bims-meluca 2023-12-17 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2023–12–17
six papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Inhibition of non-small cell lung cancer (NSCLC) proliferation through targeting G6PD.
Plasma Immune Proteins and Circulating Tumor DNA Predict the Clinical Outcome for Non-Small-Cell Lung Cancer Treated with an Immune Checkpoint Inhibitor.
The relationship between clinicopathological variables, systemic inflammation, and CT-derived body composition with survival in patients with advanced non-small cell lung cancer receiving nivolumab as a second-line treatment.
AMP-activated protein kinase is necessary for Treg cell functional adaptation to microenvironmental stress.
Metformin Suppresses Stemness of Non-Small-Cell Lung Cancer Induced by Paclitaxel through FOXO3a.
Hypoxia-induced activation of NDR2 underlies brain metastases from Non-Small Cell Lung Cancer.

PeerJ. 2023 ;11 e16503

Inhibition of non-small cell lung cancer (NSCLC) proliferation through targeting G6PD.

Makamas Chanda, Pornchai Anuntasomboon, Komkrit Ruangritchankul, Poonlarp Cheepsunthorn, Chalisa L Cheepsunthorn.

   Background: Mounting evidence has linked cancer metabolic reprogramming with altered redox homeostasis. The pentose phosphate pathway (PPP) is one of the key metabolism-related pathways that has been enhanced to promote cancer growth. The glucose 6-phosphate dehydrogenase (G6PD) of this pathway generates reduced nicotinamide adenine dinucleotide phosphate (NADPH), which is essential for controlling cellular redox homeostasis.
Objective: This research aimed to investigate the growth-promoting effects of G6PD in non-small cell lung cancer (NSCLC).
Methods: Clinical characteristics and G6PD expression levels in lung tissues of 64 patients diagnosed with lung cancer at the King Chulalongkorn Memorial Hospital (Bangkok, Thailand) during 2009-2014 were analyzed. G6PD activity in NSCLC cell lines, including NCI-H1975 and NCI-H292, was experimentally inhibited using DHEA and siG6PD to study cancer cell proliferation and migration.
Results: The positive expression of G6PD in NSCLC tissues was detected by immunohistochemical staining and was found to be associated with squamous cells. G6PD expression levels and activity also coincided with the proliferation rate of NSCLC cell lines. Suppression of G6PD-induced apoptosis in NSCLC cell lines by increasing Bax/Bcl-2 ratio expression. The addition of D-(-)-ribose, which is an end-product of the PPP, increased the survival of G6PD-deficient NSCLC cell lines.
Conclusion: Collectively, these findings demonstrated that G6PD might play an important role in the carcinogenesis of NSCLC. Inhibition of G6PD might provide a therapeutic strategy for the treatment of NSCLC.

Keywords:  DHEA; Glucose 6-phosphate dehydrogenase; Lung cancer; Metabolic reprogramming; NSCLC; Non-small cell lung cancer; PPP; Pentose phosphate pathway; Squamous cells; siG6PD

DOI:  https://doi.org/10.7717/peerj.16503
Cancers (Basel). 2023 Nov 29. pii: 5628. [Epub ahead of print]15(23):

Plasma Immune Proteins and Circulating Tumor DNA Predict the Clinical Outcome for Non-Small-Cell Lung Cancer Treated with an Immune Checkpoint Inhibitor.

Simone Stensgaard, Astrid Thomsen, Sofie Helstrup, Peter Meldgaard, Boe S Sorensen.

  Immunotherapy has altered the therapeutic landscape for patients with non-small-cell lung cancer (NSCLC). The immune checkpoint inhibitor pembrolizumab targets the PD-1/PD-L1 signaling axis and produces durable clinical responses, but reliable biomarkers are lacking. Using 115 plasma samples from 42 pembrolizumab-treated patients with NSCLC, we were able to identify predictive biomarkers. In the plasma samples, we quantified the level of 92 proteins using the Olink proximity extension assay and circulating tumor DNA (ctDNA) using targeted next-generation sequencing. Patients with an above-median progression-free survival (PFS) had significantly higher expressions of Fas ligand (FASLG) and inducible T-cell co-stimulator ligand (ICOSLG) at baseline than patients with a PFS below the median. A Kaplan-Meier analysis demonstrated that high levels of FASLG and ICOSLG were predictive of longer PFS and overall survival (OS) (PFS: 10.83 vs. 4.49 months, OS: 27.13 vs. 18.0 months). Furthermore, we identified a subgroup with high expressions of FASLG and ICOSLG who also had no detectable ctDNA mutations after treatment initiation. This subgroup had significantly longer PFS and OS rates compared to the rest of the patients (PFS: 25.71 vs. 4.52 months, OS: 34.62 vs. 18.0 months). These findings suggest that the expressions of FASLG and ICOSLG at baseline and the absence of ctDNA mutations after the start of treatment have the potential to predict clinical outcomes.

Keywords:  biomarkers; circulating tumor DNA; immune checkpoint inhibitor; immuno-oncology; immunotherapy; non-small-cell lung cancer

DOI:  https://doi.org/10.3390/cancers15235628
Cancer Med. 2023 Dec 13.

The relationship between clinicopathological variables, systemic inflammation, and CT-derived body composition with survival in patients with advanced non-small cell lung cancer receiving nivolumab as a second-line treatment.

Randa Saeed, Josh McGovern, Hugo Bench, Ross D Dolan, Donald C McMillan, Almudena Cascales.

   BACKGROUND: Second-line immunotherapy is currently recognized to help only a subset of patients with advanced forms of non-small cell lung cancer (NSCLC). The current study analyzes the connection between prior treatment host/tumor characteristics and survival in advanced NSCLC patients receiving nivolumab as a second-line therapy.
METHODS: A retrospective cohort analysis was carried out on individuals with advanced NSCLC receiving second-line Nivolumab with palliative intent between February 2016 and May 2019 across three health boards in NHS Greater Glasgow and Clyde, Lanarkshire, Ayrshire, and Arran in Scotland to examine the association between systemic inflammation, body composition, and survival were determined using computed tomography (CT).
RESULTS: The current study investigates the connection between prior treatment host/tumor characteristics and survival in advanced NSCLC patients receiving nivolumab as a second-line therapy. The majority were 65 years of age or older (51%), female (53%), had adenocarcinoma (53%), and had good performance status (ECOG 0/1) (86%). Most patients had high SFI (70%) or VFA (54%). The median overall survival after starting Nivolumab was 15 months. ECOG-PS and hypoalbuminemia were significant predictors of 12-month survival in patients with advanced NSCLC following Nivolumab treatment, according to Cox regression (p-value = 0.047 and 0.014, respectively).
CONCLUSION: In patients with advanced NSCLC receiving Nivolumab as a second-line therapy, ECOG-PS and hypoalbuminemia were strongly associated with survival. Systemic inflammation and hypoalbuminemia measurements may enhance the ECOG-PS stratification of expected outcomes.

Keywords:  ECOG-PS; NSCLC; Nivolumab; body composition; hypoalbuminemia; immunotherapy; survival; systemic inflammation

DOI:  https://doi.org/10.1002/cam4.6805
bioRxiv. 2023 Dec 01. pii: 2023.11.29.568904. [Epub ahead of print]

AMP-activated protein kinase is necessary for Treg cell functional adaptation to microenvironmental stress.

Manuel A Torres Acosta, Nurbek Mambetsariev, Carla P Reyes Flores, Kathryn A Helmin, Qianli Liu, Anthony M Joudi, Luisa Morales-Nebreda, Jonathan Gurkan, Kathleen Cheng, Hiam Abdala-Valencia, Samuel E Weinberg, Benjamin D Singer.

CD4+FOXP3+ regulatory T (Treg) cells maintain self-tolerance, suppress the immune response to cancer, and protect against tissue injury in the lung and other organs. Treg cells require mitochondrial metabolism to exert their function, but how Treg cells adapt their metabolic programs to sustain and optimize their function during an immune response occurring in a metabolically stressed microenvironment remains unclear. Here, we tested whether Treg cells require the energy homeostasis-maintaining enzyme AMP-activated protein kinase (AMPK) to adapt to metabolically aberrant microenvironments caused by malignancy or lung injury, finding that AMPK is dispensable for Treg cell immune-homeostatic function but is necessary for full Treg cell function in B16 melanoma tumors and during acute lung injury caused by influenza virus pneumonia. AMPK-deficient Treg cells had lower mitochondrial mass and exhibited an impaired ability to maximize aerobic respiration. Mechanistically, we found that AMPK regulates DNA methyltransferase 1 to promote transcriptional programs associated with mitochondrial function in the tumor microenvironment. In the lung during viral pneumonia, we found that AMPK sustains metabolic homeostasis and mitochondrial activity. Induction of DNA hypomethylation was sufficient to rescue mitochondrial mass in AMPK-deficient Treg cells, linking DNA methylation with AMPK function and mitochondrial metabolism. These results define AMPK as a determinant of Treg cell adaptation to metabolic stress and offer potential therapeutic targets in cancer and tissue injury.

DOI: https://doi.org/10.1101/2023.11.29.568904
Int J Mol Sci. 2023 Nov 22. pii: 16611. [Epub ahead of print]24(23):

Metformin Suppresses Stemness of Non-Small-Cell Lung Cancer Induced by Paclitaxel through FOXO3a.

Zhimin Tang, Yilan Zhang, Zhengyi Yu, Zhijun Luo.

  Cancer stem cells (CSCs) play a pivotal role in drug resistance and metastasis. Among the key players, Forkhead box O3a (FOXO3a) acts as a tumor suppressor. This study aimed to unravel the role of FOXO3a in mediating the inhibitory effect of metformin on cancer stemness derived from paclitaxel (PTX)-resistant non-small-cell lung cancer (NSCLC) cells. We showed that CSC-like features were acquired by the chronic induction of resistance to PTX, concurrently with inactivation of FOXO3a. In line with this, knockdown of FOXO3a in PTX-sensitive cells led to changes toward stemness, while overexpression of FOXO3a in PTX-resistant cells mitigated stemness in vitro and remarkably curbed the tumorigenesis of NSCLC/PTX cells in vivo. Furthermore, metformin suppressed the self-renewal ability of PTX-resistant cells, reduced the expression of stemness-related markers (c-MYC, Oct4, Nanog and Notch), and upregulated FOXO3a, events concomitant with the activation of AMP-activated protein kinase (AMPK). All these changes were recapitulated by silencing FOXO3a in PTX-sensitive cells. Intriguingly, the introduction of the AMPK dominant negative mutant offset the inhibitory effect of metformin on the stemness of PTX-resistant cells. In addition, FOXO3a levels were elevated by the treatment of PTX-resistant cells with MK2206 (an Akt inhibitor) and U0126 (a MEK inhibitor). Collectively, our findings indicate that metformin exerts its effect on FOXO3a through the activation of AMPK and the inhibition of protein kinase B (Akt) and MAPK/extracellular signal-regulated kinase (MEK), culminating in the suppression of stemness in paclitaxel-resistant NSCLC cells.

Keywords:  FOXO3a; NSCLC; metformin; paclitaxel (PTX); stemness

DOI:  https://doi.org/10.3390/ijms242316611
Cell Death Dis. 2023 Dec 13. 14(12): 823

Hypoxia-induced activation of NDR2 underlies brain metastases from Non-Small Cell Lung Cancer.

Jérôme Levallet, Tiphaine Biojout, Céline Bazille, Manon Douyère, Fatéméh Dubois, Dimitri Leite Ferreira, Jasmine Taylor, Sylvain Teulier, Jérôme Toutain, Nicolas Elie, Myriam Bernaudin, Samuel Valable, Emmanuel Bergot, Guénaëlle Levallet.

The molecular mechanisms induced by hypoxia are misunderstood in non-small cell lung cancer (NSCLC), and above all the hypoxia and RASSF1A/Hippo signaling relationship. We confirmed that human NSCLC (n = 45) as their brain metastases (BM) counterpart are hypoxic since positive with CAIX-antibody (target gene of Hypoxia-inducible factor (HIF)). A severe and prolonged hypoxia (0.2% O2, 48 h) activated YAP (but not TAZ) in Human Bronchial Epithelial Cells (HBEC) lines by downregulating RASSF1A/kinases Hippo (except for NDR2) regardless their promoter methylation status. Subsequently, the NDR2-overactived HBEC cells exacerbated a HIF-1A, YAP and C-Jun-dependent-amoeboid migration, and mainly, support BM formation. Indeed, NDR2 is more expressed in human tumor of metastatic NSCLC than in human localized NSCLC while NDR2 silencing in HBEC lines (by shRNA) prevented the xenograft formation and growth in a lung cancer-derived BM model in mice. Collectively, our results indicated that NDR2 kinase is over-active in NSCLC by hypoxia and supports BM formation. NDR2 expression is thus a useful biomarker to predict the metastases risk in patients with NSCLC, easily measurable routinely by immunohistochemistry on tumor specimens.

DOI: https://doi.org/10.1038/s41419-023-06345-3