bims-meluca 2025-02-16 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2025–02–16
six papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Soluble PD-L1 and Serum Vascular Endothelial Growth Factor-B May Independently Predict Prognosis in Patients with Advanced Non-Small Cell Lung Cancer Treated with Pembrolizumab.
Body Composition Analysis in Metastatic Non-Small-Cell Lung Cancer: Depicting Sarcopenia in Portuguese Tertiary Care.
Secretome and Proteome of Extracellular Vesicles Provide Protein Markers of Lung and Colorectal Cancer.
Phosphorylase kinase regulatory subunit alpha 1 as a novel biomarker involved in development and progression of lung cancer: comprehensive bioinformatic analysis and experiment validation.
Metabolic heterogeneity in tumor cells impacts immunology in lung squamous cell carcinoma.
Diagnostic Criteria for Cancer-Associated Cachexia: Insights from a Multicentre Cohort Study.

Cancers (Basel). 2025 Jan 27. pii: 421. [Epub ahead of print]17(3):

Soluble PD-L1 and Serum Vascular Endothelial Growth Factor-B May Independently Predict Prognosis in Patients with Advanced Non-Small Cell Lung Cancer Treated with Pembrolizumab.

Eleni Kokkotou, Dimitra Grapsa, Anna Papadopoulou, Stylianos Gaitanakis, Petros Bakakos, Garyfallia Poulakou, Paraskevi Moutsatsou, Konstantinos Syrigos.

  Background: Previous preclinical data have shown that the dynamic cross-talk between abnormal tumor vasculature and immune cell factors in the tumor microenvironment may exert a critical role in the progression and treatment resistance of non-small cell lung cancer (NSCLC). In the clinical setting, a variety of blood-based angiogenesis- and immune-related factors are being increasingly investigated as potential biomarkers of prognosis or treatment response in immunotherapy-treated NSCLC. We herein aimed to evaluate the clinical relevance of the peripheral blood levels of vascular endothelial growth factor-A and -B (VEGF-A and VEGF-B, respectively), soluble programmed cell death-1 (sPD-1), and programmed cell death-ligand 1 (sPD-L1) in patients with advanced NSCLC treated with immune checkpoint inhibitors (ICIs). Methods: Consecutive patients with advanced-stage, non-oncogene-addicted NSCLC, eligible to receive ICIs at the Oncology Unit of Sotiria Athens General Hospital, were prospectively recruited. A group of sex- and age-matched healthy controls was also enrolled for the evaluation of the potential diagnostic significance of the examined biomarkers. Serum levels of all biomarkers were measured using ELISA, both before and after treatment, and were correlated with standard clinicopathological features of patients, treatment response, progression-free survival (PFS), and overall survival (OS). Results: A total of 55 patients and 16 healthy controls were included in the final analysis. The mean age of patients and controls was 66.5 years (SD = 8.0 years) and 65.4 years (SD = 9.1 years), respectively. The majority of patients (65.5%) received pembrolizumab in combination with chemotherapy, while the remaining patients received pembrolizumab monotherapy. ROC curve analysis showed that VEGFB and sPD-1 were the only markers with a significant diagnostic value. Higher pre-treatment values of sPD-L1 (HR = 1.68; p = 0.040) and sPD-1 (HR = 10.96; p = 0.037) as well as higher post-treatment values of VEGF-B (HR = 2.99; p = 0.049) were all significantly associated with a reduced OS in univariate Cox regression analysis. The adverse prognostic significance of higher pre-treatment values of sPD-L1 (HR = 2.10; p = 0.014) and higher post-treatment values of VEGFB (HR = 3.37; p = 0.032) was further confirmed in multivariate analysis. Conclusions: Our study results suggest that serum levels of sPD-L1 and VEGF-B may independently predict prognosis in ICI-treated advanced-stage NSCLC.

Keywords:  VEGF-A; VEGF-B; immune checkpoint inhibitors; non-small cell lung cancer; sPD-1; sPD-L1

DOI:  https://doi.org/10.3390/cancers17030421
Cancers (Basel). 2025 Feb 05. pii: 539. [Epub ahead of print]17(3):

Body Composition Analysis in Metastatic Non-Small-Cell Lung Cancer: Depicting Sarcopenia in Portuguese Tertiary Care.

José Leão Mendes, Rita Quaresma Ferreira, Inês Mata, João Vasco Barreira, Ysel Chiara Rodrigues, David Silva Dias, Manuel Luís Capelas, Antti Mäkitie, Inês Guerreiro, Nuno M Pimenta, Paula Ravasco.

  Background/Objectives: Sarcopenia is an emergent prognostic biomarker in clinical oncology. Albeit increasingly defined through skeletal muscle index (SMI) thresholding, the literature cut-offs fail to discern heterogeneous baseline muscularity across populations. This study assesses the prognostic impact of using cohort-specific SMI thresholds in a Portuguese metastatic non-small-cell lung cancer (mNSCLC) cohort. Methods: Retrospective study including mNSCLC patients treated between January 2017 and December 2022. ImageJ v1.54 g was used to assess cross-sectional CT imaging at the third lumbar vertebra (L3) and calculate L3SMI. Sarcopenia was defined both according to Prado et al. and L3SMI thresholds derived from receiver operating characteristic analysis. Overall survival (OS) was the primary endpoint. Secondary endpoints included first-line (1L) progression-free survival (PFS) and sarcopenia subgroup analysis regarding body mass index impact on OS. Results: The initial cohort included 197 patients. Mean age was 65 years (±11.31). Most tumors were adenocarcinomas (n = 165) and presented with metastasis (n = 154). SMI was evaluable in 184 patients: cohort-specific thresholds (<49.96 cm2/m2 for men; <34.02 cm2/m2 for women) yielded 46.74% sarcopenic patients (n = 86) versus 66.30% (n = 122) per the literature definition. Cohort-specific thresholds predicted both OS (12.75 versus 21.13 months, hazard ratio [HR] 1.654, p = 0.002) and PFS (7.92 versus 9.56 months, HR 1.503, p = 0.01). Among sarcopenic patients, overweight (HR 0.417, p = 0.01) and obesity (HR 2.723, p = 0.039) had contrasting impacts on OS. Conclusions: Amid reclassification of nearly one-fifth of the cohort, cohort-specific thresholds improved sarcopenia prognostication in mNSCLC. Homogeneity regarding both cancer treatment setting and ethnicity could be key to defining sarcopenia based on SMI.

Keywords:  body composition; non-small-cell lung carcinoma; prognosis; sarcopenia; skeletal muscle index

DOI:  https://doi.org/10.3390/cancers17030539
Int J Mol Sci. 2025 Jan 25. pii: 1016. [Epub ahead of print]26(3):

Secretome and Proteome of Extracellular Vesicles Provide Protein Markers of Lung and Colorectal Cancer.

Natalia Soloveva, Svetlana Novikova, Tatiana Farafonova, Olga Tikhonova, Victor Zgoda.

  Colorectal cancer (CRC) and lung cancer (LC) are leading causes of cancer-related mortality, highlighting the need for minimally invasive diagnostic, prognostic, and predictive markers for these cancers. Proteins secreted by a tumor into the extracellular space directly, known as the tumor secretome, as well as proteins in the extra-cellular vesicles (EVs), represent an attractive source of biomarkers for CRC and LC. We performed proteomic analyses on secretome and EV samples from LC (A549, NCI-H23, NCI-H460) and CRC (Caco2, HCT116, HT-29) cell lines and targeted mass spectrometry on EVs from plasma samples of 20 patients with CRC and 19 healthy controls. A total of 782 proteins were identified across the CRC and LC secretome and EV samples. Of these, 22 and 44 protein markers were significantly elevated in the CRC and LC samples, respectively. Functional annotation revealed enrichment in proteins linked to metastasis and tumor progression for both cancer types. In EVs isolated from the plasma of patients with CRC, ITGB3, HSPA8, TUBA4A, and TLN1 were reduced, whereas FN1, SERPINA1, and CST3 were elevated, compared to healthy controls. These findings support the development of minimally invasive liquid biopsy methods for the detection, prognosis, and treatment monitoring of LC and CRC.

Keywords:  colorectal cancer; extracellular vesicles; lung cancer; proteome; secretome

DOI:  https://doi.org/10.3390/ijms26031016
J Physiol Pharmacol. 2024 Dec;75(6):

Phosphorylase kinase regulatory subunit alpha 1 as a novel biomarker involved in development and progression of lung cancer: comprehensive bioinformatic analysis and experiment validation.

Y Chen, Y Gao, L Jiang.

Lung cancer remains a critical global health issue, with the molecular intricacies and specific role of phosphorylase kinase regulatory subunit alpha 1 (PHKA1) not well understood. This study aims to utilize an integrated bioinformatic analyses and experimental validations to investigate PHKA1 in lung cancer. Bioinformatic tools provided a pan-cancer perspective, emphasizing PHKA1's oncogenic potential such as GEPIA and UALCAN revealed significantly elevated mRNA expression of PHKA1 in lung adenocarcinoma (LUAD) across various stages, highlighting its diagnostic significance. The study also explored the impact of PHKA1 on immune cells in LUAD, finding strong correlations between high PHKA1 expression and increased presence of CD4+, CD8+ T cells, and macrophages using TIMER 2.0 database. Survival analysis using Kaplan-Meier (KM) plots showed that patients with elevated PHKA1 levels had poorer prognoses, reinforcing its potential as an oncogenic gene in non-small cell lung cancer (NSCLC) by KM plotter. Immunohistochemistry by HPA database supported these findings, demonstrating increased PHKA1 protein levels in lung cancer tissues. Protein-protein interaction analysis using STRING and cytoscape identified a network of genes linked to PHKA1 in NSCLC, offering insights into its functional interactions. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis suggested that PHKA1 might be involved in the PI3K-AKT signaling pathway, known for its role in cell growth and survival, further supporting its oncogenic role. Experimental validation through RT-PCR and Western blot confirmed elevated PHKA1 expression in A549 and NCI-H460 lung cancer cells. Moreover, deletion of PHKA1 reduces cell growth and promotes apoptosis in A549 cells and confirmed by Western blot. In conclusion, this comprehensive study suggests that targeting PHKA1 in NSCLC could be a promising therapeutic strategy, highlighting its crucial role in the molecular landscape of lung cancer progression.

DOI: https://doi.org/10.26402/jpp.2024.6.08
Oncoimmunology. 2025 Dec;14(1): 2457797

Metabolic heterogeneity in tumor cells impacts immunology in lung squamous cell carcinoma.

Qian Wang, Na Sun, Chaoyang Zhang, Thomas Kunzke, Philipp Zens, Annette Feuchtinger, Sabina Berezowska, Axel Walch.

  Metabolic processes are crucial in immune regulation, yet the impact of metabolic heterogeneity on immunological functions remains unclear. Integrating metabolomics into immunology allows the exploration of the interactions of multilayered features in the biological system and the molecular regulatory mechanism of these features. To elucidate such insight in lung squamous cell carcinoma (LUSC), we analyzed 106 LUSC tumor tissues. We performed high-resolution matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to obtain spatial metabolic profiles, and immunohistochemistry to detect tumor-infiltrating T lymphocytes (TILs). Unsupervised k-means clustering and Simpson's diversity index were employed to assess metabolic heterogeneity, identifying five distinct metabolic tumor subpopulations. Our findings revealed that TILs are specifically associated with metabolite distributions, not randomly distributed. Integrating a validation cohort, we found that heterogeneity-correlated metabolites interact with CD8+ TIL-associated genes, affecting survival. High metabolic heterogeneity was linked to worse survival and lower TIL levels. Pathway enrichment analyses highlighted distinct metabolic pathways in each subpopulation and their potential responses to chemotherapy. This study uncovers the significant impact of metabolic heterogeneity on immune functions in LUSC, providing a foundation for tailoring therapeutic strategies.

Keywords:  Immunology; Spatial metabolomics; lung cancer; metabolic heterogeneity; metabolic tumor subpopulation

DOI:  https://doi.org/10.1080/2162402X.2025.2457797
J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13703

Diagnostic Criteria for Cancer-Associated Cachexia: Insights from a Multicentre Cohort Study.

Investigation on Nutrition Status and Clinical Outcome of Common Cancers (INSCOC) Group

   BACKGROUND: To explore the association between cachexia, as defined by different diagnostic criteria, and the risk of mortality in individuals with cancer. We also examined which diagnostic criteria are more feasible and appropriate for cancer-associated cachexia in clinical practice.
METHODS: A multicentre cohort study was conducted, which involved 5769 participants with cancer. The diagnosis of cachexia was made by applying the initial Fearon criteria (with the appendicular skeletal muscle mass index [ASMI]) and six modified criteria: (1) evaluating the muscle mass through the mid-upper-arm muscle area (MAMA), (2) fat-free mass index (FFMI), (3) calf circumference (CC), (4) hand grip strength (HGS), (5) neutrophil-to-lymphocyte ratio (NLR) and (6) omission of reduced muscle mass. The correlations between cancer cachexia diagnosed by different definitions and survival were assessed using Kaplan-Meier analyses and multivariable-adjusted Cox models. The sensitivity, specificity, positive likelihood ratios, negative likelihood ratios, AUC value, Youden index and weighted kappa coefficient were calculated for each set of criteria.
RESULTS: The final analysis included 5110 patients diagnosed with 15 different types of cancer, with a median age of 56. Out of these, 2490 (48.7%) were male. The prevalence of cancer cachexia based on the Fearon criteria was 26.5%, ranging from 21.8% to 32.2% with the six modified criteria. Following adjustment for age, sex, clinical stage and cancer site, cachexia defined by Fearon criteria was associated with a noteworthy increase in mortality (HR, 1.275; 95% CI, 1.136-1.430; p < 0.001), ranging from 1.237 (95% CI, 1.106-1.383; p < 0.001) to 1.382 (95% CI, 1.226-1.557; p < 0.001) by the six modified criteria. All six modified criteria presented adequate performance indicators (all p < 0.001), with sensitivity ranging from 82.4% (95% CI, 80.2%-84.3%) to 90.7% (95% CI, 89.0%-92.2%), specificity ranging from 86.9% (95% CI, 85.7%-87.9%) to 100.0% (95% CI, 99.9%-100.0%) and AUC ranging from 0.860 (95% CI, 0.850-0.869) to 0.932 (95% CI, 0.925-0.939). The modified criteria also showed strong (Fearon criteria with NLR: κ = 0.673, 95% CI, 0.651-0.695) to almost perfect (Fearon criteria without reduced muscle mass [RMM]: κ = 0.873, 95% CI, 0.857-0.888) consistency with the original Fearon criteria.
CONCLUSIONS: Cachexia defined by the Fearon criteria and the six modified criteria can predict the survival of cancer patients. All criteria provided a precise diagnosis and were feasible to use in clinical settings.

Keywords:  Fearon; cancer cachexia; mortality; muscle mass; neutrophil‐to‐lymphocyte ratio

DOI:  https://doi.org/10.1002/jcsm.13703