bims-meluca 2022-10-30 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2022–10–30
ten papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Altered acetyl-CoA metabolism presents a new potential immunotherapy target in the obese lung microenvironment.
Serum Metabolomics Profiling Reveals Metabolic Alterations Prior to a Diagnosis with Non-Small Cell Lung Cancer among Chinese Community Residents: A Prospective Nested Case-Control Study.
Potential of VEGFR2 expression as a predictive marker of PD‑1 blockade in patients with advanced NSCLC.
Identification of Master Regulators Driving Disease Progression, Relapse, and Drug Resistance in Lung Adenocarcinoma.
Preoperative Omega-6/Omega-3 Fatty Acid Ratio Could Predict Postoperative Outcomes in Patients with Surgically Resected Non-Small-Cell Lung Cancer.
A Metabolism-Related Gene Prognostic Index for Prediction of Response to Immunotherapy in Lung Adenocarcinoma.
Identifying a lactic acid metabolism-related gene signature contributes to predicting prognosis, immunotherapy efficacy, and tumor microenvironment of lung adenocarcinoma.
Impact of sarcopenia on the prognosis and treatment of lung cancer: an umbrella review.
IL-9 stimulates an anti-tumor immune response and facilitates immune checkpoint blockade in the CMT167 mouse model.
Integrated profiling of endoplasmic reticulum stress-related DERL3 in the prognostic and immune features of lung adenocarcinoma.

Cancer Metab. 2022 Oct 26. 10(1): 17

Altered acetyl-CoA metabolism presents a new potential immunotherapy target in the obese lung microenvironment.

Spencer R Rosario, Randall J Smith, Santosh K Patnaik, Song Liu, Joseph Barbi, Sai Yendamuri.

  Contrary to the "obesity paradox," which arises from retrospective studies relying on body mass index to define obesity, epidemiologic evidence suggests central or visceral obesity is associated with a higher risk for the development of lung cancer. About 60% of individuals at high risk for developing lung cancer or those already with early-stage disease are either overweight or obese. Findings from resected patient tumors and mouse lung tumor models show obesity dampens immune activity in the tumor microenvironment (TME) encouraging disease progression. In line with this, we have observed a marked, obesity-specific enhancement in the presence and phenotype of immunosuppressive regulatory T (Treg) cells in murine tumors as well as the airways of both humans and mice. Leveraging direct metabolomic measurements and robust inferred analyses from RNA-sequencing data, we here demonstrate for the first time that visceral adiposity alters the lung microenvironment via dysregulated acetyl-CoA metabolism in a direction that facilitates immune suppression and lung carcinogenesis.

Keywords:  Acetyl Co-A; Lung cancer; Metabolism; Obesity

DOI:  https://doi.org/10.1186/s40170-022-00292-x
Metabolites. 2022 Sep 27. pii: 906. [Epub ahead of print]12(10):

Serum Metabolomics Profiling Reveals Metabolic Alterations Prior to a Diagnosis with Non-Small Cell Lung Cancer among Chinese Community Residents: A Prospective Nested Case-Control Study.

Yu Xiang, Qi Zhao, Yilin Wu, Xing Liu, Junjie Zhu, Yuting Yu, Xuyan Su, Kelin Xu, Yonggen Jiang, Genming Zhao.

  The present high mortality of lung cancer in China stems mainly from the lack of feasible, non-invasive and early disease detection biomarkers. Serum metabolomics profiling to reveal metabolic alterations could expedite the disease detection process and suggest those patients who are harboring disease. Using a nested case-control design, we applied ultra-high-performance liquid chromatography/mass spectrometry (LC-MS)-based serum metabolomics to reveal the metabolomic alterations and to indicate the presence of non-small cell lung cancer (NSCLC) using serum samples collected prior to disease diagnoses. The studied serum samples were collected from 41 patients before a NSCLC diagnosis (within 3.0 y) and 38 matched the cancer-free controls from the prospective Shanghai Suburban Adult Cohort. The NSCLC patients markedly presented cellular metabolism alterations in serum samples collected prior to their disease diagnoses compared with the cancer-free controls. In total, we identified 18 significantly expressed metabolites whose relative abundance showed either an upward or a downward trend, with most of them being lipid and lipid-like molecules, organic acids, and nitrogen compounds. Choline metabolism in cancer, sphingolipid, and glycerophospholipid metabolism emerged as the significant metabolic disturbance of NSCLC. The metabolites involved in these biological processes may be the distinctive features associated with NSCLC prior to a diagnosis.

Keywords:  cancer cells metabolism; metabolomics; nested case-control study; non-small cell lung cancer (NSCLC)

DOI:  https://doi.org/10.3390/metabo12100906
Oncol Rep. 2022 Dec;pii: 214. [Epub ahead of print]48(6):

Potential of VEGFR2 expression as a predictive marker of PD‑1 blockade in patients with advanced NSCLC.

Kyoichi Kaira, Hisao Imai, Tomonori Kawasaki, Kousuke Hashimoto, Yu Miura, Ayako Shiono, Ou Yamaguchi, Atsuto Mouri, Kunihiko Kobayashi, Masanori Yasuda, Hiroshi Kagamu.

  Angiogenesis serves a crucial role in cancer progression. Vascular endothelial growth factor (VEGF) exhibits an immunosuppressive function in patients with cancer. However, it remains unclear whether expression of VEGF in tumor tissue can predict the outcome of programmed death‑1 blockade in patients with advanced non‑small cell lung cancer (NSCLC). A training (n=32) and validation (n=76) cohort of patients with advanced NSCLC who received first‑line pembrolizumab were enrolled. Immunohistochemical staining for VEGF receptor 2 (VEGFR2) and tumor‑infiltrating lymphocytes (TILs; CD4, CD8 and FOXP3) was performed in tumor specimens of both cohorts and association with clinical outcomes was assessed. The percentages of high VEGFR2 expression were 34.3% (11/32) in training cohort and 25.0% (19/76) in validation cohort. No statistically significant difference in objective response between high and low VEGFR2 expression was observed for training (27.2 vs. 45.0%) and validation (31.2 vs. 35.7%) cohorts. The positive rate of intratumoral FOXP3 was significantly associated with high VEGFR2 expression for validation cohort, but not training cohort. In validation cohort, high VEGFR2 expression in patients with non‑adenocarcinoma (non‑AC) was significantly correlated with positive FOXP3 TILs in intratumoral and stromal sites, but not CD4 and CD8. High VEGFR2 expression in both cohorts indicated a significantly worse overall survival (OS) than low VEGFR2 expression. VEGFR2 was identified as an independent prognostic marker associated with worse OS. High VEGFR2 expression was a significant marker for predicting worse OS in patients treated with first‑line pembrolizumab, particularly in those with non‑AC.

Keywords:  CD4; CD8; Foxp3; VEGF; VEGFR2; non‑small cell lung cancer; tumor‑infiltrating lymphocyte

DOI:  https://doi.org/10.3892/or.2022.8429
Front Bioinform. 2022 ;2 813960

Identification of Master Regulators Driving Disease Progression, Relapse, and Drug Resistance in Lung Adenocarcinoma.

Qiong Xu, Qiongfang Cha, Hui Qin, Bin Liu, Xueling Wu, Jiantao Shi.

  Backgrounds: Lung cancer is the leading cause of cancer related death worldwide. Current treatment strategies primarily involve surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy, determined by TNM stages, histologic types, and genetic profiles. Plenty of studies have been trying to identify robust prognostic gene expression signatures. Even for high performance signatures, they usually have few shared genes. This is not totally unexpected, since a prognostic signature is associated with patient survival and may contain no upstream regulators. Identification of master regulators driving disease progression is a vital step to understand underlying molecular mechanisms and develop new treatments. Methods: In this study, we have utilized a robust workflow to identify potential master regulators that drive poor prognosis in patients with lung adenocarcinoma. This workflow takes gene expression signatures that are associated with poor survival of early-stage lung adenocarcinoma, EGFR-TKI resistance, and responses to immune checkpoint inhibitors, respectively, and identifies recurrent master regulators from seven public gene expression datasets by a regulatory network-based approach. Results: We have found that majority of the master regulators driving poor prognosis in early stage LUAD are cell-cycle related according to Gene Ontology annotation. However, they were demonstrated experimentally to promote a spectrum of processes such as tumor cell proliferation, invasion, metastasis, and drug resistance. Master regulators predicted from EGFR-TKI resistance signature and the EMT pathway signature are largely shared, which suggests that EMT pathway functions as a hub and interact with other pathways such as hypoxia, angiogenesis, TNF-α signaling, inflammation, TNF-β signaling, Wnt, and Notch signaling pathways. Master regulators that repress immunotherapy are enriched with MYC targets, E2F targets, oxidative phosphorylation, and mTOR signaling. Conclusion: Our study uncovered possible mechanisms underlying recurrence, resistance to targeted therapy, and immunotherapy. The predicted master regulators may serve as potential therapeutic targets in patients with lung adenocarcinoma.

Keywords:  TKI resistance; immunotherapy; lung adenocarcinoma; master regulator; relapse

DOI:  https://doi.org/10.3389/fbinf.2022.813960
Curr Oncol. 2022 Sep 28. 29(10): 7086-7098

Preoperative Omega-6/Omega-3 Fatty Acid Ratio Could Predict Postoperative Outcomes in Patients with Surgically Resected Non-Small-Cell Lung Cancer.

Carlos Déniz, Carla Raba-Parodi, Eva García-Raimundo, Iván Macía, Francisco Rivas, Anna Ureña, Anna Muñoz, Camilo Moreno, Ines Serratosa, Cristina Masuet-Aumatell, Ignacio Escobar, Ricard Ramos.

  Introduction: The aim of this study was to determine whether preoperative nutritional status and inflammatory status, specifically polyunsaturated acids and the omega 6/3 ratio, would affect postoperative outcomes and complications in patients with lung cancer undergoing lung resection. Methods: This prospective observational study included 68 patients with early-stage non-small-cell lung cancer who were candidates for radical surgery. A complete nutritional assessment was performed. The primary study variable was postoperative complications and mortality in the first 30 days. Descriptive, bivariate, and logistic regression analyses were carried out. Results: A total of 50 men (73.53%) and 18 women (26.47%) underwent surgery, with a median age of 64.2 (±9.74) years. The mean omega 6/3 ratio was 17.39 (±9.45). A complication occurred in 39.7% of the study sample (n = 27), the most common being persistent air leak in 23.53% (n = 16). After performing the bivariate analysis, the only variable that remained significant was the omega 6/3 ratio; we observed that it had a prognostic value for persistent air leak (p = 0.001) independent of age, sex, comorbidity, preoperative respiratory function, and approach or type of surgery. The remaining nutritional and inflammatory markers did not have a statistically significant association (p > 0.05) with postoperative complications. However, this significance was not maintained in the multivariate analysis by a small margin (p = 0.052; 95% CI: 0.77-1.41). Conclusions: Omega 6/3 ratio may be a prognostic factor for air leak, independent of the patient's clinical and pathological characteristics.

Keywords:  fatty acids; lung cancer; prolonged air leak; ratio omega 6/3; thoracic surgery

DOI:  https://doi.org/10.3390/curroncol29100556
Int J Mol Sci. 2022 Oct 12. pii: 12143. [Epub ahead of print]23(20):

A Metabolism-Related Gene Prognostic Index for Prediction of Response to Immunotherapy in Lung Adenocarcinoma.

Bo Tang, Lanlin Hu, Tao Jiang, Yunchang Li, Huasheng Xu, Hang Zhou, Mei Lan, Ke Xu, Jun Yin, Chunxia Su, Caicun Zhou, Chuan Xu.

  Immunotherapy, such as immune checkpoint inhibitors (ICIs), is a validated strategy for treating lung adenocarcinoma (LUAD) patients. One of the main challenges in ICIs treatment is the lack of efficient biomarkers for predicting response or resistance. Metabolic reprogramming has been proven to remodel the tumor microenvironment, altering the response to ICIs. We constructed a prognostic model as metabolism-related gene (MRG) of four genes by using weighted gene co-expression network analysis (WGCNA), the nonnegative matrix factorization (NMF), and Cox regression analysis of a LUAD dataset (n = 500) from The Cancer Genome Atlas (TCGA), which was validated with three Gene Expression Omnibus (GEO) datasets (n = 442, n = 226 and n = 127). The MRG was constructed based on BIRC5, PLK1, CDKN3, and CYP4B1 genes. MRG-high patients had a worse survival probability than MRG-low patients. Furthermore, the MRG-high subgroup was more associated with cell cycle-related pathways; high infiltration of activated memory CD4+T cells, M0 macrophages, and neutrophils; and showed better response to ICIs. Contrarily, the MRG-low subgroup was associated with fatty acid metabolism, high infiltration of dendric cells, and resting mast cells, and showed poor response to ICIs. MRG is a promising prognostic index for predicting survival and response to ICIs and other therapeutic agents in LUAD, which might provide insights on strategies with ICIs alone or combined with other agents.

Keywords:  immunotherapy; lung adenocarcinoma; metabolism-related genes; prognostic index

DOI:  https://doi.org/10.3390/ijms232012143
Front Immunol. 2022 ;13 980508

Identifying a lactic acid metabolism-related gene signature contributes to predicting prognosis, immunotherapy efficacy, and tumor microenvironment of lung adenocarcinoma.

Fangchao Zhao, Zengying Wang, Zhirong Li, Shiquan Liu, Shujun Li.

  Lactic acid, once considered as an endpoint or a waste metabolite of glycolysis, has emerged as a major regulator of cancer development, maintenance, and progression. However, studies about lactic acid metabolism-related genes (LRGs) in lung adenocarcinoma (LUAD) remain unclear. Two distinct molecular subtypes were identified on basis of 24 LRGs and found the significant enrichment of subtype A in metabolism-related pathways and had better overall survival (OS). Subsequently, a prognostic signature based on 5 OS-related LRGs was generated using Lasso Cox hazards regression analysis in TCGA dataset and was validated in two external cohorts. Then, a highly accurate nomogram was cosntructed to improve the clinical application of the LRG_score. By further analyzing the LRG_score, higher immune score and lower stromal score were found in the low LRG_score group, which presented a better prognosis. Patients with low LRG_score also exhibited lower somatic mutation rate, tumor mutation burden (TMB), and cancer stem cell (CSC) index. Three more independent cohorts (GSE126044: anti-PD-1, GSE135222: anti-PD-1, and IMvigor210: anti-PD-L1) were analyzed, and the results showed that patients in the low LRG_score category were more responsive to anti-PD-1/PD-L1 medication and had longer survival times. It was also determined that gefitinib, etoposide, erlotinib, and gemcitabine were more sensitive to the low LRG_score group. Finally, we validated the stability and reliability of LRG_score in cell lines, clinical tissue samples and HPA databases. Overall, the LRG_score may improve prognostic information and provide directions for current research on drug treatment strategies for LUAD patients.

Keywords:  immunotherapy; lactic acid metabolism; lung adenocarcinoma; pyroptosis; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2022.980508
Discov Oncol. 2022 Oct 28. 13(1): 115

Impact of sarcopenia on the prognosis and treatment of lung cancer: an umbrella review.

Ting-Yu Lin, Yen-Fu Chen, Wei-Ting Wu, Der-Sheng Han, I-Chen Tsai, Ke-Vin Chang, Levent Özçakar.

   BACKGROUND: Lung cancer is the leading cause of cancer-related mortality worldwide. Sarcopenia, defined as the loss of muscle mass and function, is known to cause adverse health outcomes. The purpose of this umbrella review was to integrate published systematic reviews and meta-analyses exploring sarcopenia and lung cancer to provide comprehensive knowledge on their relationship.
METHODS: Eligible studies were searched from scientific databases until June 28, 2022. Critical appraisal was performed using A Measurement Tool to Assess Systematic Reviews (AMSTAR) 2. The impact of sarcopenia on the pathophysiology, prevalence, and prognosis of lung cancer is summarized at the level of systematic reviews or meta-analyses.
RESULTS: Fourteen reviews and meta-analyses were conducted. The methodological quality was high for one review, low for nine, and critically low for four. The most common standard for diagnosing sarcopenia in the lung cancer population is computed tomography (CT) to measure the skeletal muscle index at the third lumbar vertebra (L3). Sarcopenia was highly prevalent among patients with lung cancer, with a pooled prevalence ranging from 42.8% to 45.0%. The association between sarcopenia and increased postoperative complications and decreased disease control rates with immune checkpoint inhibitors has been demonstrated. Mortality was significantly higher in sarcopenic patients than in non-sarcopenic patients with lung cancer, regardless of the stage of disease or type of treatment.
CONCLUSIONS: Sarcopenia is a poor prognostic factor for lung cancer. Future studies are necessary to clarify the pathophysiology of sarcopenia and develop effective interventions for sarcopenia in patients with lung cancer.

Keywords:  Frailty; Malignancy; Muscle loss; Prognosis; Pulmonary

DOI:  https://doi.org/10.1007/s12672-022-00576-0
Lung Cancer. 2022 Oct 12. pii: S0169-5002(22)00645-6. [Epub ahead of print]174 14-26

IL-9 stimulates an anti-tumor immune response and facilitates immune checkpoint blockade in the CMT167 mouse model.

Yuqian Feng, Sheng Yan, Sze Kwan Lam, Frankie Chi Fat Ko, Caoyang Chen, Mahjabin Khan, James Chung-Man Ho.

   OBJECTIVES: There is mounting evidence that interleukin-9 (IL-9) is associated with various cancers although its function in lung cancer remains elusive. This study aimed to elucidate the role(s) of IL-9 in lung cancer and the mechanisms involved.
MATERIALS AND METHODS: Expression of IL-9 receptor (IL-9R) in two murine lung cancer cell lines: CMT167 and Lewis lung carcinoma (LLC) were assessed and syngeneic murine lung cancer models were established. Tumor growth, intratumoral immune responses and downstream signaling pathways in tumor-bearing mice were analyzed upon IL-9 treatment. Human lung cancer cell lines A549 and H1975 were included for in vitro validation. Synergistic effects and immune responses of IL-9 in combination with anti-PD-1 were studied.
RESULTS: IL-9R expression was only detected in CMT167 but not LLC cells. IL-9 suppressed CMT167 tumor growth and enhanced anti-tumor T cell responses, both of which were absent in IL-9R-deficient LLC model and lost upon IL-9R knockdown in CMT167 model. In CMT167 tumors, while IL-9 increased CD4+ and CD8+ T cells and dendritic cells, the cytotoxic T subset was the key driver of IL-9-induced tumor suppression. Consistently, in CMT167 and A549 cells, IL-9/IL-9R signaling promoted MHC class I upregulation. Inhibition of ERK signaling abolished IL-9-mediated MHC class I upregulation in CMT167 cells. IL-9 induced expression of PD-1 and PD-L1 on CD8+ T lymphocytes and CMT167 cells respectively. Combined IL-9 treatment with PD-1 blockade further upregulated tumor-infiltrating CD8+ T cell frequencies and synergistically suppressed tumor growth in CMT167 model.
CONCLUSION: IL-9 suppresses tumor growth by promoting tumor-derived MHC class I presentation and enhancing cytotoxic T cell immunity. Expression of IL-9R might be used as a biomarker for identification of potential target population susceptible to IL-9 treatment. Our study proposes IL-9 as a promising therapeutic immunomodulatory agent that can be used in combination with PD-1 blockade in lung cancer.

Keywords:  Dendritic cells; Immune checkpoint blockade; Interleukin-9; MHC-I; Non-small cell lung cancer

DOI:  https://doi.org/10.1016/j.lungcan.2022.10.002
Front Immunol. 2022 ;13 906420

Integrated profiling of endoplasmic reticulum stress-related DERL3 in the prognostic and immune features of lung adenocarcinoma.

Lanlan Lin, Guofu Lin, Hai Lin, Luyang Chen, Xiaohui Chen, Qinhui Lin, Yuan Xu, Yiming Zeng.

   Background: DERL3 has been implicated as an essential element in the degradation of misfolded lumenal glycoproteins induced by endoplasmic reticulum (ER) stress. However, the correlation of DERL3 expression with the malignant phenotype of lung adenocarcinoma (LUAD) cells is unclear and remains to be elucidated. Herein, we investigated the interaction between the DERL3 and LUAD pathological process.
Methods: The Cancer Genome Atlas (TCGA) database was utilized to determine the genetic alteration of DERL3 in stage I LUAD. Clinical LUAD samples including carcinoma and adjacent tissues were obtained and were further extracted to detect DERL3 mRNA expression via RT-qPCR. Immunohistochemistry was performed to evaluate the protein expression of DERL3 in LUAD tissues. The GEPIA and TIMER website were used to evaluate the correlation between DERL3 and immune cell infiltration. We further used the t-SNE map to visualize the distribution of DERL3 in various clusters at the single-cell level via TISCH database. The potential mechanisms of the biological process mediated by DERL3 in LUAD were conducted via KEGG and GSEA.
Results: It was indicated that DERL3 was predominantly elevated in carcinoma compared with adjacent tissues in multiple kinds of tumors from the TCGA database, especially in LUAD. Immunohistochemistry validated that DERL3 was also upregulated in LUAD tissues compared with adjacent tissues from individuals. DERL3 was preliminarily found to be associated with immune infiltration via the TIMER database. Further, the t-SNE map revealed that DERL3 was predominantly enriched in plasma cells of the B cell population. It was demonstrated that DERL3 high-expressed patients presented significantly worse response to chemotherapy and immunotherapy. GSEA and KEGG results indicated that DERL3 was positively correlated with B cell activation and unfolded protein response (UPR).
Conclusion: Our findings indicated that DERL3 might play an essential role in the endoplasmic reticulum-associated degradation (ERAD) process in LUAD. Moreover, DERL3 may act as a promising immune biomarker, which could predict the efficacy of immunotherapy in LUAD.

Keywords:  B cell; DERL3; endoplasmic reticulum stress; immune infiltration; lung adenocarcinoma

DOI:  https://doi.org/10.3389/fimmu.2022.906420