bims-meluca 2024-09-01 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2024–09–01
nine papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Reprogramming hematopoietic stem cell metabolism in lung cancer: glycolysis, oxidative phosphorylation, and the role of 2-DG.
Phosphoenolpyruvate carboxykinase 2-mediated metabolism promotes lung tumorigenesis by inhibiting mitochondrial-associated apoptotic cell death.
Thoracic sarcopenia was a poor prognostic predictor in patients receiving immunotherapy retain-->for advanced non-small-cell retain-->lung cancer.
Combining Metabolomics and Machine Learning to Identify Diagnostic and Prognostic Biomarkers in Patients with Non-Small Cell Lung Cancer Pre- and Post-Radiation Therapy.
Serum Splicing Factor Proline- and Glutamine-Rich Is a Diagnostic Marker for Non-Small-Cell Lung Cancer and Other Solid Cancers.
6-Phosphogluconate dehydrogenase promotes glycolysis and fatty acid synthesis by inhibiting the AMPK pathway in lung adenocarcinoma cells.
Omega-3 Fatty Acids Increase Weight and Quality of Life Scores in Patients With Advanced Non-Small Cell Lung Cancer and Cancer Cachexia: A Meta-Analysis.
Impact of PD-L1 Expression on the Overall Survival of Patients With Non-small Cell Lung Cancer Treated With Single-agent Pembrolizumab.
Advances in Predictive Biomarkers for Anti-Angiogenic Therapy in Non-Small Cell Lung Cancer.

Biol Direct. 2024 Aug 24. 19(1): 73

Reprogramming hematopoietic stem cell metabolism in lung cancer: glycolysis, oxidative phosphorylation, and the role of 2-DG.

Ziqi Guo, Yaping Liu, Xin Li, Yuying Huang, Zuping Zhou, Cheng Yang.

  Hematopoietic stem cells (HSCs) exhibit significant functional and metabolic alterations within the lung cancer microenvironment, contributing to tumor progression and immune evasion by increasing differentiation into myeloid-derived suppressor cells (MDSCs). Our aim is to analyze the metabolic transition of HSCs from glycolysis to oxidative phosphorylation (OXPHOS) in lung cancer and determine its effects on HSC functionality. Using a murine Lewis Lung Carcinoma lung cancer model, we conducted metabolic profiling of long-term and short-term HSCs, as well as multipotent progenitors, comparing their metabolic states in normal and cancer conditions. We measured glucose uptake using 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino]-2-Deoxyglucose (2-NBDG) and assessed levels of lactate, acetyl-coenzyme A, and ATP. Mitochondrial functionality was evaluated through flow cytometry, alongside the impact of the glucose metabolism inhibitor 2-DG on HSC differentiation and mitochondrial activity. HSCs under lung cancer conditions showed increased glucose uptake and lactate production, with an associated rise in OXPHOS activity, marking a metabolic shift. Treatment with 2-DG led to decreased T-HSCs and MDSCs and an increased red blood cell count, highlighting its potential to influence metabolic and differentiation pathways in HSCs. This study provides novel insights into the metabolic reprogramming of HSCs in lung cancer, emphasizing the critical shift from glycolysis to OXPHOS and its implications for the therapeutic targeting of cancer-related metabolic pathways.

Keywords:  2-DG; Glycolysis; Hematopoietic stem cells; Lung cancer; Metabolic reprogramming; Oxidative phosphorylation; Tumor microenvironment

DOI:  https://doi.org/10.1186/s13062-024-00514-w
Front Pharmacol. 2024 ;15 1434988

Phosphoenolpyruvate carboxykinase 2-mediated metabolism promotes lung tumorigenesis by inhibiting mitochondrial-associated apoptotic cell death.

Jing Zhang, Wenjuan He, Dongmei Liu, Wenyu Zhang, Huan Qin, Song Zhang, Ailan Cheng, Qiang Li, Feilong Wang.

   Background: It is unknown how cancer cells override apoptosis and maintain progression under nutrition-deprived conditions within the tumor microenvironment. Phosphoenolpyruvate carboxykinase (PEPCK or PCK) catalyzes the first rate-limiting reaction in gluconeogenesis, which is an essential metabolic alteration that is required for the proliferation of cancer cells under glucose-limited conditions. However, if PCK-mediated gluconeogenesis affects apoptotic cell death of non small cell lung cancer (NSCLC) and its potential mechanisms remain unknown.
Methods: RNA-seq, Western blot and RT-PCR were performed in A549 cell lines cultured in medium containing low or high concentrations of glucose (1 mM vs. 20 mM) to gain insight into how cancer cells rewire their metabolism under glucose-restriction conditions. Stable isotope tracing metabolomics technology (LC-MS) was employed to allow precise quantification of metabolic fluxes of the TCA cycle regulated by PCK2. Flow Cytometry was used to assess the rates of early and later apoptosis and mitochondrial ROS in NSCLC cells. Transwell assays and luciferase-based in vivo imaging were used to determine the role of PCK2 in migration and invasion of NSCLC cells. Xenotransplants on BALB/c nude mice to evaluate the effects of PCK2 on tumor growth in vivo. Western blot, Immunohistochemistry and TUNEL assays to evaluate the protein levels of mitochondrial apoptosis.
Results: This study report that the mitochondrial resident PCK (PCK2) is upregulated in dependent of endoplasmic reticulum stress-induced expression of activating transcription factor 4 (ATF4) upon glucose deprivation in NSCLC cells. Further, the study finds that PCK2-mediated metabolism is required to decrease the burden of the TCA cycles and oxidative phosphorylation as well as the production of mitochondrial reactive oxygen species. These metabolic alterations in turn reduce the activation of Caspase9-Caspase3-PARP signal pathway which drives apoptotic cell death. Importantly, silencing PCK2 increases apoptosis of NSCLC cells under low glucose condition and inhibits tumor growth both in vitro and in vivo.
Conclusion: In summary, PCK2-mediated metabolism is an important metabolic adaptation for NSCLC cells to acquire resistance to apoptosis under glucose deprivation.

Keywords:  lung tumorigenesis; metabolic reprogramming; mitochondrial apoptosis; phosphoenolpyruvate carboxykinase 2; reactive oxygen species

DOI:  https://doi.org/10.3389/fphar.2024.1434988
Acad Radiol. 2024 Aug 23. pii: S1076-6332(24)00580-4. [Epub ahead of print]

Thoracic sarcopenia was a poor prognostic predictor in patients receiving immunotherapy retain-->for advanced non-small-cell retain-->lung cancer.

Minhong Wang, Piao Yang, Lixiang Zhou, Zhan Feng.

   RATIONALE AND OBJECTIVES: Sarcopenia, as measured at the level of the third lumbar (L3) has been shown to predict the survival of cancer patients. However, many patients with advanced non-small cell lung cancer (NSCLC) do not undergo routine abdominal imaging. The objective of this study was to investigate the association of thoracic sarcopenia with survival outcomes among patients who underwent immunotherapy for NSCLC.
MATERIALS AND METHODS: In this retrospective study, patients who initiated immunotherapy for advanced NSCLC from 2019 to 2022 were enrolled. and detailed patient data were collected. Cross sectional skeletal muscle area was calculated at the fifth thoracic vertebra (T5) on pretreatment chest computed tomography (CT) scan. Gender-specific lowest quartile values was used to define sarcopenia. The risk factors were analyzed using Cox analyses. The log-rank test and the random survival forest (RSF) were used to compare progression free survival (PFS). The model's performance was assessed using calibration curve and the receiver operating characteristic curve (ROC).
RESULTS: A total of 242 patients was included (discovery cohort n = 194, validation cohort n = 48). In the discovery cohort, patients with sarcopenia exhibited significantly poorer PFS (p < 0.001) than patients without sarcopenia. Univariate cox regression revealed that sarcopenia, lung cancer stage, body mass index, smoking status, and neutrophil-to-lymphocyte ratio were predictors of poor PFS. A RSF model was constructed based on the aforementioned parameters, to evaluate the model's efficacy, the ROC curve was utilized. with an area under the curve for predicting 6-month PFS of 0.68 and for 12-month PFS of 0.69. The prediction models for survival outcomes built by the discovery cohort showed similar performance in the validation cohort.
CONCLUSION: Sarcopenia at T5 is independent prognostic factors in patients who received immunotherapy for advanced NSCLC.

Keywords:  Computed tomography; Immunotherapy; Non-small cell lung cancer; Random survival forest; Survival; Thoracic sarcopenia

DOI:  https://doi.org/10.1016/j.acra.2024.08.017
Biomolecules. 2024 Jul 24. pii: 898. [Epub ahead of print]14(8):

Combining Metabolomics and Machine Learning to Identify Diagnostic and Prognostic Biomarkers in Patients with Non-Small Cell Lung Cancer Pre- and Post-Radiation Therapy.

Mauricio Murcia-Mejía, Marta Canela-Capdevila, Raquel García-Pablo, Andrea Jiménez-Franco, Juan Manuel Jiménez-Aguilar, Joan Badía, Rocío Benavides-Villarreal, Johana C Acosta, Mónica Arguís, Alina-Iuliana Onoiu, Helena Castañé, Jordi Camps, Meritxell Arenas, Jorge Joven.

  Lung cancer is the leading cause of cancer-related deaths globally, with non-small cell lung cancer (NSCLC) accounting for over 85% of cases and poor prognosis in advanced stages. This study explored shifts in circulating metabolite levels in NSCLC patients versus healthy controls and examined the effects of conventionally fractionated radiation therapy (CFRT) and stereotactic body radiation therapy (SBRT). We enrolled 91 NSCLC patients (38 CFRT and 53 SBRT) and 40 healthy controls. Plasma metabolite levels were assessed using semi-targeted metabolomics, revealing 32 elevated and 18 reduced metabolites in patients. Key discriminatory metabolites included ethylmalonic acid, maltose, 3-phosphoglyceric acid, taurine, glutamic acid, glycocolic acid, and d-arabinose, with a combined Receiver Operating Characteristics curve indicating perfect discrimination between patients and controls. CFRT and SBRT affected different metabolites, but both changes suggested a partial normalization of energy and amino acid metabolism pathways. In conclusion, metabolomics identified distinct metabolic signatures in NSCLC patients with potential as diagnostic biomarkers. The differing metabolic responses to CFRT and SBRT reflect their unique therapeutic impacts, underscoring the utility of this technique in enhancing NSCLC diagnosis and treatment monitoring.

Keywords:  biomarkers; lung cancer; metabolomics; radiation therapy; stereotactic body radiation therapy

DOI:  https://doi.org/10.3390/biom14080898
Int J Mol Sci. 2024 Aug 12. pii: 8766. [Epub ahead of print]25(16):

Serum Splicing Factor Proline- and Glutamine-Rich Is a Diagnostic Marker for Non-Small-Cell Lung Cancer and Other Solid Cancers.

Libang Yang, Adam Gilbertsen, Blake Jacobson, Robert Kratzke, Craig A Henke.

  Cancer markers are measurable molecules in blood or tissues that are produced by tumor cells or immune cells in response to cancer progression. They play an important role in clinical diagnosis, prognosis, and therapy monitoring. Splicing factor proline- and glutamine-rich (SFPQ) plays an important role in cancer growth and metastasis. SFPQ is not only more highly expressed in non-small-cell lung cancer (NSCLC) cells than it is in controls, but also highly expressed in cancer cells in patients with other solid cancers. Thus, a new enzyme-linked immunosorbent assay (ELISA) for detecting SFPQ was developed, in which the SFPQ protein is trapped by the first specific mAb coated on a microplate, and then recognized by a second specific mAb. This assay allows for the specific detection of SFPQ in the serum of patients with solid cancer. Regarding NSCLC, the serum SFPQ levels distinguished the non-cancer controls from the patients with NSCLC, with an area under the curve of 0.876, a sensitivity of 87%, and a specificity of 94%. The serum SFPQ levels were significantly elevated in the patients with NSCLC or other solid cancers. In conclusion, serum SFPQ could be a promising novel diagnostic biomarker for NSCLC and other malignancies.

Keywords:  NSCLC; SFPQ; diagnostic marker; solid cancers

DOI:  https://doi.org/10.3390/ijms25168766
Cancer Lett. 2024 Aug 22. pii: S0304-3835(24)00572-X. [Epub ahead of print]601 217177

6-Phosphogluconate dehydrogenase promotes glycolysis and fatty acid synthesis by inhibiting the AMPK pathway in lung adenocarcinoma cells.

Jun Wu, Yong Chen, Hui Zou, Kaiyue Xu, Jiaqi Hou, Mengmeng Wang, Shuyu Tian, Mingjun Gao, Qinglin Ren, Chao Sun, Shichun Lu, Qiang Wang, Yusheng Shu, Shouyu Wang, Xiaolin Wang.

  Abnormal metabolism has emerged as a prominent hallmark of cancer and plays a pivotal role in carcinogenesis and progression of lung adenocarcinoma (LUAD). In this study, single-cell sequencing revealed that the metabolic enzyme 6-phosphogluconate dehydrogenase (PGD), which is a critical regulator of the pentose phosphate pathway (PPP), is significantly upregulated in the malignant epithelial cell subpopulation during malignant progression. However, the precise functional significance of PGD in LUAD and its underlying mechanisms remain elusive. Through the integration of TCGA database analysis and LUAD tissue microarray data, it was found that PGD expression was significantly upregulated in LUAD and closely correlated with a poor prognosis in LUAD patients. Moreover, in vitro and in vivo analyses demonstrated that PGD knockout and inhibition of its activity mitigated the proliferation, migration, and invasion of LUAD cells. Mechanistically, immunoprecipitation-mass spectrometry (IP-MS) revealed for the first time that IQGAP1 is a robust novel interacting protein of PGD. PGD decreased p-AMPK levels by competitively interacting with the IQ domain of the known AMPKα binding partner IQGAP1, which promoted glycolysis and fatty acid synthesis in LUAD cells. Furthermore, we demonstrated that the combination of Physcion (a PGD-specific inhibitor) and metformin (an AMPK agonist) could inhibit tumor growth more effectively both in vivo and in vitro. Collectively, these findings suggest that PGD is a potential prognostic biomarker and therapeutic target for LUAD.

Keywords:  6-Phosphogluconate dehydrogenase; AMPK pathway; Lung adenocarcinoma; Pentose phosphate pathway; Single-cell sequencing

DOI:  https://doi.org/10.1016/j.canlet.2024.217177
Integr Cancer Ther. 2024 Jan-Dec;23:23 15347354241275052

Omega-3 Fatty Acids Increase Weight and Quality of Life Scores in Patients With Advanced Non-Small Cell Lung Cancer and Cancer Cachexia: A Meta-Analysis.

Alfredo V Chua, Aylmer Rex B Hernandez, Marvin Jonne L Mendoza, Michael D San Juan.

   BACKGROUND: Cancer cachexia is a common debilitating weight loss syndrome in advanced cancer, particularly lung cancer. Omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, with their immune-modulating effects, have been used to improve the nutritional status of patients with cancer cachexia.
AIM: Evaluate the effects of omega-3 fatty acids in change in weight and lean body/skeletal mass, and health-related quality of life scores (HRQoL) in patients with advanced non-small cell lung cancer and cancer cachexia.
DESIGN AND DATA SOURCES: Clinical trials from electronic databases and unpublished literature (date of last search 20 December 2023) were independently reviewed and evaluated by authors for their methodological quality. Data from eligible trials were extracted and analyzed in a meta-analysis.
RESULTS: Six trials were included. Five trials (354 patients) assessed change in weight; 2 trials (132 patients) assessed change in lean body/skeletal mass and HRQoL scores (Global Health and Physical Functioning subscales). There is a significant difference in change in weight (mean difference [MD]: 1.22, 95% CI: 1.05-1.38, P < .01) and HRQoL scores (Global Health [MD: 14.40, 95% CI: 9.22-19.59, P < .01] and Physical Functioning [MD: 10.38, 95% CI: 8.50-12.27, P < .01] subscales) favoring the omega-3 fatty acids group. The change in lean body/skeletal mass is not significant (MD: 2.05, 95% CI: -0.55 to 4.66, P = .12).
CONCLUSIONS: Among patients with advanced non-small cell lung cancer and cancer cachexia, supplementation with omega-3 fatty acids leads to a significant increase in weight and HRQoL scores but not in change in lean body/skeletal mass.

Keywords:  cachexia; meta-analysis; non-small cell lung carcinoma; omega-3 fatty acids; quality of life; weight loss

DOI:  https://doi.org/10.1177/15347354241275052
In Vivo. 2024 Sep-Oct;38(5):38(5): 2434-2440

Impact of PD-L1 Expression on the Overall Survival of Patients With Non-small Cell Lung Cancer Treated With Single-agent Pembrolizumab.

Martin Svaton, Magdalena Knetki-Wroblewska, Sylwia Tabor, Petr Domecky, Ondrej Venclicek, Jana Krejci, Marie Drosslerova, Michal Hrnciarik, Daniel Hricisak, Alzbeta Bejckova, Ondrej Fischer, Martina Vitkova, Maciej Krzakowski.

   BACKGROUND/AIM: Cemiplimab in patients with non-small cell lung cancer (NSCLC) with PD-L1 (programmed death ligand type 1) expression ≥50% showed a significant improved overall survival (OS) with increasing expression of PD-L1. To our knowledge there exist no similar data published for pembrolizumab regarding the increased OS in relation to the PD-L1 expression. Therefore, the objective of our study was to determine whether improvement in OS reflects increased expression levels of PD-L1 (≥50%) in patients with NSCLC.
PATIENTS AND METHODS: Retrospective data from 9 Czech and 1 Polish comprehensive oncology Centers were used. All patients with stage IV NSCLC and PD-L1 expression ≥50% treated with pembrolizumab in daily practice were included. The groups of patients according to the expression of PD-L1 were determined as follows: PD-L1 50-59%, 60-69%, 70-79%, 80-89% and 90-100%. The log-rank test and the Cox regression model were used to compare survival between study groups.
RESULTS: A total of 617 patients were included in the study. We did not observe a statistically significant difference in OS between groups of patients with different levels of PD-L1 expression in the pooled comparison (p=0.445). Furthermore, we did not observe a statistically significant difference even when comparing OS in patients with PD-L1expression of 50-59% (reference) with the group of other patients according to the level of expression of PD-L1 in the Cox regression model including the effect covariates.
CONCLUSION: PD-L1 expression showed no significant effect on OS in patients with NSCLC with PD-L1≥50% treated with pembrolizumab.

Keywords:  Non-small cell lung cancer; PD-L1 expression; overall survival; pembrolizumab

DOI:  https://doi.org/10.21873/invivo.13712
Cancer Control. 2024 Jan-Dec;31:31 10732748241270589

Advances in Predictive Biomarkers for Anti-Angiogenic Therapy in Non-Small Cell Lung Cancer.

Weixing Zhao, Jun Jiang.

  This study aimed to explore advances in biomarkers related to anti-angiogenic therapy in patients with non-small cell lung cancer (NSCLC), thereby enhancing treatment selection, advancing personalized and precision medicine to improve treatment outcomes and patient survival rates. This article reviews key discoveries in predictive biomarkers for anti-angiogenic therapy in NSCLC in recent years, such as (1) liquid biopsy predictive biomarkers: studies have identified activated circulating endothelial cells (aCECs) via liquid biopsy as potential predictive biomarkers for the efficacy of anti-angiogenic therapy; (2) imaging biomarkers: advanced imaging technologies, such as dynamic contrast-enhanced integrated magnetic resonance positron emission tomography (MR-PET), are used to assess tumor angiogenesis in patients with NSCLC and evaluate the clinical efficacy of anti-angiogenic drugs; (3) genetic predictive biomarkers: research has explored polymorphisms of Vascular Endothelial Growth Factor Receptor-1 (VEGFR-1) and vascular endothelial growth factor-A (VEGF-A), as well as how plasma levels of VEGF-A can predict the outcomes and prognosis of patients with non-squamous NSCLC undergoing chemotherapy combined with bevacizumab. Despite progress in identifying biomarkers related to anti-angiogenic therapy, several challenges remain, including limitations in clinical trials, heterogeneity in NSCLC, and technical hurdles. Future research will require extensive clinical validation and in-depth mechanistic studies to fully exploit the potential of these biomarkers for personalized treatment.

Keywords:  anti-angiogenic therapy; bevacizumab; non-small cell lung cancer; predictive biomarkers

DOI:  https://doi.org/10.1177/10732748241270589