bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2022–05–29
eightteen papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge and Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Metabolomes of Lewis lung carcinoma metastases and normal lung tissue from mice fed different diets.
  2. Serum Biomarker Panel for Rapid Early Diagnosis of Lung Cancer.
  3. A Distinct Glucose Metabolism Signature of Lung Adenocarcinoma With Prognostic Value.
  4. Mutational Activation of the NRF2 Pathway Upregulates Kynureninase Resulting in Tumor Immunosuppression and Poor Outcome in Lung Adenocarcinoma.
  5. Association of Diabetes Severity and Mortality with Lung Squamous Cell Carcinoma.
  6. Chemoprevention of Lung Cancer with a Combination of Mitochondria-Targeted Compounds.
  7. Necrosis on pre-radiotherapy 18F-FDG PET/CT is a predictor for complete metabolic response in patients with non-small cell lung cancer.
  8. Spatial transcriptomics of macrophage infiltration in non-small cell lung cancer reveals determinants of sensitivity and resistance to anti-PD1/PD-L1 antibodies.
  9. Efficacy and safety of maintenance immune checkpoint inhibitors with or without pemetrexed in advanced non-squamous non-small cell lung cancer: a retrospective study.
  10. TCR Coexpression Signature Predicts Immunotherapy Resistance in NSCLC.
  11. Ring finger protein 180 suppresses cell proliferation and energy metabolism of non-small cell lung cancer through downregulating C-myc.
  12. Metabolic regulation by the intestinal metformin-AMPK axis.
  13. Immunotherapy Outcomes in Individuals With Non-Small Cell Lung Cancer and Poor Performance Status.
  14. Cancer, Phase Angle and Sarcopenia: The Role of Diet in Connection with Lung Cancer Prognosis.
  15. Prognostic Value and Potential Mechanism of MTFR2 in Lung Adenocarcinoma.
  16. Cytoplasmic Clusterin Suppresses Lung Cancer Metastasis by Inhibiting the ROCK1-ERK Axis.
  17. Early Assessment of Chemotherapy Response in Advanced Non-Small Cell Lung Cancer with Circulating Tumor DNA.
  18. Clinical and Biological Variables Influencing Outcome in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) Treated with Anti-PD-1/PD-L1 Antibodies: A Prospective Multicentre Study.
  1. J Nutr Biochem. 2022 May 21. pii: S0955-2863(22)00122-X. [Epub ahead of print] 109051
    Metabolomes of Lewis lung carcinoma metastases and normal lung tissue from mice fed different diets.
    Lin Yan, Sneha Sundaram, Bret M Rust, Matthew J Picklo, Michael R Bukowski.
      Metastasis is a devastating aspect of cancer. This study tested the hypothesis that metabolome of metastases differs from that of host organs by using the spontaneous metastasis model of Lewis lung carcinoma (LLC). In a 2 × 2 design, male C57BL/6 mice with or without a subcutaneous LLC inoculation were fed the standard AIN93G diet or a high-fat diet (HFD) for 12 weeks. Lung metastases from injected mice and the lungs from non-injected mice were harvested at the end of study for untargeted metabolomics of primary metabolism by using gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). We identified 91 metabolites for metabolomic analysis. The analysis demonstrated that amino acid and energy metabolism were altered the most in LLC metastases compared to the lungs. A 60% decrease in glutamine and a 25-fold elevation in sorbitol were observed in metastases. Cholesterol and its metabolite dihydrocholesterol were 50% lower in metastases than in the lungs. The HFD elevated arachidonic acid and its precursor linoleic acid in the lungs from non-cancer-bearing mice, reflecting the dietary fatty acid composition of the HFD. This elevation did not occur in metastases from HFD-fed LLC-bearing mice, suggesting alterations in lipid metabolism during LLC metastatic progression. Differences in metabolome between pulmonary LLC metastases and the normal healthy lungs can be useful in designing targeted studies for prevention and treatment of cancer spread using this LLC spontaneous metastasis model.
    Keywords:  Lewis lung carcinoma; diet; metabolome; metastasis; mice
    DOI:  https://doi.org/10.1016/j.jnutbio.2022.109051
  2. Curr Cancer Drug Targets. 2022 May 23.
    Serum Biomarker Panel for Rapid Early Diagnosis of Lung Cancer.
    Shucai Wu, Jiawen Zhang, Hongyan Wei, Ying Liu, Xianli Dai, Jinyu Xue, Ting Shen, Xinyan Liu.
       BACKGROUND: Lung cancer is the leading cause of cancer death in most countries. Although early diagnosis and treatment critically influences prognosis, lung cancers are generally only discovered in the late stages of the disease.
    OBJECTIVE: Widely-used screening and diagnostic methods are not suitable for preventive screening, and high-throughput technologies based on serum biomarkers are needed.
    METHOD: We screened 501 serum samples, including 224 lung cancer (LC), 126 disease control (DC) and 151 healthy donor (HC) samples for new serum autoantibodies as biomarkers in the early diagnosis of lung cancer. In phase I, we used HuProtTM microarrays to perform preliminary serum antibody screening on 24 LC and 24 HC samples. In phase II, we screened 60 LC, 60 DC and 60 HC serum samples using focused arrays constructed with 22 of the candidate autoantibody biomarkers screened out in phase I.
    RESULTS: After data modeling and validation, we selected four potential early LC protein biomarker candidates, IL2RB, CENPB, TP53, and XAGE1A, with individual specificities >90% and sensitivities ranging from 21.2% to 32.2%. These four biomarkers had a specificity of >90% and a sensitivity of >65.5% for early LC when they combined in a panel. Further evaluation of these four biomarker candidates using ELISA assays and 273 serum samples (140 LC, 66 DC and 67 HC) gave similar results (specificity of >91.7%, sensitivity >61.43%).
    CONCLUSION: IL2RB, CENPB, TP53, and XAGE1A combined biomarker panel holds potential for rapid screening and could improve the diagnosis of early-stage LC, thus potentially also improving its prognosis.
    Keywords:  ELISA; Lung cancer; Serum; biomarker; microarrays; rapid early diagnosis
    DOI:  https://doi.org/10.2174/1568009622666220523154333
  3. Front Genet. 2022 ;13 860677
    A Distinct Glucose Metabolism Signature of Lung Adenocarcinoma With Prognostic Value.
    Ding Li, Jiaming Liang, Wenzhou Zhang, Xuan Wu, Jie Fan.
      Background: Lung adenocarcinoma (LUAD) remains the most common type of lung cancer and is the main cause of cancer-related death worldwide. Reprogramming of glucose metabolism plays a crucial role in tumorigenesis and progression. However, the regulation of glucose metabolism is still being explored in LUAD. Determining the underlying clinical value of glucose metabolism will contribute in increasing clinical interventions. Our study aimed to conduct a comprehensive analysis of the landscape of glucose metabolism-related genes in LUAD and develop a prognostic risk signature. Methods: We extracted the RNA-seq data and relevant clinical variants from The Cancer Genome Atlas (TCGA) database and identified glucose metabolism-related genes associated with the outcome by correlation analysis. To generate a prognostic signature, least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed. Results: Finally, ten genes with expression status were identified to generate the risk signature, including FBP2, ADH6, DHDH, PRKCB, INPP5J, ABAT, HK2, GNPNAT1, PLCB3, and ACAT2. Survival analysis indicated that the patients in the high-risk group had a worse survival than those in the low-risk group, which is consistent with the results in validated cohorts. And receiver operating characteristic (ROC) curve analysis further validated the prognostic value and predictive performance of the signature. In addition, the two risk groups had significantly different clinicopathological characteristics and immune cell infiltration status. Notably, the low-risk group is more likely to respond to immunotherapy. Conclusion: Overall, this study systematically explored the prognostic value of glucose metabolism and generated a prognostic risk signature with favorable efficacy and accuracy, which help select candidate patients and explore potential therapeutic approaches targeting the reprogrammed glucose metabolism in LUAD.
    Keywords:  biomarker; glucose metabolism; lung adenocarcinoma; prognosis; risk signature
    DOI:  https://doi.org/10.3389/fgene.2022.860677
  4. Cancers (Basel). 2022 May 21. pii: 2543. [Epub ahead of print]14(10):
    Mutational Activation of the NRF2 Pathway Upregulates Kynureninase Resulting in Tumor Immunosuppression and Poor Outcome in Lung Adenocarcinoma.
    Johannes F Fahrmann, Ichidai Tanaka, Ehsan Irajizad, Xiangying Mao, Jennifer B Dennison, Eunice Murage, Julian Casabar, Jeffrey Mayo, Qian Peng, Muge Celiktas, Jody V Vykoukal, Soyoung Park, Ayumu Taguchi, Oliver Delgado, Satyendra C Tripathi, Hiroyuki Katayama, Luisa Maren Solis Soto, Jaime Rodriguez-Canales, Carmen Behrens, Ignacio Wistuba, Samir Hanash, Edwin J Ostrin.
      Activation of the NRF2 pathway through gain-of-function mutations or loss-of-function of its suppressor KEAP1 is a frequent finding in lung cancer. NRF2 activation has been reported to alter the tumor microenvironment. Here, we demonstrated that NRF2 alters tryptophan metabolism through the kynurenine pathway that is associated with a tumor-promoting, immune suppressed microenvironment. Specifically, proteomic profiles of 47 lung adenocarcinoma (LUAD) cell lines (11 KEAP1 mutant and 36 KEAP1 wild-type) revealed the tryptophan-kynurenine enzyme kynureninase (KYNU) as a top overexpressed protein associated with activated NRF2. The siRNA-mediated knockdown of NFE2L2, the gene encoding for NRF2, or activation of the NRF2 pathway through siRNA-mediated knockdown of KEAP1 or via chemical induction with the NRF2-activator CDDO-Me confirmed that NRF2 is a regulator of KYNU expression in LUAD. Metabolomic analyses confirmed KYNU to be enzymatically functional. Analysis of multiple independent gene expression datasets of LUAD, as well as a LUAD tumor microarray demonstrated that elevated KYNU was associated with immunosuppression, including potent induction of T-regulatory cells, increased levels of PD1 and PD-L1, and resulted in poorer survival. Our findings indicate a novel mechanism of NRF2 tumoral immunosuppression through upregulation of KYNU.
    Keywords:  KEAP1; NRF2; immune suppression; kynureninase; kynurenine pathway; lung adenocarcinoma; metabolism; prognostic marker
    DOI:  https://doi.org/10.3390/cancers14102543
  5. Cancers (Basel). 2022 May 22. pii: 2553. [Epub ahead of print]14(10):
    Association of Diabetes Severity and Mortality with Lung Squamous Cell Carcinoma.
    Chih-Hsiung Su, Wan-Ming Chen, Mingchih Chen, Ben-Chang Shia, Szu-Yuan Wu.
       PURPOSE: The survival impact of diabetes severity on lung cancer remains unclear. We performed head-to-head propensity score matching to estimate the survival impact of various adapted diabetes complications severity index (aDCSI) scores in patients with both diabetes and lung squamous cell carcinoma (SqCLC).
    PATIENTS AND METHODS: We enrolled patients with both diabetes and lung SqCLC and categorized them into the mild (aDCSI = 0-1) and moderate-to-severe (aDCSI ≥ 2) diabetes groups. The patients in both groups were matched at a 1:1 ratio.
    RESULTS: the matching process yielded a final cohort of 5742 patients with both diabetes and lung SqCLC (2871 patients in the mild diabetes group and 2871 patients in the moderate-to-severe diabetes groups) who were eligible for further analysis. A multivariate Cox regression analysis revealed that the adjusted hazard ratio (aHR; 95% confidence interval) of all-cause death for the mild diabetes group relative to the moderate-to-severe diabetes group was 1.17 (1.08-1.28; p = 0.0005).
    CONCLUSION: severe diabetes (aDCSI ≥ 2) is an independent prognostic factor for OS among patients with both diabetes and lung SqCLC who receive standard treatments. Preventing diabetes progression is necessary for patients with diabetes because it not only supports diabetes control but also improves survival for patients with lung SqCLC.
    Keywords:  lung cancer; propensity scores matching; severity of diabetes; squamous cell carcinoma; survival
    DOI:  https://doi.org/10.3390/cancers14102553
  6. Cancers (Basel). 2022 May 21. pii: 2538. [Epub ahead of print]14(10):
    Chemoprevention of Lung Cancer with a Combination of Mitochondria-Targeted Compounds.
    Qi Zhang, Donghai Xiong, Jing Pan, Yian Wang, Micael Hardy, Balaraman Kalyanaraman, Ming You.
      Combined treatment targeting mitochondria may improve the efficacy of lung cancer chemoprevention. Here, mitochondria-targeted honokiol (Mito-HNK), an inhibitor of mitochondrial complex I and STAT3 phosphorylation, and mitochondria-targeted lonidamine (Mito-LND), an inhibitor of mitochondrial complexes I/II and AKT/mTOR/p70S6K signaling, were evaluated for their combinational chemopreventive efficacy on mouse lung carcinogenesis. All chemopreventive treatments began one-week post-carcinogen treatment and continued daily for 24 weeks. No evidence of toxicity (including liver toxicity) was detected by monitoring serum levels of alanine aminotransferase and aspartate aminotransferase enzymes. Mito-HNK or Mito-LND treatment alone reduced tumor load by 56% and 48%, respectively, whereas the combination of Mito-HNK and Mito-LND reduced tumor load by 83%. To understand the potential mechanism(s) of action for the observed combinatorial effects, single-cell RNA sequencing was performed using mouse tumors treated with Mito-HNK, Mito-LND, and their combination. In lung tumor cells, Mito-HNK treatment blocked the expression of genes involved in mitochondrial complex ǀ, oxidative phosphorylation, glycolysis, and STAT3 signaling. Mito-LND inhibited the expression of genes for mitochondrial complexes I/II, oxidative phosphorylation, and AKT/mTOR/p70S6K signaling in lung tumor cells. In addition to these changes, a combination of Mito-HNK with Mito-LND decreased arginine and proline metabolism, N-glycan biosynthesis, and tryptophan metabolism in lung tumor cells. Our results demonstrate that Mito-LND enhanced the antitumor efficacy of Mito-HNK, where both compounds inhibited common targets (oxidative phosphorylation) as well as unique targets for each agent (STAT3 and mTOR signaling). Therefore, the combination of Mito-HNK with Mito-LND may present an effective strategy for lung cancer chemoprevention.
    Keywords:  lung cancer; mitochondria-targeted honokiol; mitochondria-targeted lonidamine; mitochondrial bioenergetics; single-cell RNA sequencing
    DOI:  https://doi.org/10.3390/cancers14102538
  7. Medicine (Baltimore). 2022 May 20. 101(20): e29227
    Necrosis on pre-radiotherapy 18F-FDG PET/CT is a predictor for complete metabolic response in patients with non-small cell lung cancer.
    Gülnihan Eren, Osman Kupik.
       ABSTRACT: To investigate necrosis on pre-radiotherapy (RT) 18F-FDG PET/CT (PETNECROSİS) as a predictor of complete metabolic response (CMR) in patients with non-small cell lung cancer (NSCLC).We evaluated patients with inoperable stage I-III NSCLC who underwent pre- and post-radiotherapy 18F-FDG PET/CT. The relationship between CMR and PETNECROSIS, SUVmax, gross tumor volume calculated with 18F-FDG PET/CT (GTVPET-CT), tumor size, histology, metabolic tumor volume (MTV), and RT dose was assessed using logistic regression analysis. To evaluate necrosis on 18F FDG PET/CT, we drew a region of interest (ROI) in the area showing visually very low/or no fluorodeoxyglucose (FDG) uptake on PET images. If the SUVmax was lower than the blood pool SUVmax and showed significantly lower attenuation (10-30 Hounsfield units [HU]) from the surrounding tissue on non-intravenous contrast-enhanced low-dose correlative CT, we defined it as necrotic (PETNECROSİS).Fifty-three patients were included in this study. The mean age was 68.1 ± 9.8 years. Twenty-one patients had adenocarcinoma, and 32 had squamous cell carcinoma. All parameters were independent of histologic status. Multivariate logistic regression analysis showed that SUVmax ≤11.6 vs >11.6, (P = .003; OR, 7.670, 95CI%: 2.013-29.231) and PETNECROSİS absence/presence were independent predictors for CMR (P = .028, OR: 6.704, 95CI% 1.214-30.394).The necrosis on 18F FDG PET/CT and SUVmax > 11.6 could be an imaging marker for the complete metabolic response after definitive chemoradiotherapy or definitive RT alone in patients with NSCLC.
    DOI:  https://doi.org/10.1097/MD.0000000000029227
  8. J Immunother Cancer. 2022 May;pii: e003890. [Epub ahead of print]10(5):
    Spatial transcriptomics of macrophage infiltration in non-small cell lung cancer reveals determinants of sensitivity and resistance to anti-PD1/PD-L1 antibodies.
    Mathieu Larroquette, Jean-Philippe Guegan, Benjamin Besse, Sophie Cousin, Maxime Brunet, Sylvestre Le Moulec, François Le Loarer, Christophe Rey, Jean-Charles Soria, Fabrice Barlesi, Alban Bessede, Jean-Yves Scoazec, Isabelle Soubeyran, Antoine Italiano.
       BACKGROUND: Tumor-associated macrophages (TAMs) having immunosuppressive properties are one of the most abundant immune cells in the tumor microenvironment (TME). Preclinical studies have highlighted the potential role of TAMs in resistance to immune checkpoint blockers (ICBs). Here, we investigated the predictive value of TAM infiltration in patients with non-small cell lung cancer (NSCLC) treated with ICBs and characterized their transcriptomic profiles.
    METHODS: Tumor samples were collected from 152 patients with NSCLC before ICB treatment onset. After immunohistochemical staining and image analysis, the correlation between CD163+ cell infiltration and survival was analyzed. Spatial transcriptomic analyses were performed using the NanoString GeoMx Immune Pathways assay to compare the gene expression profile of tumors with high or low levels of CD163+ cell infiltration and to identify determinants of response to ICBs in tumors with high CD163+ infiltration.
    RESULTS: Low intratumoral CD163+ cell infiltration was associated with longer progression-free survival (PFS; HR 0.61, 95% CI 0.40 to 0.94, p=0.023) and overall survival (OS; HR 0.48, 95% CI 0.28 to 0.80, p=0.004) under ICB treatment. Spatial transcriptomic profiles of 16 tumors revealed the upregulation of ITGAM, CD27, and CCL5 in tumors with high CD163+ cell infiltration. Moreover, in tumors with high macrophage infiltration, the upregulation of genes associated with the interferon-γ signaling pathway and the M1 phenotype was associated with better responses under immunotherapy. Surprisingly, we found also a significantly higher expression of CSF1R in the tumors of responders. Analysis of three independent data sets confirmed that high CSF1R expression was associated with an increased durable clinical benefit rate (47% vs 6%, p=0.004), PFS (median 10.89 months vs 1.67 months, p=0.001), and OS (median 23.11 months vs 2.66 months, p<0.001) under ICB treatment.
    CONCLUSIONS: Enrichment of TAMs in the TME of NSCLC is associated with resistance to immunotherapy regardless of the programmed death ligand 1 status and is driven by upregulation of CD27, ITGAM, and CCL5 gene expression within the tumor compartment. Our transcriptomic analyses identify new potential targets to alter TAM recruitment/polarization and highlight the complexity of the CSF1R pathway, which may not be a suitable target to improve ICB efficacy.
    Keywords:  immunotherapy; lung neoplasms; macrophages
    DOI:  https://doi.org/10.1136/jitc-2021-003890
  9. BMC Cancer. 2022 May 24. 22(1): 576
    Efficacy and safety of maintenance immune checkpoint inhibitors with or without pemetrexed in advanced non-squamous non-small cell lung cancer: a retrospective study.
    Xiaodong Gu, Zhiyong Shi, Lan Shao, Yuxin Zhang, Yiping Zhang, Zhengbo Song, Wenxian Wang, Guangyuan Lou.
       BACKGROUND: Advanced non-squamous non-small cell lung cancer (NS-NSCLC) patients without driver gene mutations are usually treated with immune checkpoint inhibitors (ICIs) plus pemetrexed as maintenance therapy after first-line ICIs plus 4-6 cycles of pemetrexed/platinum. Some patients in the real world receive ICIs monotherapy as maintenance therapy. No clinical study has compared the efficacy and safety of ICIs with or without pemetrexed as maintenance therapy.
    METHODS: We performed a retrospective study analyzing clinical data of patients with NS-NSCLC who were diagnosed in Zhejiang Cancer Hospital from September 2018 to May 2021 and received maintenance therapy after 4-6 cycles of ICIs plus pemetrexed/platinum. Patients were divided into ICIs plus pemetrexed group and ICIs monotherapy group. Progression Free Survival 1 (PFS1) and PFS2, defined as the interval from the date of initial treatment and maintenance therapy to the date of systemic progression/death or the last follow-up, respectively.
    RESULTS: A total of 120 patients received ICIs with or without pemetrexed as maintenance therapy. Eighty-two patients received ICIs plus pemetrexed as maintenance therapy, and 38 patients received ICIs monotherapy. There were no statistically significant difference in median PFS1 between the ICIs monotherapy group and ICIs plus pemetrexed group (12.00 months vs. 12.07 months, P = 0.979). Among patients with PD-L1 TPS < 1%, the median PFS1 was worse with ICIs monotherapy (9.50 months vs. 14.20 months, P = 0.039). Among patients with PD-L1 TPS ≥50% or 1-49%, the median PFS1 in both groups was not statistically significant (P = 0.866, P = 0.589, respectively). Results for median PFS2 were similar to median PFS1, with statistically significantly different only in patients with PD-L1 TPS < 1% (P = 0.008). The 2-year survival rates of the two groups were similar (66.7% vs. 69.5%, P = 0.812). The incidence of fatigue was significantly higher in the ICIs plus pemetrexed group (P = 0.023).
    CONCLUSIONS: ICIs with or without pemetrexed can be used as maintenance therapy after first-line ICIs plus 4-6 cycles of pemetrexed/platinum in patients with advanced NS-NSCLC based on PD-L1 expression.
    Keywords:  Adverse events; Immune checkpoint inhibitors; Maintenance therapy; Non-squamous non-small cell lung cancer; Pemetrexed
    DOI:  https://doi.org/10.1186/s12885-022-09674-2
  10. Front Pharmacol. 2022 ;13 875149
    TCR Coexpression Signature Predicts Immunotherapy Resistance in NSCLC.
    Yuntao Wang, Yi Liu, Xiaohua Li, Weiming Li, Zhihong Xue, Xiaoqian He, Weijie Xiong, Lang He, Yifeng Bai.
      Background: Lung cancer has the highest morbidity and mortality rate among types of malignant tumors, and as such, research into prolonging the survival time of patients is vital. The emergence of immune checkpoint inhibitors (ICIs) has greatly improved the survival of patients with non-small cell lung cancer (NSCLC), however, the lack of effective biomarkers to predict the prognosis of immunotherapy has made it difficult to maximize the benefits. T cell receptor (TCR) is one of the most important components for recognizing tumor cells, and with this study we aim to clarify the relationship between TCR coexpression and the prognosis of NSCLC patients receiving immunotherapy. Methods: Univariate COX regression, logistics regression, and KM survival analysis were used to evaluate the relationship between TCR coexpression and the prognosis of immunotherapy. Additionally, CIBERSORT, Gene Set Enrichment Analysis (GSEA), and single-sample GSEA (ssGSEA) algorithms were used to evaluate the tumor immune microenvironment (TIME) of NSCLC patients. Results: Univariate Cox regression analysis showed that the TCR coexpression signature can be used as a clinical prognostic indicator for NSCLC patients receiving immunotherapy (p = 0.0205). In addition, those in the NSCLC group with a high TCR coexpression signature had significantly improved progression-free survival (PFS) (p = 0.014). In the ICI treatment cohort (GSE35640). In addition, there was a high infiltration of CD8+T cells, activated memory CD4+T cells, and M1 macrophages in the TIME of those with a high TCR coexpression signature. The results of pathway enrichment analysis showed that patients with a high TCR coexpression signature had significantly activated signal pathways such as lymphocyte proliferation and activation, chemokine binding, and inflammatory cytokine production. Also, we found that patients with a high TCR coexpression signature had an elevated T cell inflammation gene expression profile (GEP). Conclusion: We show that the TCR coexpression signature may be useful as a new biomarker for the prognosis of NSCLC patients undergoing immunotherapy, with high signatures indicating better treatment response. Additionally, we found that patients with a high TCR coexpression signature had tumor immune microenvironments with beneficial anti-tumor characteristics.
    Keywords:  ICIs; NSCLC; TCR—T cell receptor; biomarker; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fphar.2022.875149
  11. World J Surg Oncol. 2022 May 21. 20(1): 162
    Ring finger protein 180 suppresses cell proliferation and energy metabolism of non-small cell lung cancer through downregulating C-myc.
    Yi Ding, Yi Lu, Xinjie Xie, Lei Cao, Shiying Zheng.
       BACKGROUND: Non-small cell lung cancer (NSCLC) causes numerous deaths worldwide. however, biomarkers for NSCLC prognosis are scarce for its heterogeneity. Proteins containing the RING finger domain RING finger protein 180 (RNF180) is a key mediator for ubiquitination, which controls cell cycle and regulates progression in certain human tumors. However, the detailed function of RNF180 in NSCLC remains unclear. In the present study, we aimed to investigate the role of RNF180 and its molecule network in NSCLC.
    METHODS: Quantitative real-time polymerase chain reaction and immunohistochemical staining were used to analyze RNF180 levels. RNA interference and lentiviral-mediated vector transfections were performed to silence and overexpress RNF180 in NSCLC cells. Furthermore, Cell Counting Kit-8 was used for assessing biological function of RNF180 in cell proliferation and a xenograft model for examining its function in vivo. The activity of glycolysis was determined by examining the level of the extracellular acidification rate (ECAR).
    RESULTS: RNF180 expression decreased in NSCLC tissues, and its expression was positively correlated with the survival rate of patients with NSCLC. Moreover, RNF180 overexpression suppressed the proliferation and glycolytic activities in NSCLC cells and restricted its tumorigenicity in vivo. Furthermore, RNF180 silencing promoted the proliferation and glycolysis metabolism of NSCLC cells, whereas C-myc inhibitor disrupted these effects. The underlying anti-oncogene of RNF180 involved in C-myc downregulation via ubiquitin-dependent degradation.
    CONCLUSIONS: Together, these results firstly indicated the anti-tumor properties of RNF180 and its correlation with NSCLC progression, thereby endorsing the potential role of RNF180 as an efficient prognostic biomarker for tumor recurrence.
    Keywords:  C-myc; Cell proliferation; Glycolysis; Non-small cell lung cancer; RING finger protein 180; Ubiquitination
    DOI:  https://doi.org/10.1186/s12957-022-02599-x
  12. Nat Commun. 2022 May 23. 13(1): 2851
    Metabolic regulation by the intestinal metformin-AMPK axis.
    Song-Yang Zhang, Tony K T Lam.
      
    DOI:  https://doi.org/10.1038/s41467-022-30477-3
  13. JNCI Cancer Spectr. 2022 Mar 02. pii: pkac013. [Epub ahead of print]6(2):
    Immunotherapy Outcomes in Individuals With Non-Small Cell Lung Cancer and Poor Performance Status.
    Rajwanth Veluswamy, Liangyuan Hu, Cardinale Smith, Jiayi Ji, Xiaoliang Wang, Juan Wisnivesky, Jose Morillo, Minal S Kale.
       BACKGROUND: Patients with non-small cell lung cancer (NSCLC) treated in real-world practice typically have worse performance status (PS) compared with clinical trial patients, and the effectiveness of immunotherapy in this population in unknown. In this study, we assessed the effectiveness of standard of care immunotherapy for the first-line treatment of stage IV patients with NSCLC with Eastern Cooperative Oncology Group (ECOG) PS greater than or equal to 2.
    METHODS: We selected ECOG PS greater than or equal to 2 patients from real-world oncology data from a deidentified database and included them if they were diagnosed with stage IV NSCLC and had documented Programmed death-ligand 1 [PD-(L)1] expression greater than 0. Patients with tumor PD-(L)1 expression of at least 50% treated with pembrolizumab monotherapy were compared with those who did not have any documented treatment. Patients with tumor PD-(L)1 expression less than 50% treated with pembrolizumab and chemotherapy were compared with those treated with pembrolizumab monotherapy and those without documented treatment.
    RESULTS: In our propensity score-adjusted analysis, patients with ECOG PS of at least 2 and tumor PD-(L)1 expression of at least 50% treated with pembrolizumab monotherapy had statistically significantly better real-world overall survival compared with those without documented treatment (adjusted hazard ratio [HR] = 0.39, 95% confidence internal [CI] = 0.32 to 0.47). For patients with tumor PD-(L)1 expression less than 50%, there was also a statistically significant real-world overall survival benefit for those who received treatment either with combination pembrolizumab plus chemotherapy (adjusted HR = 0.39, 95% CI = 0.32 to 0.46) or pembrolizumab monotherapy (adjusted HR = 0.55, 95% CI = 0.41 to 0.70) compared with patients receiving no documented treatment.
    CONCLUSIONS: Among a highly representative sample of patients with advanced NSCLC and poor PS, our findings suggest that immunotherapy may provide an important survival benefit in individuals with high PD-(L)1-expressing tumors and in conjunction with chemotherapy in tumors with low PD-(L)1 expression.
    DOI:  https://doi.org/10.1093/jncics/pkac013
  14. Lung. 2022 May 26.
    Cancer, Phase Angle and Sarcopenia: The Role of Diet in Connection with Lung Cancer Prognosis.
    Paraskevi Detopoulou, Gavriela Voulgaridou, Sousana Papadopoulou.
      Lung cancer is the most common cause of cancer death and is associated with malnutrition and sarcopenia. The detection of sarcopenia and conduction of simple body composition measurements, such as the phase angle (PhA) deriving from bioelectrical impedance analysis (BIA), can help to early identify, monitor, prevent and treat malnutrition. The present review aims to clarify the relationship between PhA and sarcopenia with the pathophysiology, clinical outcomes, and therapeutic aspects of lung cancer. PhA and sarcopenia are connected to lung cancer prognosis through various mechanisms including inflammation and oxidative stress, although more research is needed to identify the critical thresholds for increased mortality risk. Moreover, emphasis is given on the role of dietary interventions (oral nutritional supplementation, and dietary counseling) to manage sarcopenia and related variables in patients with lung cancer. Oral nutritional supplements and/or those containing n - 3 polyunsaturated fatty acids may have a positive effect on physical strength measures and muscle mass if administered at the beginning of chemotherapy. Data on sole dietary counseling or multimodal interventions are less promising so far. In the future, sophisticated body composition phenotypes deriving from the described methods along with artificial intelligence techniques could be used to design personalized nutrition interventions and timely treat these patients.
    Keywords:  Intervention; Lung cancer; Nutrition; Phase angle; Sarcopenia
    DOI:  https://doi.org/10.1007/s00408-022-00536-z
  15. Front Oncol. 2022 ;12 832517
    Prognostic Value and Potential Mechanism of MTFR2 in Lung Adenocarcinoma.
    Zengzhi Lian, Pei Pang, Yan Zhu, Wenwen Du, Jintao Zhou.
      Mitochondrial fission regulator 2 (MTFR2) belongs to the MTFR1 family, which plays a crucial role in regulating oxidative phosphorylation. Recent studies indicate that it also participates in cancer carcinogenesis and development; however, the clinical significance of MTFR2 in lung adenocarcinoma has not been fully confirmed. Our current study investigated the relationships between clinical characteristics and MTFR2 expression based on The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GSE31210) dataset, and clinical histopathological sample cohort. In addition, Kaplan-Meier and Cox regression analyses were additionally performed to evaluate the association between MTFR2 expression and patient survival. Gene set enrichment analysis (GESA) was conducted to spot possible pathways associated with MTFR2. Moreover, a single-sample GESA (ssGESA) was performed to evaluate the association between MTFR2 expression and immune cell infiltration. Cell colony formation assay, CCK-8 assay, cell cycle assay, and transwell assay were performed to verify the cell proliferation, migration, and invasion abilities after interfering with MTFR2 in lung cancer cells. Western blot assay was applied to identify the underlying protein levels. The results indicated that the elevated MTFR2 expression in lung adenocarcinoma samples correlated with T stage (P < 0.001), N stage (P = 0.005), M stage (P = 0.015), pathological stage (P = 0.002), and TP53 status (P < 0.001). Patients with a higher MTFR2 expression correlated with poorer overall survival (P < 0.01) and progression-free survival (P = 0.002). Knockdown of MTFR2 inhibited cell proliferation, migration, and invasion via AKT-cyclin D1 signaling and EMT pathways. Moreover, MTFR2 expression significantly positively correlated with Th2 cells (P < 0.001). Taken together, MTFR2 could serve as a novel prognostic indicator and therapeutic target for lung adenocarcinoma.
    Keywords:  MTFR2; cell proliferation; immunity; lung adenocarcinoma; prognosis
    DOI:  https://doi.org/10.3389/fonc.2022.832517
  16. Cancers (Basel). 2022 May 17. pii: 2463. [Epub ahead of print]14(10):
    Cytoplasmic Clusterin Suppresses Lung Cancer Metastasis by Inhibiting the ROCK1-ERK Axis.
    Shaobo Huang, Xu Li, Weiqi Gu, Xiaoyi Li, Jingjing Zhao, Jueheng Wu, Junchao Cai, Xianming Feng, Tianyu Tao.
      Clusterin (CLU) is a heterodimeric glycoprotein that has been detected in diverse human tissues and implicated in many cellular processes. Accumulating evidence indicates that the expression of secreted CLU correlates with the progression of cancers. However, the molecular mechanisms underlying its tumor-suppressive roles are incompletely uncovered. In this study, we demonstrate that precursor CLU is widely downregulated in lung cancer tissue, in which secretory CLU proteins are slightly decreased. Impressively, overexpressing CLU potently inhibits the migration, invasion and metastasis of lung cancer cells, whereas silencing CLU promotes this behavior; however, it appears that secretory CLU fails to exert similar anti-metastatic effects. Interestingly, the cytoplasmic precursor CLU binds ROCK1 to abrogate the interaction between ROCK1 and ERK and impair ERK activity, leading to the suppression of lung cancer invasiveness. Meanwhile, the expression of CLU was remarkably diminished in lung cancer bone metastasis loci when compared with subcutaneous tumors in the mouse model and hardly detected in the bone metastasis loci of lung cancer patients when compared with the primary. These findings reveal a novel insight into the function and regulation of cytoplasmic CLU in lung cancer, which might be a potential target for the diagnosis and treatment of metastatic lung cancer.
    Keywords:  Clusterin; ROCK1; lung cancer; metastasis
    DOI:  https://doi.org/10.3390/cancers14102463
  17. Cancers (Basel). 2022 May 18. pii: 2479. [Epub ahead of print]14(10):
    Early Assessment of Chemotherapy Response in Advanced Non-Small Cell Lung Cancer with Circulating Tumor DNA.
    Stephanie J Yaung, Corinna Woestmann, Christine Ju, Xiaoju Max Ma, Sandeep Gattam, Yiyong Zhou, Liu Xi, Subrata Pal, Aarthi Balasubramanyam, Nalin Tikoo, Claus Peter Heussel, Michael Thomas, Mark Kriegsmann, Michael Meister, Marc A Schneider, Felix J Herth, Birgit Wehnl, Maximilian Diehn, Ash A Alizadeh, John F Palma, Thomas Muley.
      Monitoring treatment efficacy early during therapy could enable a change in treatment to improve patient outcomes. We report an early assessment of response to treatment in advanced NSCLC using a plasma-only strategy to measure changes in ctDNA levels after one cycle of chemotherapy. Plasma samples were collected from 92 patients with Stage IIIB-IV NSCLC treated with first-line chemo- or chemoradiation therapies in an observational, prospective study. Retrospective ctDNA analysis was performed using next-generation sequencing with a targeted 198-kb panel designed for lung cancer surveillance and monitoring. We assessed whether changes in ctDNA levels after one or two cycles of treatment were associated with clinical outcomes. Subjects with ≤50% decrease in ctDNA level after one cycle of chemotherapy had a lower 6-month progression-free survival rate (33% vs. 58%, HR 2.3, 95% CI 1.2 to 4.2, log-rank p = 0.009) and a lower 12-month overall survival rate (25% vs. 70%, HR 4.3, 95% CI 2.2 to 9.7, log-rank p &lt; 0.001). Subjects with ≤50% decrease in ctDNA level after two cycles of chemotherapy also had shorter survival. Using non-invasive liquid biopsies to measure early changes in ctDNA levels in response to chemotherapy may help identify non-responders before standard-of-care imaging in advanced NSCLC.
    Keywords:  NGS; NSCLC; chemotherapy; ctDNA; early molecular response
    DOI:  https://doi.org/10.3390/cancers14102479
  18. J Pers Med. 2022 Apr 24. pii: 679. [Epub ahead of print]12(5):
    Clinical and Biological Variables Influencing Outcome in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) Treated with Anti-PD-1/PD-L1 Antibodies: A Prospective Multicentre Study.
    Erica Quaquarini, Federico Sottotetti, Francesco Agustoni, Emma Pozzi, Alberto Malovini, Cristina Maria Teragni, Raffaella Palumbo, Giuseppe Saltalamacchia, Barbara Tagliaferri, Emanuela Balletti, Pietro Rinaldi, Costanza Canino, Paolo Pedrazzoli, Antonio Bernardo.
       INTRODUCTION: Immune checkpoint inhibitors (ICIs) have become the standard of treatment for patients with non-small cell lung cancer (NSCLC). However, there are still many uncertainties regarding the selection of the patient who could benefit more from this treatment. This study aims to evaluate the prognostic and predictive role of clinical and biological variables in unselected patients with advanced NSCLC candidates to receive ICIs.
    METHODS: This is an observational and prospective study. The primary objective is the evaluation of the relationship between clinical and biological variables and the response to ICIs. Secondary objectives included: safety; assessment of the relationship between clinical and biological parameters/concomitant treatments and progression-free survival at 6 months and overall survival at 6 and 12 months. Nomograms to predict these outcomes have been generated.
    RESULTS: A total of 166 patients were included. An association with response was found in the presence of the high immunohistochemical PD-L1 expression, squamous cell histotype, and early line of treatment, whereas a higher probability of progression was seen in the presence of anemia, high LDH values and neutrophil/lymphocyte ratio (NLR), pleural involvement, and thrombosis before treatment. The nomogram showed that anemia, PD-L1 expression, NLR, and LDH represented the most informative predictor as regards the three parameters of interest.
    CONCLUSIONS: In the era of personalized medicine, the results are useful for stratifying the patients and tailoring the treatments, considering both the histological findings and the clinical features of the patients.
    Keywords:  advance stage; anemia; immune checkpoint inhibitors; non-small cell lung cancer
    DOI:  https://doi.org/10.3390/jpm12050679
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