bims-meluca 2022-08-14 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2022–08–14
eleven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Blocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer.
Statin shapes inflamed tumor microenvironment and enhances immune checkpoint blockade in non-small cell lung cancer.
The Effect of Sarcopenia and Metabolic PET-CT Parameters on Survival in Locally Advanced Non-Small Cell Lung Carcinoma.
BARX2/FOXA1/HK2 axis promotes lung adenocarcinoma progression and energy metabolism reprogramming.
Alteration in Plasma Metabolome in High-Fat Diet-Fed Monocyte Chemotactic Protein-1 Knockout Mice Bearing Pulmonary Metastases of Lewis Lung Carcinoma.
Elevated serum Cripto-1 and VEGF levels in patients with non-small cell lung cancer.
Preoperative Body Composition Combined with Tumor Metabolism Analysis by PET/CT Is Associated with Disease-Free Survival in Patients with NSCLC.
GFAT1-linked TAB1 glutamylation sustains p38 MAPK activation and promotes lung cancer cell survival under glucose starvation.
Effect of PFKFB4 on the Prognosis and Immune Regulation of NSCLC and Its Mechanism.
Circulating Fatty Acid Profile as a Biomarker for Immunotherapy in Advanced Non-Small Cell Lung Cancer.
Chronic hyperglycemia based on diabetes is independently associated with decreased survival in patients with advanced cancer treated with immune checkpoint inhibitors.

Nat Commun. 2022 Aug 08. 13(1): 4633

Blocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer.

Andre Lima Queiroz, Ezequiel Dantas, Shakti Ramsamooj, Anirudh Murthy, Mujmmail Ahmed, Elizabeth R M Zunica, Roger J Liang, Jessica Murphy, Corey D Holman, Curtis J Bare, Gregory Ghahramani, Zhidan Wu, David E Cohen, John P Kirwan, Lewis C Cantley, Christopher L Axelrod, Marcus D Goncalves.

Cancer cachexia is a common, debilitating condition with limited therapeutic options. Using an established mouse model of lung cancer, we find that cachexia is characterized by reduced food intake, spontaneous activity, and energy expenditure accompanied by muscle metabolic dysfunction and atrophy. We identify Activin A as a purported driver of cachexia and treat with ActRIIB-Fc, a decoy ligand for TGF-β/activin family members, together with anamorelin (Ana), a ghrelin receptor agonist, to reverse muscle dysfunction and anorexia, respectively. Ana effectively increases food intake but only the combination of drugs increases lean mass, restores spontaneous activity, and improves overall survival. These beneficial effects are limited to female mice and are dependent on ovarian function. In agreement, high expression of Activin A in human lung adenocarcinoma correlates with unfavorable prognosis only in female patients, despite similar expression levels in both sexes. This study suggests that multimodal, sex-specific, therapies are needed to reverse cachexia.

DOI: https://doi.org/10.1038/s41467-022-32135-0
JCI Insight. 2022 Aug 09. pii: e161940. [Epub ahead of print]

Statin shapes inflamed tumor microenvironment and enhances immune checkpoint blockade in non-small cell lung cancer.

Wenjun Mao, Yun Cai, Danrong Chen, Guanyu Jiang, Yongrui Xu, Ruo Chen, Fengxu Wang, Xuehai Wang, Mingfeng Zheng, Xinyuan Zhao, Jie Mei.

  Immune checkpoint blockade (ICB) therapy has achieved breakthroughs in the treatment of advanced non-small cell lung cancer (NSCLC). Nevertheless, the low response due to immuno-cold tumor microenvironment (TME) largely limits the application of ICB therapy. Based on the glycolytic/cholesterol synthesis axis, a stratification framework for EGFR wild-type NSCLC was developed to summarize the metabolic features of immuno-cold and immuno-hot tumors. The cholesterol subgroup displays the worst prognosis in immuno-cold NSCLC with significant enrichment of the cholesterol gene signature, indicating targeting cholesterol synthesis is essential for the therapy for immuno-cold NSCLC. Statin, the inhibitor for cholesterol synthesis, can suppress the aggressiveness of NSCLC in vitro and in vivo and also drastically reverse immuno-cold to an inflamed phenotype in vivo which exhibited a higher response to ICB therapy. Moreover, both our in-house data and meta-analysis further support that statin can significantly enhance ICB efficacy. In terms of preliminary mechanisms, statin could transcriptionally inhibit PD-L1 expression and induce ferroptosis in NSCLC cells. Overall, we reveal the significance of cholesterol synthesis in NSCLC and demonstrate the improved therapeutic efficacy of ICB in combination with statin. These findings could provide a innovative clinical insight to treat NSCLC patients with immuno-cold tumors.

Keywords:  Bioinformatics; Cancer immunotherapy; Metabolism; Oncology

DOI:  https://doi.org/10.1172/jci.insight.161940
Nutr Cancer. 2022 Aug 12. 1-10

The Effect of Sarcopenia and Metabolic PET-CT Parameters on Survival in Locally Advanced Non-Small Cell Lung Carcinoma.

Elanur Karaman, Nur Hursoy, Sibel Goksel.

  The treatment of stage III non-small cell lung cancer (NSCLC) is complex. Here, we aimed to examine the prognostic utility of sarcopenia and metabolic muscle volumes and evaluate their relationship with oncological treatments in patients with locally advanced NSCLC. Patients with unresectable stage III NSCLC were evaluated retrospectively. Muscle fields were measured, and metabolic parameters of the psoas were obtained. The skeletal muscle index (SMI), sarcopenia, sarcopenic obesity, and body mass index (BMI)-associated sarcopenia were evaluated. Fifty-three (94.6%) patients were men, and three (5.4%) were women. Sarcopenia was identified in 36 (64.3%) patients. Pretreatment sarcopenia and BMI-associated sarcopenia negatively affected overall survival (p = 0.040 and 0.023, respectively). A high psoas SUVmean (Standardized Uptake Value mean) and low mean psoas HU (Hounsfield unit) were poor prognostic factors (p = 0.009 and 0.014, respectively). SMI and muscle mass decreased after oncological treatment. Advanced age, inability to complete treatment, administration of chemoradiotherapy after chemotherapy, presence of sarcopenia, and a low mean psoas HU decreased survival. In conclusion, sarcopenia and BMI-associated sarcopenia are poor prognostic factors in patients with lung cancer. Oncological treatments can adversely affect muscle mass. The metabolic parameters of the psoas muscle can predict patient prognosis.

Keywords:  FDG-PET CT; SUVmean; muscle fields; psoas HU; sarcopenia

DOI:  https://doi.org/10.1080/01635581.2022.2110268
Transl Lung Cancer Res. 2022 Jul;11(7): 1405-1419

BARX2/FOXA1/HK2 axis promotes lung adenocarcinoma progression and energy metabolism reprogramming.

Kai Xie, Jian Feng, Dingwei Fan, Shi Wang, Jing Luo, Zhijian Ren, Chao Zheng, Yifei Diao, Ramon Andrade De Mello, Simona Tavolari, Giovanni Brandi, Anja C Roden, Binhui Ren, Yi Shen, Lin Xu.

   Background: Metabolic reprogramming is an emerging cancer feature that has recently drawn special attention since it promotes tumor cell growth and proliferation. However, the mechanism of the Warburg effect is still largely unknown. This research aimed to reveal the effects of BarH-like homeobox 2 (BARX2) in regulating tumor progression and glucose metabolism in lung adenocarcinoma (LUAD).
Methods: Expression of BARX2 was measured by quantitative real-time polymerase chain reaction (qRT-PCR) in LUAD cell line and tissues, and the tumor-promoting function of BARX2 in LUAD cells was detected in vitro and in vivo xenograft models. The metabolic effects of BARX2 were examined by detecting glucose uptake, the production levels of lactate and pyruvate, and the extracellular acidification rate (ECAR). Chromatin immunoprecipitation (ChIP) assay and luciferase reporter gene assay were used to identify the underlying molecular mechanism of BARX2 regulation of HK2. Further studies showed that transcription factor FOXA1 directly interacts with BARX2 and promotes the transcriptional activity of BARX2.
Results: BARX2 was remarkably up-regulated in LUAD tissues and positively linked to advanced clinical stage and poor prognosis. In vitro and in vivo data indicated ectopic expression of BARX2 enhanced cell proliferation and tumorigenesis, whereas BARX2 knockdown suppressed these effects. Metabolic-related experiments showed BARX2 promoted the reprogramming of glucose metabolism. Mechanistically, the BARX2/FOXA1/HK2 axis promoted LUAD progression and energy metabolism reprogramming.
Conclusions: In summary, our research first defined BARX2 as a tumor-promoting factor in LUAD and that it may act as a novel prognostic biomarker and new therapeutic target for the disease.

Keywords:  BARX2; HK2; Transcription factor; glucose metabolism; lung adenocarcinoma (LUAD)

DOI:  https://doi.org/10.21037/tlcr-22-465
Nutr Metab Insights. 2022 ;15 11786388221111126

Alteration in Plasma Metabolome in High-Fat Diet-Fed Monocyte Chemotactic Protein-1 Knockout Mice Bearing Pulmonary Metastases of Lewis Lung Carcinoma.

Lin Yan, Bret M Rust, Sneha Sundaram, Matthew J Picklo, Michael R Bukowski.

  Both clinical and laboratory studies have shown that monocyte chemotactic protein-1 (MCP-1) is involved in cancer spread. To understand the role of MCP-1 in metabolism in the presence of metastasis, we conducted an untargeted metabolomic analysis of primary metabolism on plasma collected from a study showing that MCP-1 deficiency reduces spontaneous metastasis of Lewis lung carcinoma (LLC) to the lungs in mice fed a high-fat diet (HFD). In a 2 × 2 design, wild-type (WT) or Mcp-1 knockout (Mcp-1 -/-) mice maintained on the AIN93G standard diet or HFD were subcutaneously injected with LLC cells to induce lung metastasis. We identified 87 metabolites for metabolomic analysis from this study. Amino acid metabolism was altered considerably in the presence of LLC metastases with the aminoacyl-tRNA biosynthesis pathways as the leading pathway altered. The HFD modified lipid and energy metabolism, evidenced by lower contents of arachidonic acid, cholesterol, and long-chain saturated fatty acids and higher contents of glucose and pyruvic acid in mice fed the HFD. These findings were supported by network analysis showing alterations in fatty acid synthesis and glycolysis/gluconeogenesis pathways between the 2 diets. Furthermore, elevations of the citrate cycle intermediates (citric acid, fumaric acid, isocitric acid, and succinic acid) and glyceric acid in Mcp-1 -/- mice, regardless of diet, suggest the involvement of MCP-1 in mitochondrial energy metabolism during LLC metastasis. The present study demonstrates that MCP-1 deficiency and the HFD altered plasma metabolome in mice bearing LLC metastases. These findings can be useful in understanding the impact of obesity on prevention and treatment of cancer metastasis.

Keywords:  Lewis lung carcinoma; MCP-1; Metabolome; diet; metastasis; mice; plasma

DOI:  https://doi.org/10.1177/11786388221111126
FASEB Bioadv. 2022 Aug;4(8): 539-546

Elevated serum Cripto-1 and VEGF levels in patients with non-small cell lung cancer.

Chunhua Xu, Jue Zou, Li Li, Qi Yuan, Wei Wang.

  Cripto-1 (CR-1) facilitates vascular endothelial growth factor (VEGF) expression, and these markers are associated with various tumor cell proliferation, angiogenesis, and metastasis. The main aim of our study was to investigate the clinical value of CR-1 and VEGF for non-small cell lung cancer (NSCLC) patients. Serum samples were collected from 312 patients with NSCLC and 120 healthy controls. The levels of CR-1 and VEGF were measured by enzyme-linked immunosorbent assay (ELISA). The serum levels of CR-1 and VEGF in NSCLC patients were significantly higher than those of healthy controls (p < 0.05). Elevated CR-1 levels were associated with progression of NSCLC stage and higher CR-1 was detected more in patients with distant metastasis (p < 0.05). Patients exhibiting low levels of serum CR-1 had better overall survival than those with high levels (p < 0.05). The CR-1 levels of NSCLC patients with postoperative recurrent were higher than those of nonrecurrent NSCLC patients. Our study suggests that serum CR-1 and VEGF are useful biomarker for NSCLC patients.

Keywords:  Cripto‐1; NSCLC; VEGF; biomarker; survival

DOI:  https://doi.org/10.1096/fba.2022-00002
Contrast Media Mol Imaging. 2022 ;2022 7429319

Preoperative Body Composition Combined with Tumor Metabolism Analysis by PET/CT Is Associated with Disease-Free Survival in Patients with NSCLC.

Hongpei Tan, Mengtian Ma, Jing Huang, Yuqian Dong, Jiahao Liu, Ze Mi, Kai Zheng, Shuo Hu, Pengfei Rong.

Objective: To evaluate the relationship between preoperative primary tumor metabolism and body composition in patients with NSCLC and analyze their effects on DFS.
Method: A retrospective study was conducted on 154 patients with NSCLC. All patients were scanned by baseline 18F-FDG PET/CT. SUVmax (maximum standard uptake value) of primary tumor, liver SUVmean (mean standard uptake value), and spleen SUVmean were measured by AW workstation. The skeletal muscle area (SMA), skeletal muscle mass index (SMI), skeletal muscle radiation density (SMD), visceral fat area (VFA), visceral adipose tissue index (VATI), and skeletal muscle visceral fat ratio (SVR) were measured by ImageJ software. Kaplan-Meier survival analysis was used to evaluate the impact of the above parameters on DFS.
Results: Compared with the low SUVmax group of primary tumors, the mean values of SMA, VFA, and VATI in the high SUVmax group were significantly higher. In addition, there were obvious differences in histopathological type, pathological differentiation, AJCC stage, and T stage between the two groups. Univariate analysis of DFS showed that VFA, VATI, pathological differentiation, tumor SUVmax, AJCC stage, tumor T stage, and N stage all affected the DFS of patients except for the parameters reflecting skeletal muscle content. Multivariate regression analysis showed that only VFA and SUVmax were associated with DFS. Kaplan-Meier survival analysis showed that high SUVmax, low VFA, high T stage, and high N stage were related to the decrease of DFS.
Conclusion: ：Preoperative 18F-FDG PET/CT could comprehensively evaluate the primary tumor SUVmax, skeletal muscle, and visceral fat in patients with NSCLC. The combination of primary tumor SUVmax and visceral fat area can well evaluate the prognosis of patients with NSCLC.

DOI: https://doi.org/10.1155/2022/7429319
Cell Discov. 2022 Aug 09. 8(1): 77

GFAT1-linked TAB1 glutamylation sustains p38 MAPK activation and promotes lung cancer cell survival under glucose starvation.

Shupei Wei, Qin Zhao, Ke Zheng, Peiying Liu, Nannan Sha, Yingzi Li, Chunmin Ma, Jingjie Li, Lingang Zhuo, Guanxin Liu, Wenhua Liang, Yuhui Jiang, Tao Chen, Nanshan Zhong.

Reprogrammed cell metabolism is deemed as one of the hallmarks of cancer. Hexosamine biosynthesis pathway (HBP) acts as an "energy sensor" in cells to regulate metabolic fluxes. Glutamine-fructose-6-phosphate amidotransferase 1 (GFAT1), the rate-limiting enzyme of HBP, is broadly found with elevated expression in human cancers though its exact and concrete role in tumorigenesis still remains unknown and needs further investigation. P38 mitogen-activated protein kinase (MAPK) is an important component of stress-signaling pathway and plays a critical role in cell fate decision, whereas the underlying mechanism of its activation under nutrient stress also remains elusive. In this study, we show that glucose deprivation induces the interaction of GFAT1 with transforming growth factor β-activated kinase 1 binding protein 1 (TAB1) in a TAB1 S438 phosphorylation-dependent manner. Subsequently, the binding of GFAT1 to TAB1 facilitates TTLL5-GFAT1-TAB1 complex formation, and the metabolic activity of GFAT1 for glutamate production further contributes to TTLL5-mediated TAB1 glutamylation. In consequence, TAB1 glutamylation promotes the recruitment of p38α MAPK and thus drives p38 MAPK activation. Physiologically, GFAT1-TAB1-p38 signaling promotes autophagy occurrence and thus protects tumor cell survival under glucose deficiency. Clinical analysis indicates that both GFAT1 and TAB1 S438 phosphorylation levels correlate with the poor prognosis of lung adenocarcinoma patients. These findings altogether uncover an unidentified mechanism underlying p38 MAPK signaling regulation by metabolic enzyme upon nutrient stress and provide theoretical rationality of targeting GFAT1 for cancer treatment.

DOI: https://doi.org/10.1038/s41421-022-00423-0
Int J Gen Med. 2022 ;15 6341-6353

Effect of PFKFB4 on the Prognosis and Immune Regulation of NSCLC and Its Mechanism.

Yong Zhou, Yongfei Fan, Binzhe Qiu, Ming Lou, Xiaoshuang Liu, Kai Yuan, Jichun Tong.

   Background: NSCLC (non-small cell lung cancer) has become the malignancy with the highest incidence and mortality rate worldwide. Fructose-6-phosphate 2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) is a key regulator of glycolysis with both kinase and phosphatase activities. The Warburg effect, or increased glycolysis in tumors, provides the metabolic basis for cancer cell proliferation and metastasis, and the Warburg pathway enzyme PFKFB4 is a newly identified important kinase. This study aimed to elucidate the poor prognostic relevance of PFKFB4 in non-small cell lung cancer tissues and its relationship with immune cell infiltration, immune cell biomarkers, and immune checkpoints.
Methods: In this study, immunohistochemical methods were used to assess PFKFB4 expression levels in 140 surgical specimens from patients with histologically confirmed non-small cell lung cancer and to investigate the relationship between PFKFB4 expression levels and the patients' clinicopathological characteristics. The impact of PFKFB4 expression on prognosis was evaluated using Kaplan-Meier survival analysis and Cox regression analysis.
Results: When compared to normal paracrine tissues, PFKFB4 expression was enhanced in lung cancer tissues, and Kaplan-Meier survival analysis revealed that patients with high PFKFB4 expression had a worse prognosis. In NSCLC, PFKFB4 was found to be associated with immune cell infiltration and immunological checkpoints.
Conclusion: PFKFB4 expression may be upregulated as a sign of poor prognosis in NSCLC, and PFKFB4 may be implicated not only in the genesis and progression of NSCLC but also in its immunological control.

Keywords:  NSCLC; PFKFB4; immune cells; prognostic marker

DOI:  https://doi.org/10.2147/IJGM.S369126
Clin Lung Cancer. 2022 Jul 21. pii: S1525-7304(22)00155-3. [Epub ahead of print]

Circulating Fatty Acid Profile as a Biomarker for Immunotherapy in Advanced Non-Small Cell Lung Cancer.

Giulia Galli, Paola Antonia Corsetto, Claudia Proto, Giuseppe Lo Russo, Monica Ganzinelli, Eliana Rulli, Lorenzo Legramandi, Daniele Morelli, Roberto Ferrara, Arsela Prelaj, Diego Signorelli, Alessandro De Toma, Marta Brambilla, Mario Occhipinti, Sara Manglaviti, Mattia Boeri, Antonia Martinetti, Andrea Vingiani, Mario Paolo Colombo, Angela Maria Rizzo, Valter Torri, Filippo de Braud, Sabina Sangaletti, Antonio Sica, Marina Chiara Garassino.

   INTRODUCTION: Lipid metabolism impacts immune cell differentiation, activation, and functions, modulating inflammatory mediators, energy homeostasis, and cell membrane composition. Despite preclinical evidence, data in humans lack concerning tumors and immunotherapy (IO). We aimed at investigating the correlations between circulating lipids and the outcome of non-small cell lung cancer (NSCLC) patients treated with IO.
MATERIALS AND METHODS: We identified all patients with advanced NSCLC treated with IO at our Institution with available baseline plasma samples. Fatty acids (FAs) were analyzed through gas chromatography. Survival curves were estimated by the Kaplan-Meier method. Cox multivariate models were constructed through a stepwise procedure, with entry and exit P value set at .2.
RESULTS: We identified 112 patients, mostly with performance status 1 (65.2%) and PD-L1≥1% (75.3%). Median progression-free survival (PFS) and overall survival (OS) were 2.8 and 11.0 months, respectively. Multivariable model for survival identified a positive association of circulating free (FFA) C16:0 (P .005) and esterified (EFA) C16:1 (P .030) with PFS, and a positive association of EFA C16:1 (P .001) and EFA C18:0 (P .020) with OS. EFA C16:0 was negatively associated with PFS (P .008).
CONCLUSION: FFA C16:0 and FAs derived from its unsaturation (EFA C16:1) and elongation (EFA C18:0) are associated with a better outcome in NSCLC patients treated with IO. It is conceivable that the ratio among those FAs may modify membrane fluidity and receptor activity, influencing IO efficacy. These data pave the way for the investigation of lipid-modulating strategies in association with IO in NSCLC.

Keywords:  Fatty acids; Immunotherapy; Lipid metabolism; Membrane fluidity; Non-small cell lung cancer

DOI:  https://doi.org/10.1016/j.cllc.2022.07.010
Anticancer Drugs. 2022 Aug 09.

Chronic hyperglycemia based on diabetes is independently associated with decreased survival in patients with advanced cancer treated with immune checkpoint inhibitors.

Emre Yekedüz, Elif Berna Köksoy, Sati Coşkun Yazgan, Göktürk Karataş, Filiz Çay Şenler, Güngör Utkan, Hakan Akbulut, Ahmet Demirkazik, Yüksel Ürün.

Immune checkpoint inhibitors (ICIs) have started a new era in treating patients with cancer. The effect of comorbidities and concomitant drug use on ICIs have become of interest in those patients. Data about the impact of hyperglycemia on response to ICIs in cancer patients are limited. All advanced-stage cancer patients treated with ICIs in Ankara University Medical Oncology Department were retrospectively evaluated. Patients treated in expanded access programs or clinical trials were excluded from the study. A total of 137 patients were included in this study. The most common primary tumor type was malign melanoma (32.8%) and nivolumab (62.3%) was the most common used ICI. More than half of patients (57.7%) had lung metastasis at the initiation of ICIs. Thirty-five patients (25.5%) had diabetes before initiating ICIs. Median baseline fasting glucose level was higher in patients with diabetes than those without diabetes (117 mg/dl vs. 99 mg/dl, P = 0.002). In all patients, median overall survival and progression-free survival were 11.3 [95% confidence interval (CI), 8.1-14.4) and 5.9 (95% CI, 3.6-8.3) months, respectively. In multivariate analysis, diabetes was found to increase risk of death [hazard ratio (HR), 2.09; 95% CI, 1.27-3.43, P = 0.004) and disease progression (HR, 2.01, 95% CI, 1.29-3.09, P = 0.002). Hyperglycemia might decrease response to ICIs in patients with advanced cancer. This research area is still an unmet need in the immunotherapy era. Prospective studies are needed to elucidate the effect of hyperglycemia on the response to ICIs.

DOI: https://doi.org/10.1097/CAD.0000000000001354