis, complemented by single-cell analysis in serial samples of pHBEC cultures focusing on basal cell differentiation. RESULTS: COPD-IV was characterised by a prosecretory phenotype (twofold increase in MUC5AC+) at the expense of the multiciliated epithelium (threefold reduction in Ac-Tub+), resulting in an increased resilience towards particle-induced cell damage (fivefold reduction in transepithelial electrical resistance), as exemplified by environmentally abundant doses of zinc oxide nanoparticles. Exposure of COPD-II cultures to cigarette smoke extract provoked the COPD-IV characteristic, prosecretory phenotype. Time-resolved single-cell transcriptomics revealed an underlying COPD-IV unique basal cell state characterised by a twofold increase in KRT5+ (P=0.018) and LAMB3+ (P=0.050) expression, as well as a significant activation of Wnt-specific (P=0.014) and Notch-specific (P=0.021) genes, especially in precursors of suprabasal and secretory cells. CONCLUSION: We identified COPD stage-specific gene alterations in basal cells that affect the cellular composition of the bronchial elevator and may control disease-specific epithelial resilience mechanisms in response to environmental nanoparticles. The identified phenomena likely inform treatment and prevention strategies.

Paravertebral fibrous pseudotumor: Four cases of a distinctive tumefactive lesion overlapping with eosinophilic angiocentric fibrosis and tumoral erythema elevatum diutinum.

Eosinophilic angiocentric fibrosis (EAF) is a rare tumefactive fibroinflammatory disease with predilection for the upper respiratory tract, characterized by concentric (onionskin) fibrosis around small arterioles with variable intervening storiform fibrosis admixed with chronic inflammatory infiltrates rich in eosinophils. Erythema elevatum diutinum (EED), another autoimmunological disorder that mainly affects acral sites and extensor surfaces, is characterized by neutrophilic leukocytoclastic vasculitis. Rarely, older EED lesions may present as tumefactive nodular (pseudotumoral) fibrous masses closely mimicking EAF. We herein describe four patients (all males) aged 66-70 years who presented with large (median, 7 cm) tumor-like fibrous lesions in the paravertebral region not associated with a known clinical autoimmune disease. All cases were resected surgically with the suspicion of a neoplasm. They displayed a strikingly similar histological appearance with combined features of EAF and nodular fibrous EED. None had evidence of obliterative phlebitis or increased IgG4: IgG ratio. The etiology of this distinctive lesion and its predilection for the paravertebral area of males remains obscure. A distinctive tumefactive localized reaction to trauma caused by degenerative disease of adjacent vertebrae might be a possible explanation.

Preoperative risk factors predict perioperative allogenic blood transfusion in patients undergoing primary lung cancer resections: a retrospective cohort study from a high-volume thoracic surgery center.

BACKGROUND: Our study aimed to identify preoperative predictors for perioperative allogenic blood transfusion (ABT) in patients undergoing major lung cancer resections in order to improve the perioperative management of patients at risk for ABT. METHODS: Patients admitted between 2014 and 2016 in a high-volume thoracic surgery clinic were retrospectively evaluated in a cohort study based on a control group without ABT and the ABT group requiring packed red blood cell units within 15 days postoperatively until discharge. The association of ABT with clinically established parameters (sex, preoperative anemia, liver and coagulation function, blood groups, multilobar resections) was analyzed by contingency tables, receiver operating characteristics (ROC) and logistic regression analysis, taking into account potential covariates. RESULTS: 60 out of 529 patients (11.3%) required ABT. N1 and non-T1 tumors, thoracotomy approach, multilobar resections, thoracic wall resections and Rhesus negativity were more frequent in the ABT group. In multivariable analyses, female sex, preoperative anemia, multilobar resections, as well as serum alanine-aminotransferase levels, thrombocyte counts and Rhesus negativity were identified as independent predictors of ABT, being associated with OR (95% Confidence interval, p-value) of 2.44 (1.23-4.88, p = 0.0112), 18.16 (8.73-37.78, p < 0.0001), 5.79 (2.50-13.38, p < 0.0001), 3.98 (1.73-9.16, p = 0.0012), 2.04 (1.04-4.02, p = 0.0390) and 2.84 (1.23-6.59, p = 0.0150), respectively. CONCLUSIONS: In patients undergoing major lung cancer resections, multiple independent risk factors for perioperative ABT apart from preoperative anemia and multilobar resections were identified. Assessment of these predictors might help to identify high risk patients preoperatively and to improve the strategies that reduce perioperative ABT.

[SARS-CoV-2-Infection and Interstitial Lung Disease: Position paper of the German Respiratory Society]. / SARS-CoV-2-Infektion und interstitielle Lungenerkrankungen ­ Positionspapier der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin.

The SARS-CoV-2 pandemic had a tremendous impact on diagnosis and treatment of interstitial lung diseases (ILD). Especially in the early phase of the pandemic, when the delta variant was prevailling, a huge number of viral pneumonias were observed, which worsened pre-existing, triggered de novo occurence or discovery of previously subclincal interstitial lung diseases. The effect of SARS-CoV-2 infection - without or with accompanying viral pneumonia - on the further development of pre-existing ILD as well of new pulmonary inflitrates and consolidiations is difficult to predict and poses a daily challenge to interdisciplinary ILD boards. This position paper of the German Respiratory Society (DGP e.V.) provides answers to the most pressing questions based on current knowledge.

Lung fibrosis in autoimmune diseases and hypersensitivity: how to separate these from idiopathic pulmonary fibrosis.

Lung involvement in autoimmune diseases (AID) is uncommon, but may precede other organ manifestations. A diagnostic problem is chronicity presenting with lung fibrosis. A new category of interstitial pneumonia with autoimmune features for patients with clinical symptoms of AID and presenting with usual interstitial pneumonia (UIP) enables antifibrotic treatment for these patients. Hypersensitivity pneumonia (HP) and other forms of lung fibrosis were not included into this category. As these diseases based on adverse immune reactions often present with unspecific clinical symptoms, a specified pathological diagnosis will assist the clinical evaluation. We aimed to establish etiology-relevant differences of patterns associated with AID or HP combined with lung fibrosis. We retrospectively evaluated 51 cases of AID, and 29 cases of HP with lung fibrosis, and compared these to 24 cases of idiopathic pulmonary fibrosis (UIP/IPF). Subacute AID and HP most often presented with organizing pneumonia (OP), whereas chronicity was associated with UIP. Unspecified fibrosis was seen in a few cases, whereas NSIP pattern was rare. In 9 cases, the underlying etiology could not be defined. Statistically significant features differentiating chronic AID or HP from UIP/IPF are lymphocytic infiltrations into myofibroblastic/fibroblastic foci. Other features significantly associated with AID and HP were granulomas, isolated Langhans giant cells, and protein deposits, but seen in only a minority of cases. A combination of UIP with one of these features enabled a specific etiology-based diagnosis. Besides the antifibrotic drug regimen, additional therapies might be considered.

Inhibiting eicosanoid degradation exerts antifibrotic effects in a pulmonary fibrosis mouse model and human tissue.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a disease with high 5-year mortality and few therapeutic options. Prostaglandin (PG) E2 exhibits antifibrotic properties and is reduced in bronchoalveolar lavage from patients with IPF. 15-Prostaglandin dehydrogenase (15-PGDH) is the key enzyme in PGE2 metabolism under the control of TGF-ß and microRNA 218. OBJECTIVE: We sought to investigate the expression of 15-PGDH in IPF and the therapeutic potential of a specific inhibitor of this enzyme in a mouse model and human tissue. METHODS: In vitro studies, including fibrocyte differentiation, regulation of 15-PGDH, RT-PCR, and Western blot, were performed using peripheral blood from healthy donors and patients with IPF and A549 cells. Immunohistochemistry, immunofluorescence, 15-PGDH activity assays, and in situ hybridization as well as ex vivo IPF tissue culture experiments were done using healthy donor and IPF lungs. Therapeutic effects of 15-PGDH inhibition were studied in the bleomycin mouse model of pulmonary fibrosis. RESULTS: We demonstrate that 15-PGDH shows areas of increased expression in patients with IPF. Inhibition of this enzyme increases PGE2 levels and reduces collagen production in IPF precision cut lung slices and in the bleomycin model. Inhibitor-treated mice show amelioration of lung function, decreased alveolar epithelial cell apoptosis, and fibroblast proliferation. Pulmonary fibrocyte accumulation is also decreased by inhibitor treatment in mice, similar to PGE2 that inhibits fibrocyte differentiation from blood of healthy donors and patients with IPF. Finally, microRNA 218-5p, which is downregulated in patients with IPF, suppressed 15-PGDH expression in vivo and in vitro. CONCLUSIONS: These findings highlight the role of 15-PGDH in IPF and suggest 15-PGDH inhibition as a promising therapeutic approach.

Prevention of COVID-19 in Thoracic Surgery Patients: Lessons Learned during the First Pandemic Wave.

BACKGROUND: The aim of this retrospective study was to investigate the implementation of measures to prevent perioperative COVID-19 in thoracic surgery during the first wave of the COVID-19 pandemic 2020 allowing a continued surgical treatment of patients. METHODS: The implemented preventive measures in patient management of the thoracic surgery department of the Asklepios Lung Clinic Munich-Gauting, Germany were retrospectively analyzed. Postoperative COVID-19 incidence before and after implementation of preventive measures was investigated. Patients admitted for thoracic surgical procedures between March and May 2020 were included in the study. Patient characteristics were analyzed. For the early detection of putative postoperative COVID-19 symptoms, typical post-discharge symptomatology of thoracic surgery patients was compared to non-surgical patients hospitalized for COVID-19. RESULTS: Thirty-five surgical procedures and fifty-seven surgical procedures were performed before and after implementation of the preventive measures, respectively. Three patients undergoing thoracic surgery before implementation of preventive measures developed a COVID-19 pneumonia post-discharge. After implementation of preventive measures, no postoperative COVID-19 cases were identified. Fever, dyspnea, dry cough and diarrhea were significantly more prevalent in COVID-19 patients compared to normally recovering thoracic surgery patients, while anosmia, phlegm, low energy levels, body ache and nausea were similarly frequent in both groups. CONCLUSIONS: Based on the lessons learned during the first pandemic wave, we here provide a blueprint for successful easily implementable preventive measures minimizing SARS-CoV-2 transmission to thoracic surgery patients perioperatively. While symptoms of COVID-19 and the normal postoperative course of thoracic surgery patients substantially overlap, we found dyspnea, fever, cough, and diarrhea significantly more prevalent in COVID-19 patients than in normally recovering thoracic surgery patients. These symptoms should trigger further diagnostic testing for postoperative COVID-19 in thoracic surgery patients.

IL-1 receptor blockade skews inflammation towards Th2 in a mouse model of systemic sclerosis.

The interleukin (IL)-1 family of cytokines is strongly associated with systemic sclerosis (SSc) and pulmonary involvement, but the molecular mechanisms are poorly understood. The aim of this study was to assess the role of IL-1α and IL-1ß in pulmonary vascular and interstitial remodelling in a mouse model of SSc.IL-1α and IL-1ß were localised in lungs of SSc patients and in the fos-related antigen-2 (Fra-2) transgenic (TG) mouse model of SSc. Lung function, haemodynamic parameters and pulmonary inflammation were measured in Fra-2 TG mice with or without 8 weeks of treatment with the IL-1 receptor antagonist anakinra (25 mg·kg-1·day-1). Direct effects of IL-1 on pulmonary arterial smooth muscle cells (PASMCs) and parenchymal fibroblasts were investigated in vitroFra-2 TG mice exhibited increased collagen deposition in the lung, restrictive lung function and enhanced muscularisation of the vasculature with concomitant pulmonary hypertension reminiscent of the changes in SSc patients. Immunoreactivity of IL-1α and IL-1ß was increased in Fra-2 TG mice and in patients with SSc. IL-1 stimulation reduced collagen expression in PASMCs and parenchymal fibroblasts via distinct signalling pathways. Blocking IL-1 signalling in Fra-2 TG worsened pulmonary fibrosis and restriction, enhanced T-helper cell type 2 (Th2) inflammation, and increased the number of pro-fibrotic, alternatively activated macrophages.Our data suggest that blocking IL-1 signalling as currently investigated in several clinical studies might aggravate pulmonary fibrosis in specific patient subsets due to Th2 skewing of immune responses and formation of alternatively activated pro-fibrogenic macrophages.

Resident cell lineages are preserved in pulmonary vascular remodeling.

Pulmonary vascular remodeling is the main pathological hallmark of pulmonary hypertension disease. We undertook a comprehensive and multilevel approach to investigate the origin of smooth muscle actin-expressing cells in remodeled vessels. Transgenic mice that allow for specific, inducible, and permanent labeling of endothelial (Cdh5-tdTomato), smooth muscle (Acta2-, Myh11-tdTomato), pericyte (Cspg4-tdTomato), and fibroblast (Pdgfra-tdTomato) lineages were used to delineate the cellular origins of pulmonary vascular remodeling. Mapping the fate of major lung resident cell types revealed smooth muscle cells (SMCs) as the predominant source of cells that populate remodeled pulmonary vessels in chronic hypoxia and allergen-induced murine models. Combining in vivo cell type-specific, time-controlled labeling of proliferating cells with a pulmonary artery phenotypic explant assay, we identified proliferation of SMCs as an underlying remodeling pathomechanism. Multicolor immunofluorescence analysis showed a preserved pattern of cell type marker localization in murine and human pulmonary arteries, in both donors and idiopathic pulmonary arterial hypertension (IPAH) patients. Whilst neural glial antigen 2 (chondroitin sulfate proteoglycan 4) labeled mostly vascular supportive cells with partial overlap with SMC markers, PDGFRα-expressing cells were observed in the perivascular compartment. The luminal vessel side was lined by a single cell layer expressing endothelial markers followed by an adjacent and distinct layer defined by SMC marker expression and pronounced thickening in remodeled vessels. Quantitative flow cytometric analysis of single cell digests of diverse pulmonary artery layers showed the preserved separation into two discrete cell populations expressing either endothelial cell (EC) or SMC markers in human remodeled vessels. Additionally, we found no evidence of overlap between EC and SMC ultrastructural characteristics using electron microscopy in either donor or IPAH arteries. Lineage-specific marker expression profiles are retained during pulmonary vascular remodeling without any indication of cell type conversion. The expansion of resident SMCs is the major underlying and evolutionarily conserved paradigm of pulmonary vascular disease pathogenesis. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

The proteasome regulator PSME4 modulates proteasome activity and antigen diversity to abrogate antitumor immunity in NSCLC.

Immunotherapy revolutionized treatment options in cancer, yet the mechanisms underlying resistance in many patients remain poorly understood. Cellular proteasomes have been implicated in modulating antitumor immunity by regulating antigen processing, antigen presentation, inflammatory signaling and immune cell activation. However, whether and how proteasome complex heterogeneity may affect tumor progression and the response to immunotherapy has not been systematically examined. Here, we show that proteasome complex composition varies substantially across cancers and impacts tumor-immune interactions and the tumor microenvironment. Through profiling of the degradation landscape of patient-derived non-small-cell lung carcinoma samples, we find that the proteasome regulator PSME4 is upregulated in tumors, alters proteasome activity, attenuates presented antigenic diversity and associates with lack of response to immunotherapy. Collectively, our approach affords a paradigm by which proteasome composition heterogeneity and function should be examined across cancer types and targeted in the context of precision oncology.

Predicting Long-term Survival After Lung Metastasectomy in Patients With Malignant Germ-cell Tumors.

BACKGROUND/AIM: The aim of the study was to identify predictors of long-term survival and propose an improved risk stratification in patients with pulmonary germ-cell metastases admitted for pulmonary metastasectomy. PATIENTS AND METHODS: Thirty-four patients admitted to the Division of Thoracic Surgery Munich, Germany, from 04/1994 until 09/2017 were retrospectively analyzed. The impact of clinical parameters on survival was calculated using Kaplan-Meier, multivariate Cox regression analysis and receiver-operator curves. RESULTS: Ten-year overall survival was 75.3%. Elevated American Society of Anesthesiologists score, metachronous metastasis, embryonal histology, intrathoracic lymph node involvement, brain metastases and thoracic wall infiltration were significant predictors of reduced survival. With the independent predictors (embryonal histology, metachronous metastasis and thoracic wall infiltration), a germinal non-seminomatous lung metastasis risk of death score (GLUMER) was calculated, accurately predicting survival (area under curve=0.8839, p=0.0023). CONCLUSION: In patients with pulmonary germ-cell metastases, intrathoracic lymph node involvement, embryonal carcinoma, metachronous metastasis and thoracic wall infiltration represent negative predictors of long-term survival. The GLUMER score might represent a promising tool for use in adapted follow-up care in high-risk patients.

Bronchoscopic Probe-Based Confocal Laser Endomicroscopy to Diagnose Diffuse Parenchymal Lung Diseases.

Background: Diagnosis of diffuse parenchymal lung disease (DPLD) is based on clinical evaluation, radiological imaging and histology. However, additional techniques are warranted to improve diagnosis. Aims and objective: Probe based confocal laser endomicroscopy (pCLE) allows real time in vivo visualisation of the alveolar compartment during bronchoscopy based on autofluorescence of elastic fibres. We used pCLE (Cellvizio®, Mauna Kea Technology. Inc, Paris, France) to characterise alveolar patterns in patients with different types of DPLD. Methods: In this pilot study we included 42 therapy naive patients (13 female, age 72.6 +/- 2.3 years), who underwent bronchoscopy for workup of DPLD. pCLE images were obtained during rigid bronchoscopy in affected lung segments according to HR-CT scan, followed by cryobiopsies in the identical area. Diagnoses were made by a multidisciplinary panel. The description of pCLE patterns was based on the degree of distortion of the hexagonal alveolar pattern, the density of alveolar structures, the presence of consolidations or loaded alveolar macrophages (AM). The assessment was performed by 2 investigators blinded for the final diagnosis. Results: The normal lung showed a typical alveolar loop pattern. In amiodarone lung disease loaded AM were predominant. COP showed characteristic focal consolidations. IPF was characterized by significant distortion and destruction, NSIP showed significant increase in density, and chronic HP presented with consolidations, mild distortion and density. Conclusion: pCLE shows potential as an adjunctive bronchoscopic imaging technique in the differential diagnosis of DPLD. Structured and quantitative analysis of the images is required.

Correction: Lung cancer stem cells and their aggressive progeny, controlled by EGFR/MIG6 inverse expression, dictate a novel NSCLC treatment approach.

[This corrects the article DOI: 10.18632/oncotarget.26817.].

Phospholipid dynamics in ex vivo lung cancer and normal lung explants.

In cancer cells, metabolic pathways are reprogrammed to promote cell proliferation and growth. While the rewiring of central biosynthetic pathways is being extensively studied, the dynamics of phospholipids in cancer cells are still poorly understood. In our study, we sought to evaluate de novo biosynthesis of glycerophospholipids (GPLs) in ex vivo lung cancer explants and corresponding normal lung tissue from six patients by utilizing a stable isotopic labeling approach. Incorporation of fully 13C-labeled glucose into the backbone of phosphatidylethanolamine (PE), phosphatidylcholine (PC), and phosphatidylinositol (PI) was analyzed by liquid chromatography/mass spectrometry. Lung cancer tissue showed significantly elevated isotopic enrichment within the glycerol backbone of PE, normalized to its incorporation into PI, compared to that in normal lung tissue; however, the size of the PE pool normalized to the size of the PI pool was smaller in tumor tissue. These findings indicate enhanced PE turnover in lung cancer tissue. Elevated biosynthesis of PE in lung cancer tissue was supported by enhanced expression of the PE biosynthesis genes ETNK2 and EPT1 and decreased expression of the PC and PI biosynthesis genes CHPT1 and CDS2, respectively, in different subtypes of lung cancer in publicly available datasets. Our study demonstrates that incorporation of glucose-derived carbons into the glycerol backbone of GPLs can be monitored to study phospholipid dynamics in tumor explants and shows that PE turnover is elevated in lung cancer tissue compared to normal lung tissue.

Distribution and prognostic significance of gluconeogenesis and glycolysis in lung cancer.

Inhibition of glycolysis has been considered as a therapeutic approach in aggressive cancers including lung cancer. Abbreviated gluconeogenesis, mediated by phosphoenolpyruvate carboxykinase (PEPCK), was recently discovered to partially circumvent the need for glycolysis in lung cancer cells. However, the interplay of glycolysis and gluconeogenesis in lung cancer is still poorly understood. Here, we analyzed the expression of GLUT1, the prime glucose transporter, and of PCK1 and PCK2, the cytoplasmic and mitochondrial isoforms of PEPCK, in 450 samples of non-small cell lung cancer (NSCLC) and in 54 NSCLC metastases using tissue microarrays and whole tumor sections. Spatial distribution was assessed by automated image analysis. Additionally, glycolytic and gluconeogenic gene expression was inferred from The Cancer Genome Atlas (TCGA) datasets. We found that PCK2 was preferentially expressed in the lung adenocarcinoma subtype, while GLUT1 expression was higher in squamous cell carcinoma. GLUT1 and PCK2 were inversely correlated, GLUT1 showing elevated expression in larger tumors while PCK2 was highest in smaller tumors. However, a mixed phenotype showing the presence of both, glycolytic and gluconeogenic cancer cells was frequent. In lung adenocarcinoma, PCK2 expression was associated with significantly improved overall survival, while the opposite was found for GLUT1. The metabolic tumor microenvironment and the 3-dimensional context play an important role in modulating both pathways, since PCK2 expression preferentially occurred at the tumor margin and hypoxia regulated both, glycolysis and gluconeogenesis, in NSCLC cells in vitro, albeit in opposite directions. PCK1/2 expression was enhanced in metastases compared to primary tumors, possibly related to the different environment. The results of this study show that glycolysis and gluconeogenesis are activated in NSCLC in a tumor size and oxygenation modulated manner and differentially correlate with outcome. The frequent co-activation of gluconeogenesis and glycolysis in NSCLC should be considered in potential future therapeutic strategies targeting cancer cell metabolism.

Clinical Course of Three Postoperative Symptomatic COVID-19 Cases in Patients After Lung Lobectomy.

The novel coronavirus disease 2019 is a highly contagious viral infection caused by the severe acute respiratory syndrome coronavirus 2 virus. Its rapid spread and severe clinical presentation influence patient management in all specialties including thoracic surgery. We report 3 cases of coronavirus disease 2019 occurring in patients shortly after thoracotomy and thoracoscopy procedures, illustrating the imminent threat of severe acute respiratory syndrome coronavirus 2 infection for thoracic surgery patients.

Advanced interstitial lung fibrosis with emphysema and pulmonary hypertension with no evidence for interstitial lung disease on high resolution CT.

The diagnosis of idiopathic pulmonary arterial hypertension (iPAH) is complex and, besides invasive hemodynamic evaluation, includes several diagnostic steps to exclude any underlying diseases. The role of a decreased diffusion capacity of the lung for carbon monoxide (DLCO) is a matter of discussion. Here, we present a 76-year-old man with a smoking history of 30 pack-years who was diagnosed with iPAH after chronic thromboembolic pulmonary hypertension was excluded based on a negative perfusion scan, an underlying heart disease was excluded based on echocardiography and right heart catheterization, and a significant lung disease was excluded based on lung function test (FVC = 101% predicted, FEV1 = 104% predicted, FEV1/FVC = 77, TLC = 97% predicted) and thin-slice computed tomography (CT) scan. Just DLCO was reduced to 40% predicted, suggesting a possible structural lung disease. Postmortem examination demonstrated severe interstitial lung fibrosis combined with microscopic emphysema. This indicates that both CT imaging and pulmonary function test may be insensitive to a diffuse peripheral combined pattern of fibrosis and emphysema and that DLCO may be the only sensitive marker of this significant lung pathology.

Lung cancer stem cells and their aggressive progeny, controlled by EGFR/MIG6 inverse expression, dictate a novel NSCLC treatment approach.

The lung cancer stem cell (LuCSC) model comprises an attractive framework to explore acquired drug resistance in non-small cell lung cancer (NSCLC) treatment. Here, we used NSCLC cell line model to translate cellular heterogeneity into tractable populations to understand the origin of lung cancers and drug resistance. The epithelial LuCSCs, presumably arising from alveolar bipotent stem/progenitor cells, were lineage naïve, noninvasive, and prone to creating aggressive progeny expressing AT2/AT1 markers. LuCSC-holoclones were able to initiate rimmed niches, where their specialization created pseudo-alveoli structures. Mechanistically, LuCSC transitioning from self-renewal (ß-catenin and Nanog signaling) to malignant lineage differentiation is regulated by EGFR activation and the inverse inhibition of tumor suppressor MIG6. We further identified the functional roles of endogenous EGFR signaling in mediating progeny invasiveness and their ligands in LuCSC differentiation. Importantly, drug screening demonstrated that EGFR driving progeny were strongly responsive to TKIs; however, the LuCSCs were exclusively resistant but sensitive to AMPK agonist Metformin, antibiotic Salinomycin and to a lesser degree Carboplatin. Our data reveals previously an unknown mechanism of NSCLC resistance to EGFR-TKIs, which is associated with LuCSCs bearing a silenced EGFR and inversely expressed MIG6 suppressor gene. Taken altogether, successful NSCLC treatment requires development of a novel combination of drugs, efficiently targeting both LuCSCs and heterogeneous progeny.

Influence of eukaryotic translation initiation factor 6 on non-small cell lung cancer development and progression.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Dysregulation of protein synthesis plays a major role in carcinogenesis, a process regulated at multiple levels, including translation of mRNA into proteins. Ribosome assembly requires correct association of ribosome subunits, which is ensured by eukaryotic translation initiation factors (eIFs). eIFs have become targets in cancer therapy studies, and promising data on eIF6 in various cancer entities have been reported. Therefore, we hypothesised that eIF6 represents a crossroad for pulmonary carcinogenesis. High levels of eIF6 are associated with shorter patient overall survival in adenocarcinoma (ADC), but not in squamous cell carcinoma (SQC) of the lung. We demonstrate significantly higher protein expression of eIF6 in ADC and SQC than in healthy lung tissue based on immunohistochemical data from tissue microarrays (TMAs) and on fresh frozen lung tissue. Depletion of eIF6 in ADC and SQC lung cancer cell lines inhibited cell proliferation and induced apoptosis. Knockdown of eIF6 led to pre-rRNA processing and ribosomal 60S maturation defects. Our data indicate that eIF6 is upregulated in NSCLC, suggesting an important contribution of eIF6 to the development and progression of NSCLC and a potential for new treatment strategies against NSCLC.