bims-meluca 2024-08-04 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2024–08–04
seven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

WFDC2 is a potential prognostic and immunotherapy biomarker in lung adenocarcinoma.
Differential prognostic impact and potential molecular mechanisms of PCDHGA12 expression in lung adenocarcinoma and squamous cell carcinoma.
Prognostic value of blood GRHL2 in patients with non-small-cell lung cancer after radiotherapy and chemotherapy.
SLC4A4 as a novel biomarker involved in immune system response and lung adenocarcinoma progression.
The influence of nutritional status, lipid profile, leptin concentration and polymorphism of genes encoding leptin and neuropeptide Y on the effectiveness of immunotherapy in advanced NSCLC patients.
Exploring the relationship between anorexia and therapeutic efficacy in advanced lung cancer treatment: a retrospective study.
Stable isotope-resolved metabolomics analyses of metabolic phenotypes reveal variable glutamine metabolism in different patient-derived models of non-small cell lung cancer from a single patient.

J Int Med Res. 2024 Jul;52(7): 3000605241258893

WFDC2 is a potential prognostic and immunotherapy biomarker in lung adenocarcinoma.

Bo Min, Yan Wang.

   OBJECTIVE: The prognosis of lung adenocarcinoma (LUAD), which is the most common type of lung cancer, remains poor. Little is known about the function and mechanism of whey acidic protein four-disulfide core domain 2 (WFDC2) in LUAD.
METHODS: In this study, we used online databases to compare WFDC2 expression between LUAD and normal tissues, to analyze the relationship between WFDC2 and overall survival, and to investigate the potential roles of WFDC2.
RESULTS: We found that WFDC2 protein and mRNA expression levels were significantly higher in LUAD tissue than in normal tissue, and high WFDC2 mRNA expression was associated with better overall survival. WFDC2 mRNA expression was correlated with the mutation status of TP53. The biological function of WFDC2 was associated with the cell cycle, and low WFDC2 mRNA expression was associated with an elevated tumor mutational burden and neoantigen levels. A negative relationship was observed between WFDC2 and immune gene expression, and high WFDC2 mRNA expression was found in patients with LUAD and low programed cell death 1 mRNA expression.
CONCLUSIONS: We propose that WFDC2 is associated with clinical benefits of immune checkpoint inhibitors in LUAD.

Keywords:  Lung adenocarcinoma; immune checkpoint; mRNA; programed cell death-1; survival; whey acidic protein four-disulfide core domain 2

DOI:  https://doi.org/10.1177/03000605241258893
Int Immunopharmacol. 2024 Jul 26. pii: S1567-5769(24)01248-7. [Epub ahead of print]139 112727

Differential prognostic impact and potential molecular mechanisms of PCDHGA12 expression in lung adenocarcinoma and squamous cell carcinoma.

Xiangqian Xu, Jun Zhang, Tangie Yao, Xiaokai Zhao, Qingyuan Wu, Chenghua Lu, Xiaoyan Guo, Shiyun Xie, Lei Qiu, Rongrong Bi, Honghao Xue.

  Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), subtypes of non-small cell lung cancer (NSCLC), exhibit distinct characteristics. The expression and prognostic significance of Protocadherin Gamma Subfamily A, 12 (PCDHGA12) in NSCLC remain unexplored. This study analyzed transcriptomic and genomic datasets from TCGA to investigate PCDHGA12 expression and its prognostic relevance in LUAD and LUSC. We found PCDHGA12 mRNA and protein levels were downregulated in both LUAD and LUSC tissues compared to adjacent non-cancerous tissues, with high PCDHGA12 expression correlating with lower overall survival in LUSC but not in LUAD. GSEA revealed a unique enrichment pattern associated with PCDHGA12 low expression in LUSC, especially in the DNA repair pathway. Co-expression analysis showed associations of PCDHGA12 with focal adhesion and the PI3K-AKT pathway in LUAD, and additionally with ECM-receptor interaction in LUSC. Hub gene prognosis analysis identified genes correlated with prognosis only in LUSC, reflecting PCDHGA12's influence. Mutation analysis linked with PCDHGA12 identified differential mutations in SPTA1, KEAP1, and TNR in LUAD, and a notable NAV3 mutation in LUSC. Additionally, immuno-infiltration analysis reveals a positive correlation between PCDHGA12 expression and immune cell infiltration. Specifically, lower PCDHGA12 expression in LUSC is associated with higher levels of CD8 T cells and DCs, lower levels of Tregs and M0 macrophages, and increased expression of HMGB1 and TNFRSF18. These genetic and immunological differences may account for the significant prognostic disparity of PCDHGA12 levels between LUAD and LUSC. Further experimental studies are essential to validate these associations and investigate potential targeted and immunotherapeutic strategies.

Keywords:  Immune infiltration; Mutation analysis; NSCLC; PCDHGA12; Prognosis

DOI:  https://doi.org/10.1016/j.intimp.2024.112727
Biomark Med. 2024 Jul 29. 1-7

Prognostic value of blood GRHL2 in patients with non-small-cell lung cancer after radiotherapy and chemotherapy.

Qian Zheng, Wenjing Ji, Ruirui Sun, Kejun Dai.

  Aim: We aimed to investigate the predictive value of the Grainyhead-like 2 (GRHL2) expression from circulating blood for recurrence, metastasis and overall death on patients with non-small-cell lung cancer (NSCLC). Materials & Methods: We collected blood samples from 122 patients who were admitted to our hospital for NSCLC. Results: Multivariable Cox proportional-hazards analysis in adjusted Model II showed that compared with GRHL2-negative expression, positive expression in patients with NSCLC was associated with increased death risk (HR = 7.0, 95% CI: 2.1-20.9, p = 0.03) and risk for composite end point (HR = 8.2, 95% CI: 4.0-27.1, p <0.01). Conclusion: This study supported that elevated circulating GRHL2 expression might be considered as a candidate prognostic biomarker for poor prognosis among these NSCLC patients.

Keywords:  GRHL2; lung cancer; metastasis; overall death; recurrence

DOI:  https://doi.org/10.1080/17520363.2024.2366161
Int Immunopharmacol. 2024 Jul 30. pii: S1567-5769(24)01277-3. [Epub ahead of print]140 112756

SLC4A4 as a novel biomarker involved in immune system response and lung adenocarcinoma progression.

Siyu Quan, Na Li, Shihai Lian, Yuanyuan Wang, Yang Liu, Jianbo Liu, Zewei Zhang, Dejun Gao, Yun Li.

   BACKGROUND: Altered expression and activity of solute carrier family 4 member 4 (SLC4A4) could affect the growth, survival and metastasis of tumor cells. Currently, the role of SLC4A4 in lung adenocarcinoma (LUAD) immunotherapy and prognosis was not entirely clear.
METHODS: We analyzed SLC4A4 expression in LUAD tissues and cell lines using quantitative reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry. The effects of SLC4A4 overexpression on angiogenesis, cell migration, invasion, and epithelial-mesenchymal transition were examined. Public databases helped construct a risk model evaluating SLC4A4's expression on LUAD prognosis and immunotherapy response. Additionally, a xenograft model, flow cytometry, and enzyme-linked immunosorbent assay further explored SLC4A4's role in tumor immune microenvironment infiltration.
RESULTS: Upregulation of SLC4A4 promoted apoptosis in the LUAD cell line and significantly inhibited the migration and invasive ability of cancer cells (P<0.01). A total of 10 key genes (including SIGLEC6, RHOV, PIR, MOB3B, MIR3135B, LPAR6, KRT8, ITGA2, CPS1, and C6) were screened according to SLC4A4 expression, immune score and stromal score, and a prognostic model with good outcome was constructed (AUC values of which in the training cohort at 1,3, and 5 years reached 0.73, 0.73, and 0.72, respectively). Importantly, we demonstrated that high expression of SLC4A4 was able to increase the proliferation level and cytokine secretion of CD8+ T cells for the purpose of promoting the immune system response to LUAD.
CONCLUSION: Our study revealed that SLC4A4 can serve as a prognostic indicator for LUAD, providing new insights into the treatment and diagnosis of LUAD.

Keywords:  Immune infiltration; Immune score; Lung adenocarcinoma; Risk score; SLC4A4

DOI:  https://doi.org/10.1016/j.intimp.2024.112756
BMC Cancer. 2024 Aug 01. 24(1): 937

The influence of nutritional status, lipid profile, leptin concentration and polymorphism of genes encoding leptin and neuropeptide Y on the effectiveness of immunotherapy in advanced NSCLC patients.

Małgorzata Frąk, Anna Grenda, Paweł Krawczyk, Barbara Kuźnar-Kamińska, Paweł Pazdrowski, Karolina Kędra, Izabela Chmielewska, Janusz Milanowski.

   INTRODUCTION: Neuropeptide Y is a neurotransmitter in the nervous system and belongs to the orexigenic system that increases appetite. Its excessive secretion leads to obesity. Leptin is a pro-inflammatory adipokine (produced in adipose tissue) induced in obesity and may mediate increased antitumor immunity in obesity (including the promotion of M1 macrophages). Leptin and neuropeptide Y gene polymorphisms, causing increased leptin levels and the occurrence of obesity, and lipid profile disorders, may increase the effectiveness of immunotherapy.
MATERIALS AND METHODS: In 121 patients with advanced NSCLC without mutations in the EGFR gene and rearrangements of the ALK and ROS1 genes, undergoing immunotherapy (1st and 2nd line of treatment) or chemoimmunotherapy (1st line of treatment), we assessed BMI, lipid profile, PD-L1 expression on cancer cells using the immunohistochemical method (clone SP263 antibody), leptin concentration in blood serum by ELISA, polymorphisms in the promoter region of the genes for leptin (LEP) and neuropeptide Y (NPY) by real-time PCR.
RESULTS: Leptin concentration was significantly higher in obese patients than in patients with normal or low weight (p = 0.00003) and in patients with disease stabilization compared to patients with progression observed during immunotherapy (p = 0.012). Disease control occurred significantly more often in patients with the GA or AA genotype than patients with the GG genotype in the rs779039 polymorphism of the LEP gene. The median PFS in the entire study group was five months (95% CI: 3-5.5), and the median OS was 12 months (95% CI: 8-16). Median PFS was highest in patients with TPS ≥ 50% (6.5 months) and in obese patients (6.6 months). Obese patients also had a slightly longer median OS compared to other patients (23.8 vs. 13 months). The multivariate Cox logistic regression test showed that the only factor reducing the risk of progression was TPS ≥ 50% (HR = 0.6068, 95% CI: 0.4001-0.9204, p = 0, 0187), and the only factor reducing the risk of death was high leptin concentration (HR = 0.6743, 95% CI: 0.4243-1.0715, p = 0.0953).
CONCLUSION: Assessment of nutritional status, serum leptin concentration and polymorphisms in the LEP gene may be of additional importance in predicting the effectiveness of immunotherapy and chemoimmunotherapy in patients with advanced NSCLC.

Keywords:  Immunotherapy; Leptin; Lipid profile; Non-small cell lung cancer; Obesity

DOI:  https://doi.org/10.1186/s12885-024-12716-6
Thorac Cancer. 2024 Jul 29.

Exploring the relationship between anorexia and therapeutic efficacy in advanced lung cancer treatment: a retrospective study.

Kosei Doshita, Tateaki Naito, Suguru Matsuda, Meiko Morita, Motoki Sekikawa, Keita Miura, Hiroaki Kodama, Michitoshi Yabe, Noboru Morikawa, Yuko Iida, Nobuaki Mamesaya, Haruki Kobayashi, Ryo Ko, Kazushige Wakuda, Akira Ono, Haruyasu Murakami, Hirotsugu Kenmotsu, Toshiaki Takahashi.

   BACKGROUND: Chemotherapy-induced anorexia is a common occurrence in patients undergoing treatment for advanced lung cancer. However, the relationship between chemotherapy-induced anorexia and weight loss during platinum-based chemotherapy combined with immune checkpoint inhibitors is unclear. This study explored the relationship between chemotherapy-induced anorexia and therapeutic outcomes in patients with stage IV non-small-cell lung cancer undergoing platinum-based chemotherapy combined with immune checkpoint inhibitors.
METHODS: The study retrospectively reviewed the medical records of 106 patients with stage IV non-small-cell lung cancer treated with platinum-based chemotherapy and immune checkpoint inhibitors between January 2019 and October 2022. The incidence of weight loss and its association with treatment efficacy was assessed in the chemotherapy-induced anorexia group. Chemotherapy-induced anorexia, nausea, and vomiting were evaluated using Common Terminology Criteria for Adverse Events v 5.0. Progression-free and overall survival were used to measure treatment efficacy.
RESULTS: Chemotherapy-induced anorexia was observed in 13.2% of patients. These patients exhibited significant weight loss at 6 and 9 weeks after treatment initiation compared to those in the non-chemotherapy-induced anorexia group. Progression-free and overall survival were shorter in the chemotherapy-induced anorexia group than in the non-chemotherapy-induced anorexia group, but the difference was not statistically significant.
CONCLUSIONS: Chemotherapy-induced anorexia was associated with significant weight loss and reduced treatment efficacy in patients with stage IV non-small-cell lung cancer. These results highlight the importance of implementing robust supportive care for chemotherapy-induced anorexia to mitigate weight loss and uphold treatment effectiveness during platinum-based chemotherapy combined with immune checkpoint inhibitors.

Keywords:  anorexia; chemotherapy; immune checkpoint inhibitors; non‐small cell lung cancer; treatment efficacy

DOI:  https://doi.org/10.1111/1759-7714.15403
Metabolomics. 2024 Jul 27. 20(4): 87

Stable isotope-resolved metabolomics analyses of metabolic phenotypes reveal variable glutamine metabolism in different patient-derived models of non-small cell lung cancer from a single patient.

Connor J Kinslow, Michael Bousamra Ll, Yihua Cai, Jun Yan, Pawel K Lorkiewicz, Ahmad Al-Attar, Jinlian Tan, Richard M Higashi, Andrew N Lane, Teresa W-M Fan.

   INTRODUCTION: Stable isotope tracers have been increasingly used in preclinical cancer model systems, including cell culture and mouse xenografts, to probe the altered metabolism of a variety of cancers, such as accelerated glycolysis and glutaminolysis and generation of oncometabolites. Comparatively little has been reported on the fidelity of the different preclinical model systems in recapitulating the aberrant metabolism of tumors.
OBJECTIVES: We have been developing several different experimental model systems for systems biochemistry analyses of non-small cell lung cancer (NSCLC1) using patient-derived tissues to evaluate appropriate models for metabolic and phenotypic analyses.
METHODS: To address the issue of fidelity, we have carried out a detailed Stable Isotope-Resolved Metabolomics study of freshly resected tissue slices, mouse patient derived xenografts (PDXs), and cells derived from a single patient using both 13C6-glucose and 13C5,15N2-glutamine tracers.
RESULTS: Although we found similar glucose metabolism in the three models, glutamine utilization was markedly higher in the isolated cell culture and in cell culture-derived xenografts compared with the primary cancer tissue or direct tissue xenografts (PDX).
CONCLUSIONS: This suggests that caution is needed in interpreting cancer biochemistry using patient-derived cancer cells in vitro or in xenografts, even at very early passage, and that direct analysis of patient derived tissue slices provides the optimal model for ex vivo metabolomics. Further research is needed to determine the generality of these observations.

Keywords:  Cancer metabolism; Non-small cell lung cancer; Patient-derived xenografts; Preclinical models; Primary cell culture; Stable isotope-resolved metabolomics

DOI:  https://doi.org/10.1007/s11306-024-02126-x