bims-meluca 2026-03-01 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2026–03–01
six papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Circulating Inflammatory and Mitochondrial Biomarkers Associated with Cachexia in Advanced Non-Small Cell Lung Cancer.
Tumor-Derived LIF Promotes GDF15-Driven Cachexia and Adverse Outcomes in Gastric Cancer.
Stage-Dependent Metabolic Responses to Oral Nutritional Supplementation in Cancer Cachexia: A Single-Arm Pilot Study.
High Fat Diet and Obesity Each Increase Tumor Cell Proliferation and Muscle Wasting in Experimental Cancer Cachexia.
Impact of TP53, KEAP1 and STK11 mutations in localized-stage NSCLC: A European thoracic oncology platform lungscape project.
Targeting one-carbon metabolic vulnerabilities of metastasis with therapeutic potential.

Cancers (Basel). 2026 Feb 17. pii: 655. [Epub ahead of print]18(4):

Circulating Inflammatory and Mitochondrial Biomarkers Associated with Cachexia in Advanced Non-Small Cell Lung Cancer.

Kamya Sankar, Elham Kazemian, Nicole Lorona, Carlos D Cruz-Hernández, Alex K Bryant, Mitra Mastali, Akil A Merchant, Jennifer Van Eyk, Karen L Reckamp, Puneeth Iyengar, Neil A Bhowmick, Jane C Figueiredo.

  Background: Cancer-associated cachexia is a multifactorial metabolic syndrome characterized by progressive skeletal muscle and/or adipose tissue loss and affects approximately 40% of patients with non-small cell lung cancer (NSCLC). However, reliable circulating biomarkers for early detection and risk stratification remain undefined. Based on prior observations linking elevated circulating mitochondrial DNA (mtDNA) to cachexia, we hypothesized that mtDNA and inflammatory protein levels in plasma could predict cachexia onset and trajectories. Methods: We evaluated 27 patients with stage IV NSCLC enrolled in the SeroNet-CORALE cohort with plasma samples collected between 2020 and 2023. Forty biomarkers were quantified at two timepoints (T1 and T2) using a multiplexed MesoScale Discovery platform. Associations between log2-transformed biomarker levels and cachexia status were assessed using Firth's penalized logistic regression. Results: Among 27 patients (65% female; mean age 65 ± 10 years; 89% adenocarcinoma histology), cachectic patients exhibited lower body mass index at both time points (T1: 21.0 ± 2.0 vs. 27.0 ± 7.0; T2: 21.8 ± 4.9 vs. 25.2 ± 4.9). At T1, cachexia was strongly associated with elevated GDF15 (OR 4.29; 95% CI 1.04-29.74; p = 0.044) and IL-15 (OR 43.83; 95% CI 2.39->999; p = 0.007), whereas IL-4 had a protective association (OR 0.09; 95% CI 0.00-0.66; p = 0.013). At T2, cachexia was associated with higher mtDNA levels (OR 2.13; 95% CI 1.07-7.69; p = 0.022) and lower levels of IL-15, IL12/IL23p40, and MDC. Conclusions: Distinct inflammatory and mitochondrial biomarkers tracked cachexia evolution in advanced NSCLC, with early GDF-15/IL-15 elevations and later increases in circulating mtDNA. Larger longitudinal studies are warranted to validate these findings and define their clinical relevance.

Keywords:  biomarkers; cachexia; mitochondrial DNA; non-small cell lung cancer

DOI:  https://doi.org/10.3390/cancers18040655
Cells. 2026 Feb 16. pii: 355. [Epub ahead of print]15(4):

Tumor-Derived LIF Promotes GDF15-Driven Cachexia and Adverse Outcomes in Gastric Cancer.

Cristina Di Giorgio, Nicola Natalizi, Maria Rosaria Sette, Martina Bordoni, Benedetta Sensini, Ginevra Lachi, Eleonora Giannelli, Francesca Paniconi, Luigi Cari, Silvia Marchianò, Michele Biagioli, Elva Morretta, Maria Chiara Monti, Bruno Charlier, Fabrizio Dal Piaz, Angela Zampella, Eleonora Distrutti, Luigina Graziosi, Annibale Donini, Stefano Fiorucci.

  Cancer cachexia is a multifactorial metabolic syndrome characterized by progressive skeletal muscle and adipose tissue loss, systemic inflammation, and poor clinical outcomes, and represents a major unmet clinical need in gastric cancer. Growth Differentiation Factor 15 (GDF15) is a key mediator of cachexia-associated anorexia and tissue wasting; however, the upstream mechanisms regulating its expression in gastric cancer remain poorly defined. Leukemia Inhibitory Factor (LIF), a pleiotropic cytokine implicated in tumor progression and metabolic dysregulation, has emerged as a potential regulator of cachexia-related pathways. Here, we investigated the association between LIF in regulating GDF15 expression and its relationship with metabolic, inflammatory, and body composition alterations in gastric cancer. Transcriptomic profiling of paired neoplastic and non-neoplastic gastric mucosa from 61 gastric cancer patients revealed a significant upregulation of both LIF and GDF15 in tumor tissue, with a strong positive correlation between their expression levels. High GDF15 expression was associated with reduced overall survival, a finding validated in independent TCGA-STAD and ACRG cohorts. Intratumoral bile acid profiling uncovered a marked enrichment of primary bile acids and a depletion of secondary bile acids, resulting in reduced levels of bile acids with endogenous LIF receptor (LIFR) antagonist activity; elevated primary, LIFR non-antagonist bile acids were associated with worse survival outcomes. Clinically, increased LIF and GDF15 expression correlated with weight loss, heightened inflammatory burden, reduced serum protein and albumin levels, and impaired body composition in a sub-cohort of 19 patients. Notably, LIF expression showed a significant inverse association with both lumbar skeletal muscle index (L3SMI) and subcutaneous adipose tissue index (SATI). Mechanistically, experimental models demonstrated that LIF enhances proliferative activity in gastric cancer spheroids and exerts paracrine effects that impair myogenic differentiation and suppress hepatic metabolic gene expression. Collectively, these findings identify the LIF/GDF15 axis as a central driver of cancer-associated cachexia in gastric cancer and highlight LIF signaling as a potential therapeutic target.

Keywords:  bile acids; cancer cachexia; gastric cancer; growth differentiation factor 15 (GDF15); leukemia inhibitory factor (LIF); metabolic remodeling; skeletal muscle wasting

DOI:  https://doi.org/10.3390/cells15040355
Nutrients. 2026 Feb 11. pii: 597. [Epub ahead of print]18(4):

Stage-Dependent Metabolic Responses to Oral Nutritional Supplementation in Cancer Cachexia: A Single-Arm Pilot Study.

Sora Kang, Harin Sim, Samantha O'Keeffe, Junyoung O Park, Wonhyoung Seo, Jeong Suk Koh, Myung-Won Lee, Ik-Chan Song, Hyo-Jin Lee, Deog-Yeon Jo, Yea Eun Kang, Hyon-Seung Yi, Hyewon Ryu.

   BACKGROUND/OBJECTIVES: Cancer cachexia is a multifactorial syndrome characterized by involuntary weight loss and muscle wasting, leading to impaired quality of life and poor clinical outcomes. Although oral nutritional supplements (ONS) are recommended to support inadequate oral intake during chemotherapy, their effects on underlying metabolic alterations and gut microbiome composition, particularly across different stages of cachexia remain unclear. This single-arm pilot study aimed to evaluate the feasibility and metabolic effects of an 8-week ONS intervention in patients with cancer cachexia undergoing chemotherapy.
METHODS: This study was conducted at the Chungnam National University Hospital, Daejeon, Republic of Korea between January 2023 and October 2023. The primary endpoints were feasibility outcomes, including adherence, tolerability, attrition rate, and ONS-related adverse events. Secondary outcomes included body composition, physical performance, biochemical markers, quality of life, plasma GDF-15 levels, serum metabolomics, and gut microbiome composition. Assessment of secondary outcomes and multi-omics profiling was performed at baseline and after 8 weeks. Patients were stratified into severe and non-severe cachexia groups and analyzed.
RESULTS: A total of 10 patients (median age 65 years, range 42-76) participated. Primary cancer types included cholangiocarcinoma (n = 4), colorectal (n = 4), and gallbladder cancer (n = 2). Adherence was 82%, with excellent tolerability and no ONS-related adverse events. Body composition, quality of life, and gut microbiome showed no significant changes. Hand-grip strength and walking-speed were slightly improved after 8 weeks intervention (p = 0.014 for hand-grip strength; p = 0.021 for walking-speed, Wilcoxon signed-rank test) in overall cohort. Metabolomics identified 10 metabolites, predominantly fatty acids, with significant between-group differential responses (p < 0.05, Mann-Whitney U test). Non-severe cachexia patients showed reductions in circulating fatty acids following ONS, consistent with attenuated lipolysis and reduced endogenous fat mobilization, whereas severe cachexia patients demonstrated increases, suggesting limited metabolic responsiveness to nutritional intervention. Fatty acid metabolism emerged as the predominant discriminatory pathway.
CONCLUSIONS: This study showed the feasibility of integrating ONS with multi-omics profiling. Our findings suggest that metabolic alterations might precede clinically detectable changes, potentially providing a rationale for early intervention. Specifically, certain fatty acids were identified as candidate biomarkers that warrant further validation in larger cohorts.

Keywords:  cancer cachexia; metabolites; microbiome; oral nutritional supplements; sarcopenia; single-arm pilot study

DOI:  https://doi.org/10.3390/nu18040597
Am J Physiol Cell Physiol. 2026 Feb 21.

High Fat Diet and Obesity Each Increase Tumor Cell Proliferation and Muscle Wasting in Experimental Cancer Cachexia.

Brittany R Counts, Andrea Bonetto, Ho Lam Chan, Ernie D Au, Yanlin Jiang, Marion E Couch, Denis C Guttridge, Michael C Ostrowski, Leonidas G Koniaris, Teresa A Zimmers.

  High fat diet (HFD) and associated obesity are suggested to predispose to cancer development, complicate cancer treatment, and accelerate mortality. Paradoxically, obese patients with lung cancer are reported to live longer, suggesting that high body mass is protective. Given that cachexia-tumor-induced weight loss with adipose and muscle wasting-is prevalent in lung cancer, we speculated that obese patients might survive longer due to the protective effect of larger tissue reservoirs, slowing time to fatal wasting. Thus, we modeled this condition using lean and high fat diet (HFD)-induced obese mice with Lewis lung carcinoma (LLC) tumors versus non-tumor bearing controls. We also assessed the effects of feeding HFD to lean mice with and without LLC tumors. HFD and obese-HFD without tumors gained weight over the study, with obese HFD mice exhibiting low muscle mass with obesity at endpoint. Low fat diet (LFD)-fed lean mice with LLC tumors (LFD-LLC) showed no change in total body weight, but exhibited reduced skeletal muscle, heart, and fat pad mass along with hepatosplenomegaly at endpoint. HFD and pre-existing obesity both modified the response to Lewis lung carcinoma (LLC) tumors. HFD did not affect tumor-induced weight loss, fat loss, or tumor burden, but worsened loss of gastrocnemius, tibialis anterior, and heart muscle, prevented hepatosplenomegaly, and enhanced tumor cell proliferation and expression of the cachexia-inducing cytokine, Interleukin-6 (IL-6). Obese-HFD mice showed greater tumor burden versus LFD and the worst cachexia phenotypes, including greater weight loss and muscle loss than HFD or LFD. This worsened cachexia was associated with increased blood-born inflammatory cytokines, increased phosphorylated STAT3 in muscle, and increased IL-6 expression in muscle, spleen, and tumor. Obese-HFD was associated with the highest rate of tumor cell proliferation in vivo and serum from obese HFD mice increased LLC cell proliferation in vitro. Thus, HFD and pre-existing obesity each separately enhance inflammation, cachexia, and tumor growth. These distinct contributions of HFD and chronic adiposity are potential therapeutic targets to slow cachexia and tumor growth in cancer.

Keywords:  Interleukin-6; cancer cachexia; high fat diet; obesity; skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00545.2025
Eur J Cancer. 2026 Feb 17. pii: S0959-8049(26)00363-1. [Epub ahead of print] 116583

Impact of TP53, KEAP1 and STK11 mutations in localized-stage NSCLC: A European thoracic oncology platform lungscape project.

Miguel A Molina-Vila, Zoi Tsourti, Katerina Vervita, Jordi Bertran-Alamillo, Beatriz García-Peláez, Keith M Kerr, Lukas Bubendorf, Line Bille Madsen, Wojciech Biernat, Albrecht Stenzinger, Martina Haberecker, Fiona Blackhall, Saraswati Pokharel, Núria Jordana-Ariza, Marta Vives-Usano, Patrick Vagenknecht, Urania Dafni, Roswitha Kammler, Stephen P Finn, Solange Peters, Rolf A Stahel, Rafael Rosell.

   BACKGROUND: TP53, STK11 and KEAP1 mutations are frequent in localized-stage non-small cell lung cancer (NSCLC). However, their prognostic and predictive role has not been fully investigated, particularly in relation to adjuvant treatment.
METHODS: Tumor samples from a training cohort of 350 surgically resected ETOP Lungscape NSCLC patients and a validation cohort of 161 additional patients were genotyped using Next Generation Sequencing (NGS). TP53 mutations were classified as "disruptive" (d) or "non-disruptive" (nd) according to their predicted impact. Disruptive mutations are those leading to complete loss of function of the p53 protein.
RESULTS: Among the 350 patients of the training cohort, 11 % harbored mutations in KEAP1 and 14 % in STK11. Regarding TP53 status, 31 % were wild type, 35 % carried TP53-d and 34 % TP53-nd mutations. For the 161 patients receiving adjuvant chemotherapy, TP53-d mutations associated with better time to relapse (TTR). Significantly shorter TTR and overall survival (OS) were observed in KEAP1 mutant patients while STK11 mutations correlated with better outcomes. Among the 186 patients not receiving chemotherapy, significantly worse OS was observed in KEAP1 mutant patients, while TP53 or STK11 status did not affect outcome. In a baseline-matched sub-cohort (n = 206), selected within the training cohort, the interaction between TP53 mutations and chemotherapy was statistically significant for all endpoints. The findings for KEAP1 but not for TP53 were validated in a second cohort of 161 patients.
CONCLUSIONS: TP53-d and STK11 mutations might have a predictive impact in localized-stage NSCLC, but further investigation is needed. KEAP1 mutations associate with worse outcomes, especially in patients receiving adjuvant chemotherapy.

Keywords:  KEAP1; Localized; Mutations; NSCLC; Predictive; Prognostic; STK11; TP53

DOI:  https://doi.org/10.1016/j.ejca.2026.116583
bioRxiv. 2026 Feb 10. pii: 2026.02.07.704548. [Epub ahead of print]

Targeting one-carbon metabolic vulnerabilities of metastasis with therapeutic potential.

Yanlin Yu, Weiping Chen, Glenn Merlino.

Evidence has shown that tumor progression is associated with the acquisition of growing autonomy and the creation of a complex signaling network through various signal pathways. Which particular signaling pathway is involved in the metastasis of a specific cancer is unclear. Here, we applied metastatic functional screening and identified that one-carbon and SSP metabolism pathways, as well as related genes, are associated with tumor metastasis inhibition. We engineered the cancer cells with poorly or highly metastatic potential to confirm the metabolism pathways regulating the ability to colonize different tissue sites. We also asked whether the restriction of the metabolism pathways by known inhibitors. We then identified three new compounds that can inhibit the expression of these genes and block tumor metastasis. Our findings uncovered a mechanism by which tumor cells reprogram their metabolism to promote migration, invasion, and survival at distant sites in tumor metastasis, offering a rational strategy to guide clinical treatment. The identified novel molecular proteins and pathways represent a promising therapeutic target for metastatic disease.

DOI: https://doi.org/10.64898/2026.02.07.704548