bims-meluca 2022-06-19 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2022–06–19
nine 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

Study on plasma amino acids and piperonamide as potential diagnostic biomarkers of non-small cell lung cancer.
Assessment of body composition and association with clinical outcomes in patients with lung and colorectal cancer.
Predicting the efficacy of first-line immunotherapy by combining cancer cachexia and tumor burden in advanced non-small cell lung cancer.
miR-16-5p regulates aerobic glycolysis and tumorigenesis of NSCLC cells via LDH-A/lactate/NF-κB signaling.
Survival Outcomes and Treatment Patterns in Patients With NFE2L2 and/or KEAP1 Mutation-Positive Advanced Squamous Cell NSCLC Using a Real-World Clinico-Genomic Database.
Targeting BRAF-mutant non-small cell lung cancer: Current status and future directions.
Identifying Immune Cell Infiltration and Effective Diagnostic Biomarkers in Lung Adenocarcinoma by Comprehensive Bioinformatics Analysis and In Vitro Study.
SHC1 Promotes Lung Cancer Metastasis by Interacting with EGFR.
Proteomic analysis of plasma-derived exosomes identifies biomarkers that distinguish brain and liver metastasis in lung cancer patients.

Transl Cancer Res. 2022 May;11(5): 1269-1284

Study on plasma amino acids and piperonamide as potential diagnostic biomarkers of non-small cell lung cancer.

Caifa Zhang, Yuanyuan Wang, Yunfeng Cao, Linyang Shi, Ruonan Wang, Ningning Sheng, Qingjun Wang, Zhitu Zhu.

   Background: The value of plasma threonine, cysteine, and piperonamide as diagnostic biomarkers for non-small cell lung cancer (NSCLC) has been rarely explored. The lack of a validation set containing confounders is common to most previous metabolomics studies. The purpose of this study was to explore and validate the value of plasma amino acids and piperonamide as diagnostic biomarkers for NSCLC using liquid chromatography-tandem mass spectrometry (LC-MS/MS).
Methods: A total of 250 participants were included in this study, including 167 patients with pathologically confirmed NSCLC and 83 healthy controls (HCs). These participants were divided into training set, validation set 1, and validation set 2 in chronological order and in a certain proportion. The plasma levels of 22 amino acids and 1 piperonamide in these pre-treatment NSCLC patients and HCs were measured by LC-MS/MS. Metabolic biomarkers were identified after multivariate analysis, univariate analysis, receiver operating characteristic (ROC) analysis. Furthermore, these biomarkers and transcriptomic data were subjected to joint pathway analysis.
Results: The area under the ROC curve (AUC) values for threonine, piperonamide, arginine, alanine, cysteine, methionine, and histidine in the integrated data set were 0.911, 0.848, 0.909, 0.869, 0.786, 0.597 and 0.637, respectively. This panel composed of these 7 metabolites showed good diagnostic capability for NSCLC (the AUC of this diagnostic panel in each data set was greater than 0.9). The specificity of this diagnostic panel in validation set 2, which included confounders, was 0.970, similar to that of the other datasets. The presence of confounding factors had little effect on the diagnostic accuracy of this panel. The ROC analysis of this diagnostic panel between all stage I NSCLC patients and HCs showed AUC, sensitivity, and specificity of 1.000, 1.000, and 0.988, respectively. Moreover, PSAT1, SHMT2, AOC3, and MAOB were found to be involved in the metabolism of threonine and cysteine.
Conclusions: Plasma amino acids and piperonamide have potential as diagnostic biomarkers in NSCLC. This metabolic biomarker panel appears useful for the diagnosis and screening of NSCLC. In addition, metabolomic and transcriptomic integration pathway analysis may help elucidate the mechanism of NSCLC occurrence and development and even reveal new treatment vulnerabilities.

Keywords:  Non-small cell lung cancer (NSCLC); amino acids; diagnosis; metabolomics; transcriptomics

DOI:  https://doi.org/10.21037/tcr-22-865
BJR Open. 2021 ;3(1): 20210048

Assessment of body composition and association with clinical outcomes in patients with lung and colorectal cancer.

Naomi S Sakai, Anisha Bhagwanani, Timothy Jp Bray, Margaret A Hall-Craggs, Stuart Andrew Taylor.

Objectives: To assess body composition in patients with non-small cell lung cancer (NSCLC) and colorectal cancer using whole-body MRI and relate this to clinical outcomes.
Methods: 53 patients with NSCLC (28 males, 25 females; mean age 66.9) and 74 patients with colorectal cancer (42 males, 32 females; mean age 62.9) underwent staging whole-body MRI scans, which were post-processed to derive fat mass (FM), fat free mass (FFM) and skeletal muscle (SM) indices and SM fat fraction (FF). These were compared between the two cancer cohorts using two-sided t-tests and the chi-squared test. Measurements of body composition were correlated with outcomes including length of hospital stay, metastatic status and mortality.
Results: Patients with NSCLC had significantly lower FFM (p = 0.0071) and SM (p = 0.0084) indices. Mean SM FF was greater in patients with NSCLC (p = 0.0124) and was associated with longer hospital stay (p = 0.035). There was no significant relationship between FM, FFM and SM indices and length of hospital stay, metastatic status or mortality.
Conclusions: Patients with NSCLC had lower FFM and SM indices than patients with colorectal cancer and greater SMFF, indicating lower SM mass with fatty infiltration. These findings reflect differences in the phenotype of the two groups and suggest patients with lung cancer are more likely to require additional nutritional support.
Advances in knowledge: Body composition differs between NSCLC and colorectal cancer. Patients with NSCLC have both a reduced SM mass and greater SM FF suggesting that they are more nutritionally deplete than patients with colorectal cancer.

DOI: https://doi.org/10.1259/bjro.20210048
Thorac Cancer. 2022 Jun 13.

Predicting the efficacy of first-line immunotherapy by combining cancer cachexia and tumor burden in advanced non-small cell lung cancer.

Taichi Miyawaki, Tateaki Naito, Kosei Doshita, Hiroaki Kodama, Mikiko Mori, Naoya Nishioka, Yuko Iida, Eriko Miyawaki, Nobuaki Mamesaya, Haruki Kobayashi, Shota Omori, Ryo Ko, Kazushige Wakuda, Akira Ono, Hirotsugu Kenmotsu, Haruyasu Murakami, Keita Mori, Hideyuki Harada, Masahiro Endo, Kazuhisa Takahashi, Toshiaki Takahashi.

   BACKGROUND: Cancer cachexia and tumor burden predict efficacies of programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors and chemotherapy or pembrolizumab in non-small cell lung cancer (NSCLC). There are no predictive models that simultaneously assess cancer cachexia and tumor burden.
METHODS: In the present retrospective study, we reviewed the medical records of patients with advanced NSCLC who received cancer immunotherapy as first-line systemic therapy. Clinical immune predictive scores were defined according to multivariate analysis of progression-free survival (PFS) and overall survival (OS).
RESULTS: A total of 157 patients were included in the present study (75 treated with PD-1/PD-L1 inhibitors + chemotherapy; 82, pembrolizumab monotherapy). Multivariate analysis for PFS revealed that PD-L1 tumor proportion scores <50%, a total target lesion diameter ≥76 mm, and cancer cachexia were independently associated with poor PFS. Multivariate analysis for OS revealed that ≥4 metastases and cancer cachexia were significantly associated with poor OS. In the immune predictive model, the median PFS was 21.7 months in the low-risk group (N = 41); 7.6 in the medium-risk group (N = 64); and 3.0 in the high-risk group (N = 47). The median OS were not reached, 22.4 and 9.1 months respectively. Our immune predictive model was significantly associated with PFS (p < 0.001) and OS (p < 0.001).
CONCLUSION: We proposed the immune predictive model, including tumor burden and cancer cachexia, which may predict the efficacy and survival outcome of first-line immunotherapy in advanced NSCLC.

Keywords:  cancer cachexia; immune checkpoint inhbitor; non-small cell lung cancer; predictive model; tumor burden

DOI:  https://doi.org/10.1111/1759-7714.14529
Life Sci. 2022 Jun 14. pii: S0024-3205(22)00422-2. [Epub ahead of print] 120722

miR-16-5p regulates aerobic glycolysis and tumorigenesis of NSCLC cells via LDH-A/lactate/NF-κB signaling.

Shweta Arora, Prithvi Singh, Gulnaz Tabassum, Ravins Dohare, Mansoor Ali Syed.

   BACKGROUND AND AIM: Cancer cells exhibit Warburg effect, characterized by increased glycolysis followed by fermentative conversion of pyruvate to lactate. Upregulation of Lactate Dehydrogenase-A (LDH-A) is elucidated to be a dominant molecular mediator of the phenomenon. Also, microRNA (miRNA) dysregulation participates in malignant progression and dissemination in several cancers. miR-16-5p is considerably reduced in lung cancers (LC), suggesting its tumor-suppressive role. However, its role in the regulation of aerobic glycolysis remains unknown. Our study aims to identify the regulatory roles of miR-16-5p/LDH-A in Non-small cell lung cancer (NSCLC).
MAIN METHODS: We evaluated the differential expression of LDH-A and its prognostic potential in NSCLC tissues using online databases. We performed Tissue analysis using Immunohistochemistry (IHC); In-vitro cellular analysis including transient transfection, cellular proliferation, migration, and colony forming analysis. We also performed cell survival, metabolic, cell cycle, apoptotic, ROS generation and Immunocytochemistry (ICC) analyses to identify the role of miR-16-5p/LDH-A in aerobic glycolysis and tumorigenesis of NSCLC.
KEY FINDINGS: We have identified that miR-16-5p directly targets LDH-A by binding to the complementary binding regions present in its 3'-UTR region, leading to degradation, sequentially leading to reduced lactate accumulation, glucose uptake and ATP levels. Our study also demonstrated the role of lactate accumulation in promoting NSCLC tumorigenesis via activation of NF-κB signaling pathway. However, miR-16-5p mediated targeting of LDH-A downregulates the expression of NF-κB associated genes, along with increased ROS generation, apoptosis, and cell cycle arrest.
SIGNIFICANCE: In conclusion, our findings identify miR-16-5p/LDH-A/lactate/NF-κB as an important link between metabolism and NSCLC cells tumorigenesis.

Keywords:  Aerobic glycolysis; LDH-A; Lactate; NF-κB; NSCLC; miR-16-5p

DOI:  https://doi.org/10.1016/j.lfs.2022.120722
Clin Lung Cancer. 2022 May 11. pii: S1525-7304(22)00104-8. [Epub ahead of print]

Survival Outcomes and Treatment Patterns in Patients With NFE2L2 and/or KEAP1 Mutation-Positive Advanced Squamous Cell NSCLC Using a Real-World Clinico-Genomic Database.

Yanyu Wu, Yu Yin, Victoria Crossland, Sylvie Vincent, Paul K Paik, Neil Lineberry, Douglas V Faller.

   BACKGROUND: NFE2L2 and/or KEAP1 mutations are associated with worse prognosis in all non-small cell lung cancer (NSCLC). We determined real-world survival outcomes and treatment patterns among patients with advanced squamous cell NSCLC by NFE2L2 and KEAP1 mutation status.
PATIENTS AND METHODS: A retrospective study (January 2011-December 2018) was conducted using a de-identified US-based clinico-genomic database. Adult patients with advanced squamous cell NSCLC with ≥ 2 in-network visits and comprehensive genomic profiling during the study period were included. Outcomes included real-world progression free survival (rwPFS) by line of therapy and overall survival (OS). The real-world effectiveness of anti-PD-1/PD-L1 first-line therapy was also evaluated in patients with a NFE2L2 and/or KEAP1 mutation.
RESULTS: Of 703 patients included (median age: 70.0 years), 31.6% had a NFE2L2 and/or KEAP1 mutation. The most common first- and second-line treatments regardless of mutation status were platinum-based chemotherapies and anti-PD-1/PD-L1 therapies. The most common third-line treatment was anti-PD-1/PD-L1 therapy in patients with a NFE2L2 and/or KEAP1 mutation and single-agent chemotherapy in patients with wild-type disease. Patients with a NFE2L2 and/or KEAP1 mutation versus wild-type disease had significantly shorter rwPFS (4.54 vs. 6.25 months; P = .003) following first- but not second- or third-line therapy and shorter median OS (13.59 vs. 17.37 months; P = .4105). No survival differences were observed in patients with a NFE2L2 and/or KEAP1 mutation receiving first-line anti-PD-1/PD-L1 therapies versus other therapies.
CONCLUSIONS: Patients with advanced squamous cell NSCLC with a NFE2L2 and/or KEAP1 mutation have poor real-world survival, highlighting the need for a genotype-directed therapeutic strategy in this population.

Keywords:  Kelch-like ECH-associated protein 1 gene mutation; Non-small cell lung cancer; Nuclear factor erythroid 2 like 2 gene mutation; PD-1/PD-L1 therapy; Retrospective

DOI:  https://doi.org/10.1016/j.cllc.2022.05.008
Lung Cancer. 2022 May 26. pii: S0169-5002(22)00459-7. [Epub ahead of print]169 102-114

Targeting BRAF-mutant non-small cell lung cancer: Current status and future directions.

Mariona Riudavets, Priscilla Cascetta, David Planchard.

  Lung cancer harbouring BRAF mutations accounts for 4% of all non-small cell lung cancer (NSCLC) cases, identifying a relevant subset of patients that need to be promptly managed. Three subtypes of BRAF mutations have been described: class I (V600E), and class II and III (non-V600), with different prognostic and predictive outcomes. Pivotal phase II trials have demonstrated the efficacy of the double BRAF/MEK inhibition with dabrafenib plus trametinib in patients harbouring V600E mutations, making BRAF a mandatory requirement in the genetic portrait of advanced non-squamous lung cancer patients. However, non-V600 mutations represent around 50% of BRAF-mutant NSCLC patients, for which no specific targeted approaches are approved. A paradigm shift from the double BRAF/MEK inhibition to combinations with agents with distinct mechanisms of action, such as immune-checkpoint inhibitors, pan-RAF and selective ERK 1/2 inhibitors, is under investigation and may change the therapeutic landscape of BRAF-driven NSCLC. This paper provides a practical, concise and updated review on the therapeutic strategies in NSCLC with BRAF mutations.

Keywords:  BRAF mutations; MAPK pathway; Non-V600; Non-small cell lung cancer; RAF inhibitors; V600E

DOI:  https://doi.org/10.1016/j.lungcan.2022.05.014
Front Oncol. 2022 ;12 916947

Identifying Immune Cell Infiltration and Effective Diagnostic Biomarkers in Lung Adenocarcinoma by Comprehensive Bioinformatics Analysis and In Vitro Study.

Xinyan Li, Xi Chen, Yixiao Yuan, RuiQing Zhai, William C Cho, Xiulin Jiang.

  Family with sequence similarity 72B (FAM72B) has been characterized in the regulation of neuronal development. Nevertheless, the prognostic value of FAM72B expression and its function in the immune microenvironment of lung adenocarcinoma (LUAD) currently remains elusive. In this study, by adopting bioinformatics methodology and experimental verification, we found that FAM72B was upregulated in lung cancer tissues and cell lines, and a higher FAM72B level predicted an unfavorable clinical outcome in LUAD patients. The knockdown of FAM72B significantly inhibited cell proliferation, cell migration, and induced cell apoptosis in LUAD. The receiver operating characteristic curve suggested that FAM72B had a high predictive accuracy for the outcomes of LUAD. Kyoto Encyclopedia of Genes and Genomes and Gene Set Enrichment Analyses confirmed that FAM72B-related genes were involved in cell proliferation and immune-response signaling pathway. Moreover, upregulated FAM72B expression was significantly associated with immune cell infiltration in the LUAD tumor microenvironment. Meanwhile, a potential ceRNA network was constructed to identify the lncRNA-AL360270.2/TMPO-AS1/AC125807.2/has-let-7a/7b/7c/7e/7f/FAM72B regulatory axis that regulates FAM72B overexpression in LUAD and is associated with a poor prognosis. We also confirmed that AL360270.2, TMPO-AS1, and AC125807.2 were significantly upregulated in LUAD cell lines than in human bronchial epithelial cells. In conclusion, FAM72B may serve as a novel biomarker in predicting the clinical prognosis and immune status for lung adenocarcinoma.

Keywords:  FAM72B; ceRNA; immune infiltration; lung adenocarcinoma; prognosis biomarker

DOI:  https://doi.org/10.3389/fonc.2022.916947
J Oncol. 2022 ;2022 3599832

SHC1 Promotes Lung Cancer Metastasis by Interacting with EGFR.

Pan Yang, Wei Li, Xiaoping Li.

The study aims to explore the biological function of SHC1 in the development and progression of lung cancer. Meanwhile, the effect of SHC1 and EGFR on lung cancer was analyzed. The expression of SHC1 in lung cancer and adjacent tissues was analyzed by bioinformatics and immunohistochemistry. Meanwhile, the relationship between SHC1 expression and prognosis was analyzed. SHC1 overexpression and knockdown cell lines were constructed by overexpression plasmid and knockdown plasmid. Cell proliferation was detected by CCK-8. Cell invasion was detected by transwell. Apoptosis was detected by TUNEL. Interaction between SHC1 and EGFR was detected. The expression of SHC1 in lung adenocarcinoma tissues was significantly higher than that in paracancer tissues. Lung cancer patients with high SHC1 expression have a poor prognosis. The proliferation and invasion of SHC1 decreased with SHC1 knockout but increased after overexpression. EGFR may be a key interaction protein of SHC1. Overexpression of EGFR increases the oncogenic effect of SHC1. In conclusion, SHC1 plays a carcinogenic role in lung cancer. EGFR expression was significantly correlated with SHC1 and maybe a key interaction protein of SHC1. SHC1 interacts with EGFR to form a protein complex, which may be a new target for lung cancer metastasis.

DOI: https://doi.org/10.1155/2022/3599832
Cancer Lett. 2022 Jun 09. pii: S0304-3835(22)00266-X. [Epub ahead of print] 215782

Proteomic analysis of plasma-derived exosomes identifies biomarkers that distinguish brain and liver metastasis in lung cancer patients.

Sini Li, Yan Qu, Lihui Liu, Xue Zhang, Yan He, Chao Wang, Yufeng Guo, Li Yuan, Zixiao Ma, Hua Bai, Jie Wang.

  Brain or liver metastases are the main causes of lung cancer-related death. Accumulating evidence has suggested that circulating exosomal proteins in the blood could mediate cancer metastasis. In this study, we analyzed the proteomic profiles of plasma exosomes derived from 67 lung cancer patients ((including 26 solitary brain metastasis (BM), 16 solitary liver metastasis (LM), 25 local advanced (LA)), and 5 healthy controls (HC), and explored organ-specific proteomic biomarkers. Our results indicated the homogeneity and heterogeneity in brain and liver metastasis-related differentially expressed exosomal proteins (BM-DEEPs, LM-DEEPs). In terms of homogeneity, they were mainly involved in the collagen-containing extracellular matrix and ECM-receptor interaction. In terms of heterogeneity, the BM-DEEPs were significantly enriched in S100 protein and calcium-dependent protein, while the LM-DEEPs were mainly enriched in integrin, lipoprotein, heat shock protein and proteoglycans. Moreover, our study also revealed the heterogeneity in plasma-derived exosome proteomics in patients with non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC), which partly explained the different metastatic characteristics of NSCLC and SCLC. Additionally, we further proposed some reliable diagnostic marker of BM and LM in lung cancer patients. For the first time, we revealed the comprehensive and comparative proteomic profiles of plasma-derived exosomes from lung cancer patients with solitary brain and liver metastasis, which could serve as excellent resource for further studies investigating lung cancer metastasis.

Keywords:  Brain metastasis; Exosomes; Liver metastasis; Lung cancer; Proteomics

DOI:  https://doi.org/10.1016/j.canlet.2022.215782