bims-meluca 2024-05-26 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2024–05–26
eight papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Restoring adiponectin via rosiglitazone ameliorates tissue wasting in mice with lung cancer.
Combination of plasma MMPs and PD-1-binding soluble PD-L1 predicts recurrence in gastric cancer and the efficacy of immune checkpoint inhibitors in non-small cell lung cancer.
Multiplex analysis for the identification of plasma protein biomarkers for predicting lung cancer immunotherapy response.
Different lactate metabolism subtypes reveal heterogeneity in clinical outcomes and immunotherapy in lung adenocarcinoma patients.
Extracellular vesicles in non-small cell lung cancer stemness and clinical applications.
Cancer cachexia as a predictor of adverse outcomes in patients with non-small cell lung cancer: A meta-analysis.
Mitochondrial respiratory function is preserved under cysteine starvation via glutathione catabolism in NSCLC.
Metabolomic analysis reveals macrophage metabolic reprogramming and polarization under different nutritional cues.

Acta Physiol (Oxf). 2024 May 23. e14167

Restoring adiponectin via rosiglitazone ameliorates tissue wasting in mice with lung cancer.

Henning Tim Langer, Shakti Ramsamooj, Ezequiel Dantas, Anirudh Murthy, Mujmmail Ahmed, Tanvir Ahmed, Seo-Kyoung Hwang, Rahul Grover, Rita Pozovskiy, Roger J Liang, Andre Lima Queiroz, Justin C Brown, Eileen P White, Tobias Janowitz, Marcus D Goncalves.

   AIM: To investigate systemic regulators of the cancer-associated cachexia syndrome (CACS) in a pre-clinical model for lung cancer with the goal to identify therapeutic targets for tissue wasting.
METHODS: Using the Kras/Lkb1 (KL) mouse model, we found that CACS is associated with white adipose tissue (WAT) dysfunction that directly affects skeletal muscle homeostasis. WAT transcriptomes showed evidence of reduced adipogenesis, and, in agreement, we found low levels of circulating adiponectin. To preserve adipogenesis and restore adiponectin levels, we treated mice with the PPAR-γ agonist, rosiglitazone.
RESULTS: Rosiglitazone treatment increased serum adiponectin levels, delayed weight loss, and preserved skeletal muscle and adipose tissue mass, as compared to vehicle-treated mice. The preservation of muscle mass with rosiglitazone was associated with increases in AMPK and AKT activity. Similarly, activation of the adiponectin receptors in muscle cells increased AMPK activity, anabolic signaling, and protein synthesis.
CONCLUSION: Our data suggest that PPAR-γ agonists may be a useful adjuvant therapy to preserve tissue mass in lung cancer.

Keywords:  AMPK; adiponectin; cachexia; lung cancer; muscle wasting

DOI:  https://doi.org/10.1111/apha.14167
Front Pharmacol. 2024 ;15 1384731

Combination of plasma MMPs and PD-1-binding soluble PD-L1 predicts recurrence in gastric cancer and the efficacy of immune checkpoint inhibitors in non-small cell lung cancer.

Fumihiko Ando, Takeru Kashiwada, Shoko Kuroda, Takenori Fujii, Ryotaro Takano, Yoshishige Miyabe, Shinobu Kunugi, Takashi Sakatani, Akihiko Miyanaga, Tomoko Asatsuma-Okumura, Masaaki Hashiguchi, Yoshikazu Kanazawa, Ryuji Ohashi, Hiroshi Yoshida, Masahiro Seike, Akihiko Gemma, Yoshiko Iwai.

   Background: The tumor microenvironment (TME) impacts the therapeutic efficacy of immune checkpoint inhibitors (ICIs). No liquid biomarkers are available to evaluate TME heterogeneity. Here, we investigated the clinical significance of PD-1-binding soluble PD-L1 (bsPD-L1) in gastric cancer (GC) patients and non-small cell lung cancer (NSCLC) patients treated with PD-1/PD-L1 blockade.
Methods: We examined bsPD-L1, matrix metalloproteinases (MMPs), and IFN-γ levels in plasma samples from GC patients (n = 117) prior to surgery and NSCLC patients (n = 72) prior to and 2 months after ICI treatment. We also examined extracellular matrix (ECM) integrity, PD-L1 expression, and T cell infiltration in tumor tissues from 25 GC patients by Elastica Masson-Goldner staining and immunohistochemical staining for PD-L1 and CD3, respectively.
Results: bsPD-L1 was detected in 17/117 GC patients and 16/72 NSCLC patients. bsPD-L1 showed strong or moderate correlations with plasma MMP13 or MMP3 levels, respectively, in both GC and NSCLC patients. bsPD-L1 expression in GC was associated with IFN-γ levels and intra-tumoral T cell infiltration, whereas MMP13 levels were associated with loss of ECM integrity, allowing tumor cells to access blood vessels. Plasma MMP3 and MMP13 levels were altered during ICI treatment. Combined bsPD-L1 and MMP status had higher predictive accuracy to identify two patient groups with favorable and poor prognosis than tumor PD-L1 expression: bsPD-L1+MMP13high in GC and bsPD-L1+(MMP3 and MMP13)increased in NSCLC were associated with poor prognosis, whereas bsPD-L1+MMP13low in GC and bsPD-L1+(MMP3 or MMP13)decreased in NSCLC were associated with favorable prognosis.
Conclusion: Plasma bsPD-L1 and MMP13 levels indicate T cell response and loss of ECM integrity, respectively, in the TME. The combination of bsPD-L1 and MMPs may represent a non-invasive tool to predict recurrence in GC and the efficacy of ICIs in NSCLC.

Keywords:  MMP13; T cell response; extracellular matrix integrity; soluble PD-L1; tumor microenvironment

DOI:  https://doi.org/10.3389/fphar.2024.1384731
Ther Adv Med Oncol. 2024 ;16 17588359241254218

Multiplex analysis for the identification of plasma protein biomarkers for predicting lung cancer immunotherapy response.

Moonki Hong, Sang Wook Lee, Byoung Chul Cho, Min Hee Hong, Sun Min Lim, Nak-Jung Kwon.

   Background: Programmed death-ligand (PD-L1) expression serves as a predictive biomarker for immune checkpoint inhibitor (ICI) sensitivity in non-small cell lung cancer (NSCLC). Nevertheless, the development of biomarkers that reliably predict ICI response remains an ongoing endeavor due to imperfections in existing methodologies.
Objectives: ICIs have led to a new paradigm in the treatment of NSCLC. The current companion PD-L1 diagnostics are insufficient in predicting ICI response. Therefore, we sought whether the Olink platform could be applied to predict response to ICIs in NSCLC.
Design: We collected blood samples from patients with NSCLC before ICI treatment and retrospectively analyzed proteomes based on their response to ICI.
Methods: Overall, 76 NSCLC patients' samples were analyzed. Proteomic plasma analysis was performed using the Olink platform. Intraplate reproducibility, validation, and statistical analyses using elastic net regression and generalized linear models with clinical parameters were evaluated.
Results: Intraplate coefficient of variation (CV) assays ranged from 3% to 6%, and the interplate CV was 14%. In addition, the Pearson correlation coefficient of the Olink Normalized Protein eXpression data was validated. No statistical differences were observed in the analyses of progressive disease and response to ICIs. Furthermore, no single proteome showed prognostic value in terms of progression-free survival.
Conclusion: In this study, the proximity extension assay-based approach of the Olink panel could not predict the patient's response to ICIs. Our proteomic analysis failed to achieve predictive value in both response or progression to ICIs and progression-free survival (PFS).

Keywords:  Olink; immune checkpoint inhibitors; non-small-cell lung cancer; proteomics

DOI:  https://doi.org/10.1177/17588359241254218
Heliyon. 2024 May 30. 10(10): e30781

Different lactate metabolism subtypes reveal heterogeneity in clinical outcomes and immunotherapy in lung adenocarcinoma patients.

Jing Zhang, Yun Bao, Yang Li, Xin Shi, Xiangyu Su, Xuejun He.

   Background: The excessive accumulation of lactate within the tumor microenvironment (TME) has been demonstrated to facilitate tumor advancement and evade the immune system. Nonetheless, the metabolic status of lactate in lung adenocarcinoma (LUAD) remains uncertain.
Method: By analyzing the transcriptome profile of patients with LUAD, we created a lactate metabolism score (LMS) to predict survival. We then conducted a comprehensive examination of the biological functions and immune infiltration among different LMS patient groups. Moreover, we assessed the LMS predictive efficacy in chemotherapy and immunotherapy. Finally, we validated the detrimental phenotypic effects of SLC16A3 on LUAD cell lines (PC9 and A549) through in vitro experiments. We collected clinical samples to assess the prognostic impact of SLC16A3.
Results: We constructed an LMS model with 6 lactate metabolism regulatory factors using LASSO regression. The high LMS model indicates worse clinical outcomes for LUAD patients. High LMS patients are associated with metabolic dysregulation and increased infiltration of M0 and M1 macrophages. Low LMS patients are related to upregulated citric acid metabolism pathways and memory immune cells. High LMS patients are suitable for traditional chemotherapy, while patients with low LMS are more likely to benefit from immunotherapy. Lastly, downregulating SLC16A3 significantly reduces the proliferative and invasive capabilities of LUAD cell lines. Clinical cohort shows that patients with high expression of SLC16A3 have a worse prognosis.
Conclusions: The LMS model constructed based on the lactate metabolism pathway displays high effectiveness in predicting the outcome of patients with LUAD. LMS can offer direction regarding chemotherapy as well as immunotherapy in LUAD.

Keywords:  Drug resistance; Immune microenvironment; Lactate metabolism; Lung adenocarcinoma (LUAD); SLC16A3

DOI:  https://doi.org/10.1016/j.heliyon.2024.e30781
Front Immunol. 2024 ;15 1369356

Extracellular vesicles in non-small cell lung cancer stemness and clinical applications.

Prita Pandya, Dania S Al-Qasrawi, Skyeler Klinge, Verline Justilien.

  Non-small cell lung carcinoma (NSCLC) accounts for 85% of lung cancers, the leading cause of cancer associated deaths in the US and worldwide. Within NSCLC tumors, there is a subpopulation of cancer cells termed cancer stem cells (CSCs) which exhibit stem-like properties that drive NSCLC progression, metastasis, relapse, and therapeutic resistance. Extracellular vesicles (EVs) are membrane-bound nanoparticles secreted by cells that carry vital messages for short- and long-range intercellular communication. Numerous studies have implicated NSCLC CSC-derived EVs in the factors associated with NSCLC lethality. In this review, we have discussed mechanisms of EV-directed cross-talk between CSCs and cells of the tumor microenvironment that promote stemness, tumor progression and metastasis in NSCLC. The mechanistic studies discussed herein have provided insights for developing novel NSCLC diagnostic and prognostic biomarkers and strategies to therapeutically target the NSCLC CSC niche.

Keywords:  biomarkers; cancer stem cells; extracellular vesicles; metastasis; non-small cell lung cancer; oncogenic signaling; therapeutic targeting; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1369356
Clin Nutr. 2024 May 18. pii: S0261-5614(24)00171-7. [Epub ahead of print]43(7): 1618-1625

Cancer cachexia as a predictor of adverse outcomes in patients with non-small cell lung cancer: A meta-analysis.

Junfang Zhang, Xuan Tang, Wenbo Zhang, Ying Xu, Heng Zhang, Yu Fan.

   INTRODUCTION: Cancer cachexia is a complex problem characterized by weight loss due to skeletal muscle and adipose tissue reduction. The purpose of this meta-analysis is to examine the association between cancer cachexia and adverse outcomes in patients with non-small cell lung cancer (NSCLC).
METHODS: A comprehensive search was conducted in the PubMed, Web of Science, and Embase databases from their inception to January 15, 2024. Retrospective or prospective studies that investigated the cancer cachexia as a predictor of overall survival (OS), progression-free survival (PFS), overall response rate (ORR), or disease control rate (DCR) in NSCLC patients were included in this analysis.
RESULTS: Sixteen studies, comprising 5919 NSCLC patients, were identified. The pooled prevalence of cachexia in NSCLC patients was 39%, with individual studies reporting rates ranging from 19% to 63.8%. A meta-analysis using a random effects model showed that cachexia was associated with reduced OS (hazard ratio [HR] 1.84; 95% confidence interval [CI] 1.54-2.21) and PFS (HR 1.49; 95% CI 1.27-1.73). Subgroup analysis indicated that cancer cachexia significantly predicted OS, regardless of study design, NSCLC subtypes, cancer stage, definitions of cachexia, or follow-up duration. However, there was no clear association between cancer cachexia and ORR or DCR.
CONCLUSIONS: Cancer cachexia emerges is a negative prognostic factor for OS and PFS in NSCLC patients. Assessing cancer cachexia can improve risk classification for survival outcomes in this patient population.

Keywords:  Meta-analysis; Non-small cell lung cancer; Overall response rate; Overall survival; Progression-free survival; cachexia

DOI:  https://doi.org/10.1016/j.clnu.2024.05.025
Nat Commun. 2024 May 18. 15(1): 4244

Mitochondrial respiratory function is preserved under cysteine starvation via glutathione catabolism in NSCLC.

Nathan P Ward, Sang Jun Yoon, Tyce Flynn, Amanda M Sherwood, Maddison A Olley, Juliana Madej, Gina M DeNicola.

Cysteine metabolism occurs across cellular compartments to support diverse biological functions and prevent the induction of ferroptosis. Though the disruption of cytosolic cysteine metabolism is implicated in this form of cell death, it is unknown whether the substantial cysteine metabolism resident within the mitochondria is similarly pertinent to ferroptosis. Here, we show that despite the rapid depletion of intracellular cysteine upon loss of extracellular cystine, cysteine-dependent synthesis of Fe-S clusters persists in the mitochondria of lung cancer cells. This promotes a retention of respiratory function and a maintenance of the mitochondrial redox state. Under these limiting conditions, we find that glutathione catabolism by CHAC1 supports the mitochondrial cysteine pool to sustain the function of the Fe-S proteins critical to oxidative metabolism. We find that disrupting Fe-S cluster synthesis under cysteine restriction protects against the induction of ferroptosis, suggesting that the preservation of mitochondrial function is antagonistic to survival under starved conditions. Overall, our findings implicate mitochondrial cysteine metabolism in the induction of ferroptosis and reveal a mechanism of mitochondrial resilience in response to nutrient stress.

DOI: https://doi.org/10.1038/s41467-024-48695-2
Clin Chim Acta. 2024 May 19. pii: S0009-8981(24)01987-9. [Epub ahead of print]560 119735

Metabolomic analysis reveals macrophage metabolic reprogramming and polarization under different nutritional cues.

Zhongxiao Zhang, Zhou Peng, Rui Wang, Xirong Guo, Jianfang Gao.

   BACKGROUND AND AIMS: Obesity-induced chronic inflammation and metabolic abnormalities are highly relevant to the functional dysregulation of macrophages, especially under obese conditions. Hyperglycemia and hyperlipidemia, central to obesity, directly alter macrophage activity. However, the impacts of different nutritional cues on the intricate metabolic networks in macrophages remain unclear.
MATERIALS AND METHODS: In this study, we employed metabolomic approaches to examine the metabolic responses of macrophages to high glucose, high fat and their coexistence, aiming to delineate the molecular mechanisms of nutritional factors on macrophage activation and obesity-related diseases from a metabolic perspective.
RESULTS: Our findings revealed that different nutritional conditions could reprogram key metabolism in macrophages. Additionally, we identified a metabolite derived from macrophages, Long-Chain Phosphatidylcholine (LPC), which exerts beneficial effects on obese mice. It ameliorates the obesity phenotype and improves glucose metabolism profiles. This discovery suggests that LPC has a significant therapeutic potential in the context of obesity-induced metabolic dysfunctions. Our study unveils the metabolic phenotype of macrophages in high-fat and high-sugar environments and uncovers a macrophage-derived metabolite that significantly ameliorates the obesity phenotype.
CONCLUSION: This finding reveals a potential dialogue mechanism between macrophages and adipocytes, shedding light on the complex interplay of immune and metabolic systems in obesity. This discovery not only enhances our understanding of obesity's underlying mechanisms but also opens up new avenues for therapeutic interventions targeting macrophage-adipocyte interactions.

Keywords:  Macrophage; Metabolic reprogramming; Metabolomic; Obesity

DOI:  https://doi.org/10.1016/j.cca.2024.119735