bims-meluca 2025-05-11 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2025–05–11
seven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Distinct roles for the thioredoxin and glutathione antioxidant systems in Nrf2-Mediated lung tumor initiation and progression.
Prevalence and Development of Cachexia Before and After Diagnosis of Non-small Cell Lung Cancer.
Cancer, malnutrition and inflammatory biomarkers. Why do some cancer patients lose more weight than others?
The potential of TAOK1 as a new therapeutic target for the treatment of cancer cachexia-associated muscle atrophy.
Directional interactions from non-small cell lung cancer to brain glucose metabolism revealed by total-body PET imaging.
Histone H1.4K75 acetylation promotes tumor growth and migration by regulating p53 and ERK1/2 pathway in non-small lung cancer.
BCL-2 mutant B7H6-CAR-T cells synergized with venetoclax for treating small cell lung cancer.

Redox Biol. 2025 Apr 30. pii: S2213-2317(25)00166-1. [Epub ahead of print]83 103653

Distinct roles for the thioredoxin and glutathione antioxidant systems in Nrf2-Mediated lung tumor initiation and progression.

Amanda M Sherwood, Basma A Yasseen, Janine M DeBlasi, Samantha Caldwell, Gina M DeNicola.

  Redox regulators are emerging as critical mediators of lung tumorigenesis. NRF2 and its negative regulator KEAP1 are commonly mutated in human lung cancers, leading to NRF2 accumulation and constitutive expression of NRF2 target genes, many of which are at the interface between antioxidant function and anabolic processes that support cellular proliferation. Nrf2 activation promotes lung tumor initiation and early progression in murine models of lung cancer, but which Nrf2 targets mediate these phenotypes is unknown. Nrf2 regulates two parallel antioxidant systems mediated by thioredoxin reductase 1 (TXNRD1) and glutathione reductase (GSR), which promote the reduction of protein antioxidant thioredoxin (TXN) and tripeptide antioxidant glutathione (GSH), respectively. We deleted TXNRD1 and GSR alone, or in combination, in lung tumors harboring mutations in KrasG12D and Nrf2D29H. We found that tumor initiation was promoted by expression of GSR, but not TXNRD1, regardless of Nrf2 status. In contrast, Nrf2D29H tumors, but not Nrf2WT, were dependent on TXNRD1 for tumor progression, while GSR was dispensable. Simultaneous deletion of GSR and TXNRD1 reduced initiation and progression independent of Nrf2 status, but surprisingly did not completely abrogate tumor formation. Thus, the thioredoxin and glutathione antioxidant systems play unique roles in tumor initiation and progression.

Keywords:  Glutathione (GSH); Glutathione reductase (GSR); Kelch-like ECH-Associated protein 1 (KEAP1); Non-small cell lung cancer (NSCLC); Nuclear factor erythroid 2-related factor 2 (NRF2); Reactive oxygen species (ROS); Thioredoxin (TXN); Thioredoxin reductase (TXNRD1)

DOI:  https://doi.org/10.1016/j.redox.2025.103653
Am J Clin Oncol. 2025 May 05.

Prevalence and Development of Cachexia Before and After Diagnosis of Non-small Cell Lung Cancer.

L Anne Gilmore, Jonas Willmann, Santiago Olaechea, Brian W Gilmore, Edward Christopher Dee, Mihir Rao, Bhavani S Gannavarapu, Shivaek Venkateswaran, Christian M Alvarez, Chul Ahn, Dirk K M de Ruysscher, Urvi A Shah, Neil M Iyengar, Daniel R Gomez, Rodney Infante, Puneeth Iyengar.

   OBJECTIVE: Cachexia is commonly defined based on weight loss at the time of cancer diagnosis. However, regular weight measurements before cancer diagnosis are often lacking and may be subject to recall bias if retrospectively self-reported by patients. To analyze the development and progression of cachexia, we employ body weight trajectories from 1 year before and after diagnosis of non-small cell lung cancer (NSCLC). We hypothesized that cachexia could be detected as early as 1 year before NSCLC diagnosis and that cachexia prevalence would increase in the year following diagnosis.
METHODS: This retrospective study included consecutive patients with NSCLC treated at UTSW between 2005 and 2019 who had body weight measurements before and after NSCLC diagnosis recorded in their electronic health records. Weights were binned in 3-month intervals. Cachexia was defined per the International Consensus Definition of cachexia, that is, loss of >5% body weight 12 months preceding cancer diagnosis for patients with BMI ≥20 kg/m2 or weight loss of >2% for patients with a BMI <20 kg/m2. The association of disease stage and primary treatment with weight changes was investigated.
RESULTS: Among 4294 patients screened, 661 patients were included in the final analysis. Patients had a mean age of 69.3 (SD: 10.6) years, and a majority were current/former smokers (83%), identified as white (76%), and were diagnosed with either stage I (47%) or stage IV (28%) nonsquamous NSCLC (78%). At cancer diagnosis, 28% (n=183) presented with cachexia, having incurred a mean loss of 8.6 (SEM: 0.4%) (P<0.0001) of body weight within the year before cancer diagnosis. Weight loss after cancer diagnosis was comparable in patients with and without cachexia at cancer diagnosis (P=0.05). By 12 months postcancer diagnosis, 58% of patients (n=383) met the criteria for cachexia based on weight loss. Weight loss consistent with cachexia occurred over a median period of 220 (IQR: 265) days.
CONCLUSION: Weight loss in patients with cachexia at NSCLC diagnosis may commence as early as 12 months before cancer diagnosis. Within a year after a cancer diagnosis, more than half of patients develop cachexia, particularly those with advanced disease. These findings support the integration of early nutritional and pharmacological interventions in patients with NSCLC.

Keywords:  cachexia; lung cancer; non–small cell lung cancer; stage; survival; treatment; weight loss

DOI:  https://doi.org/10.1097/COC.0000000000001211
Contemp Oncol (Pozn). 2025 ;29(1): 45-54

Cancer, malnutrition and inflammatory biomarkers. Why do some cancer patients lose more weight than others?

Aleksandra Kapała, Katarzyna Różycka, Ewelina Grochowska, Aleksandra Gazi, Emilia Motacka, Marcin Folwarski.

   Introduction: Malnutrition is highly prevalent in cancer patients, significantly influencing their clinical outcomes and prognosis. The study was conducted to investigate the association between inflammatory biomarkers, nutritional status and progression of the disease across various types of cancers.
Material and methods: Retrospective data from 200 consecutive Caucasian cancer patients admitted to a major oncology hospital for cancer treatment were analyzed according to age, sex, cancer type, nutritional status (percentage body weight loss - %BWL), body mass index (BMI), percentage of dietary intake from the calculated requirement for nutrients (%DI)), and laboratory results (albumin levels, total protein concentration, C-reactive protein - CRP). Inflammatory biomarkers such as prognostic nutritional index (PNI), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were assessed.
Results: Prognostic nutritional index (ρ = -0.464, p < 0.001), PLR (ρ = 0.293, p = 0.019), albumin level (ρ = -0.490, p < 0.001), platelet count (ρ = 0.114, p = 0.370), neutrophil count (ρ = 0.273, p = 0.030), CRP (ρ = 0.293, p = 0.019) and lymphocyte count (ρ = -0.288, p = 0.021) were significantly associated with %BWL. No significant association was found with NLR. Cancer dissemination was significantly associated with PNI (OR: 0.93, 95% CI: 0.88-0.98), PLR (OR: 1.00, 95% CI: 1.00-1.01), albumin (OR: 0.86, 95% CI: 0.80-0.93), platelet count (OR: 1.01, 95% CI: 1.00-1.01), %BWL (OR: 1.06, 95% CI: 1.02-1.10) and %DI (OR: 0.97, 95% CI: 0.96-0.99) but not with NLR, total protein level, total lymphocyte count, or BMI. For patients with albumin levels below 35 g/l, the likelihood of disseminated cancer was more than five times higher (OR: 5.45, 95% CI: 2.05-14.48).
Conclusions: The intensity of inflammation may be responsible for the severity of malnutrition and cancer prognosis.

Keywords:  body weight loss; cancer; inflammatory biomarkers; malnutrition; systemic inflammation

DOI:  https://doi.org/10.5114/wo.2025.147939
Pharmacol Res. 2025 May 06. pii: S1043-6618(25)00188-4. [Epub ahead of print] 107763

The potential of TAOK1 as a new therapeutic target for the treatment of cancer cachexia-associated muscle atrophy.

Ruiqin Zhang, Nan Li, Ke Yu, Qiongsen Wang, Meng Fan, Xiongwen Zhang, Xuan Liu.

  Cancer cachexia, a multifactorial metabolic syndrome impacts 50-80% cancer patients, is mainly characterized by skeletal muscle atrophy. In this study, we demonstrated that the thousand-and-one amino acid kinase 1 (TAOK1) was activated in both C2C12 myotubes treated with simulated cancer cachexia injuries as well as in muscle tissues of mice inoculated with various types of tumor cells. Results of phosphoproteomic analysis also showed the increase in phosphorylation of TAOK1 in myotubes induced by simulated cancer cachexia injuries. Knockdown of TAOK1 in C2C12 myoblasts resulted in resistance to cancer cachexia-associated myotube atrophy. Comparing the protein expression profiles of C2C12-TAOK1-KO myotubes and that of control myotubes using proteomic analysis found that, TAOK1 knockout resulted in increased expression of muscle-related proteins and decreased expression of proteins related to MAPK pathway and ubiquitin-proteasome system (UPS). Results of Western blotting analysis confirmed the involvement of TAOK1/MAPK/FoxO3/UPS pathway in cancer cachexia-associated myotube atrophy, and suggested that TAOK1 knockout could ameliorate increased protein degradation but not decreased protein synthesis under cancer cachexia. CP43, a synthesized TAOK1 inhibitor, could ameliorate both in vitro myotube atrophy of C2C12 myotubes under simulated cancer cachexia injuries as well as in vivo muscle atrophy of cancer cachexia mice inoculating with C26 colon tumor cells. In conclusion, our study provides evidence that TAOK1 plays critical roles in activation of protein degradation under cancer cachexia thus targeting TAOK1 might be a potential therapy strategy for treatment of cancer cachexia-associated muscle atrophy.

Keywords:  C2C12 myotubes; MAPK pathway; TAOK1; cancer cachexia; muscle atrophy; tumor-bearing mice; ubiquitin-proteasome system

DOI:  https://doi.org/10.1016/j.phrs.2025.107763
Eur J Nucl Med Mol Imaging. 2025 May 09.

Directional interactions from non-small cell lung cancer to brain glucose metabolism revealed by total-body PET imaging.

Tianzheng Zhong, Yanhua Duan, Kun Li, Jianfeng Qiu, Zhaoping Cheng, Weizhao Lu.

   PURPOSE: Imaging markers for lung-brain interaction and brain metastasis of non-small cell lung cancer (NSCLC) are lacking. This study aimed to explore the effect of NSCLC on brain glucose metabolism using total-body positron emission tomography (PET) imaging.
METHODS: Fifty-six healthy controls (HCs) and 42 NSCLC patients underwent total-body PET imaging. Concentrations of serum tumor markers were obtained for NSCLC patients. Pseudo-time series data of NSCLC were generated based on the tumor, node, metastasis (TNM) staging system. A novel causal metabolic covariance network (CaMCN) between NSCLC and brain glucose metabolism was conducted with maximum and mean of standardized uptake value (SULmax and SULmean), serum tumor markers as the seed series, respectively. Reliability was evaluated by reverse CaMCN analysis. Finally, post-hoc analysis was performed on brain regions that exhibited causality from NSCLC.
RESULTS: CaMCN analysis demonstrated significant causality from NSCLC to glucose uptake of the posterior fossa regions, the anatomic "watershed areas" and the gray-white matter junction in the frontal, temporal and occipital lobes. Reverse CaMCN analysis demonstrated significant distinctions from the original CaMCN results. Post-hoc analysis revealed that glucose uptake in the inferior temporal gyrus, thalamus, superior frontal gyrus, precentral gyrus and postcentral gyrus exhibited significant differences among HCs and different stages of NSCLC.
CONCLUSION: The proposed method can capture causal relationships from NSCLC to brain metabolism, providing pathophysiological insights into the lung-brain interaction in NSCLC. Moreover, the identified brain regions were the areas where NSCLC brain metastases frequently occur, holding the promise as biomarkers for brain metastases of NSCLC.

Keywords:  Brain metastasis; Causal analysis; Lung-brain interaction; Non-small cell lung cancer; Total-body positron emission tomography

DOI:  https://doi.org/10.1007/s00259-025-07324-w
Biochem Biophys Res Commun. 2025 Apr 28. pii: S0006-291X(25)00594-7. [Epub ahead of print]768 151880

Histone H1.4K75 acetylation promotes tumor growth and migration by regulating p53 and ERK1/2 pathway in non-small lung cancer.

Wenqi Chen, Xinyue Duan, Zhebiao Zhu, Yajing Han, Yong Li.

  Histone H1.4 is a member of the linker histone H1 family, and its post-translational modifications (PTMs) are essential for its function. However, the role of H1.4 PTM in cancer development is not fully understood. Here, we report the discovery of a previously uncharacterized acetylation site at lysine 75 (K75) of H1.4 in non-small cell lung cancer (NSCLC). Point mutation of K75 with arginine (H1.4K75R) markedly suppressed cellular viability and migration in A549 and H1299 cells, and inhibit tumor growth in xenografts mouse models. Moreover, RNA-sequencing and Western Blot analyses revealed that H1.4K75 acetylation orchestrates dual regulatory effects, potentiating ERK1/2 signaling while repressing the p53 pathway. In summary, our studies show that H1.4K75 acetylation is essential for cell viability, migration and tumor growth in NSCLC, and may be a therapeutic target for NSCLC.

Keywords:  Acetylation; Cell migration; Cell viability; Histone H1.4; NSCLC

DOI:  https://doi.org/10.1016/j.bbrc.2025.151880
J Immunother Cancer. 2025 May 07. pii: e010073. [Epub ahead of print]13(5):

BCL-2 mutant B7H6-CAR-T cells synergized with venetoclax for treating small cell lung cancer.

Huihui Zhang, Liliang Xia, Wendi Xuzhang, Ziming Li, Junshi Zhang, Fanlin Li, Chen Cheng, Jiawen Wang, Xincheng Zong, Xuanming Yang, Shun Lu.

   BACKGROUND: Patients with small cell lung cancer (SCLC) generally have a poor prognosis, with an exceptionally high proliferative rate and a strong propensity for early metastasis, indicating the urgent need for novel therapies. The development of chimeric antigen receptor (CAR)s targeting solid tumors is limited owing to the lack of target antigens and low efficacy. In this study, we aimed to discover new targets for SCLC CAR-T therapy and develop CAR-T-based combinational treatment against SCLC in preclinical models.
METHODS: The in vitro antitumor activity of B7H6-specific CAR-T cell was evaluated. Venetoclax-resistant B7H6 CAR-T cell were designed and the synergistic effect of venetoclax and B7-H6 CAR-T cells was tested in vitro and in vivo.
RESULT: B7H6 is highly expressed in SCLC tumors. CAR-T cell against B7H6 displayed antigen-specific antitumor efficacy. BCL-2(D103E)-expressing CAR-T cells showed resistance to venetoclax-induced apoptosis. The combinational treatment of venetoclax and BCL-2(D103E)-expressing B7H6-targeting showed potent anti-SCLC effect in vitro and in vivo.
CONCLUSIONS: Our findings suggest that the combination of BCL-2 mutant-expressing B7H6-targeting CAR-T cells and venetoclax could be a promising novel strategy against B7H6-expressing SCLCs and other solid tumors, providing the foundation for CAR-T cells and proapoptotic small molecules therapy in patients with SCLCs in a clinical trial.

Keywords:  Adoptive cell therapy - ACT; Chimeric antigen receptor - CAR; Immunotherapy; Lung Cancer; Solid tumor

DOI:  https://doi.org/10.1136/jitc-2024-010073