bims-meluca 2025-12-28 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2025–12–28
six papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

High glucose enhances lung cancer cell aggressiveness: The impacts of GLUT1, UAP1, UGP2, and N-linked Glycosylation.
TPI1 promotes tumor progression and M2 macrophage polarization: Integrated pan-cancer and lung adenocarcinoma insights.
SLC16A3 in lung adenocarcinoma regulates glycolysis and lactate release to facilitate M2 polarization of tumor-associated macrophages : Short Title: SLC16A3 reinforces macrophage M2 polarization through glycolysis.
CD26 as a potential therapeutic target for lung adenocarcinoma.
Inhibition of MDM2 by nutlin-3 decreased pyroptosis but increased apoptosis of lung carcinoma cells under 5-FU chemotherapy.
CD155 reprograms glycolysis via the YAP/TEAD1-GLUT1 axis to promote lung adenocarcinoma progression and M2 macrophage polarization: a metabolic-immune target visualized by 18F-FDG PET/CT.

Glycobiology. 2025 Dec 26. pii: cwaf089. [Epub ahead of print]

High glucose enhances lung cancer cell aggressiveness: The impacts of GLUT1, UAP1, UGP2, and N-linked Glycosylation.

Chatchai Phoomak, Charupong Saengboonmee, Marta Baro, Kanadit Piriyapairoje, Teeranai Ittiudomrak, Joseph N Contessa, Sopit Wongkham.

  Lung cancer remains the leading cause of cancer-related deaths globally, underscoring the need for novel therapeutic strategies. The relationship between high glucose levels, N-linked glycosylation, and cancer progression has been observed across various cancers, but its underlying mechanisms are not fully understood. Recent studies using CRISPR-Cas9 screens have highlighted the roles of glucose transporter 1 (GLUT1), UDP-N-acetylglucosamine pyrophosphorylase 1 (UAP1), and UDP-glucose pyrophosphorylase 2 (UGP2) in N-linked glycosylation. This study aims to elucidate how glucose influences lung cancer progression by examining its impact on aggressive phenotypes in A549 and PC-9 cell lines. The aggressive phenotypes-proliferation, colony formation, migration, and invasion- were investigated using MTT, and Boyden chamber assays. N-linked glycosylation status was monitored via lectin blot with Con A and PHA-E and molecular shift of GP130. Glucose dependently enhanced aggressive phenotypes in these cells through increased expression of GLUT1, UAP1, UGP2, and enhanced N-linked glycosylation. Conversely, inhibiting GLUT1 activity by selective inhibitors or knocking-out UAP1, and UGP2 expression using CRISPR-Cas9 significantly reduced aggressive behaviors and glycosylation levels. These observations were modulated through mediators of cell cycle (cyclin D1, p21, XIAP) and EMT (E-cadherin, vimentin, slug, snail). Notably, high expression of either GLUT1, UAP1, or UGP2, and the coordinated expression of these genes in tumor tissues correlated with poor survival outcomes in lung cancer patients. Our findings highlight the roles of GLUT1-UAP1-UGP2 axis and N-linked glycosylation in high glucose-induced progression of lung cancer cells. GLUT1, UAP1, and UGP2 may serve as prognostic markers and potential targets for future lung cancer treatments.

Keywords:  High glucose; Lung adenocarcinoma; Metastasis; N-glycosylation; Proliferation

DOI:  https://doi.org/10.1093/glycob/cwaf089
Biochem Biophys Res Commun. 2025 Dec 16. pii: S0006-291X(25)01815-7. [Epub ahead of print]797 153099

TPI1 promotes tumor progression and M2 macrophage polarization: Integrated pan-cancer and lung adenocarcinoma insights.

Xuan Liu, Xiufeng Gao, Ranran Ma, Jing Wang, Tongtong Zha, Youming Huang.

  Triosephosphate isomerase 1 (TPI1), a glycolytic enzyme, has been increasingly implicated in cancer progression, yet its expression landscape across tumor types and functional roles in tumor immunity remain poorly defined. Here, we performed integrated pan-cancer analyses combining transcriptomic, proteomic, and single-cell RNA-sequencing datasets to characterize TPI1 expression, prognostic significance, mutational associations, and immune infiltration. TPI1 was found to be broadly overexpressed in tumors compared with normal tissues, and its high expression correlated with poor prognosis, increased tumor mutational burden, and reduced adaptive immune cell infiltration. In lung adenocarcinoma (LUAD), TPI1 was enriched in malignant epithelial and myeloid populations and associated with immunosuppressive stromal features. A TPI1-based prognostic model stratified LUAD patients by overall survival, immune phenotype, and mutational status. Functional assays demonstrated that TPI1 promotes M2-like macrophage polarization in THP-1 cells, enhances LUAD epithelial cell proliferation, migration, and clonogenicity, and contributes to resistance to KRAS inhibitors in KRAS-mutant LUAD cells. Collectively, these findings establish TPI1 as a dual modulator of tumor progression and immune remodeling in LUAD, highlighting its potential as both a prognostic biomarker and a therapeutic target.

Keywords:  Immune remodeling; KRAS inhibitor resistance; Lung adenocarcinoma; Pan-cancer analysis; TPI1

DOI:  https://doi.org/10.1016/j.bbrc.2025.153099
Cancer Immunol Immunother. 2025 Dec 23. 75(1): 25

SLC16A3 in lung adenocarcinoma regulates glycolysis and lactate release to facilitate M2 polarization of tumor-associated macrophages : Short Title: SLC16A3 reinforces macrophage M2 polarization through glycolysis.

Peirui Chen, Qiusha Qing, Hongxia Gao, Zheng Qin, Jing Lv.

   BACKGROUND: SLC16A3 is considered to affect the malignant progression of lung adenocarcinoma (LUAD), but its mechanism remains elusive. Lactate secretion can facilitate the M2 polarization of macrophages, which are essential components of the tumor immune microenvironment (TIME).
METHODS: Based on the Cancer Genome Atlas (TCGA) database, differential expression analysis of SLC16A3 in LUAD was undertaken and the Pearson correlation analysis was on SLC16A3 and targets of M2 macrophages. Pathway enrichment analysis on SLC16A3 was achieved by utilizing the gene set enrichment analysis (GSEA). The expression of SLC16A3 in cells was examined by qPCR and Western blot (WB). The levels of glycolysis marker proteins in cells were tested by WB. The Glucose test kit, lactate test kit, Seahorse energy metabolism analyzer, and pHrodo™ Green AM intracellular indicator reagent kit were applied in assessing cellular glycolysis levels. CCK-8, scratch assay, Transwell assay, and flow cytometry were conducted to evaluate the malignant phenotype and apoptosis level of cancer cells. Flow cytometry and Enzyme-linked immunosorbent assay (ELISA) were utilized to assess the polarization of macrophages. Finally, a mouse model of allograft tumors was created, and the effects of SLC16A3 on glycolysis and M2 polarization of macrophages in vivo were evaluated by tracking tumor growth and detecting related protein distribution through Immunohistochemistry.
RESULTS: SLC16A3 was greatly upregulated in LUAD. Knocking down SLC16A3 remarkably repressed the malignant phenotype of LUAD cells and reinforced apoptosis. The results derived from GSEA manifested that SLC16A3 had a higher enrichment in the glycolysis pathway. SLC16A3 positively modulated the extracellular and intracellular levels of lactate and glycolysis. Pearson correlation analysis uncovered a positive linkage between SLC16A3 and M2 macrophage markers. According to the rescue experiment, glycolysis inhibitors were observed to greatly reduce the enhancement in M2 polarization of macrophages caused by overexpression of SLC16A3. The final mouse experiment demonstrated that SLC16A3 boosted tumor growth in vivo and enhanced tumor glycolysis level and M2 macrophage infiltration in the TIME.
CONCLUSION: SLC16A3 in LUAD modulates the glycolysis pathway to facilitate M2 polarization of macrophages.

Keywords:  Glycolysis; Lung adenocarcinoma; M2 macrophages; SLC16A3; Tumor immune suppression

DOI:  https://doi.org/10.1007/s00262-025-04264-0
Front Oncol. 2025 ;15 1552587

CD26 as a potential therapeutic target for lung adenocarcinoma.

Wolfgang Jungraithmayr, Birte Ohm, Martina Haberecker, Alessandra Curioni-Fontecedro, Florian Janker, Ignacio Gil-Bazo, Alex Soltermann, Michaela Kirschner, Walter Weder, Isabelle Opitz, Jae-Hwi Jang.

   Introduction: CD26/dipeptidyl peptidase 4 (CD26, DPP4) is a transmembrane exopeptidase that modulates tumorigenesis in different malignancies. We demonstrated before that CD26 inhibition decreases lung tumor growth in experimental models. Here, we analyzed the prognostic significance of CD26 expression and its correlation with epithelial-to-mesenchymal transition (EMT) markers in a large series of patients with non-small cell lung cancer (NSCLC).
Patients and methods: NSCLC samples from operated patients were analyzed using immunohistochemistry (IHC) for the expression of CD26 and EMT markers. CD26 was scored semi-quantitatively employing tissue microarrays. Lung cancer cell lines [H460, Lewis lung carcinoma (LLC)] were tested for EMT markers, and a colony formation assay was used to test the effect of treatment with the CD26 inhibitor vildagliptin.
Results: Tumor samples from 904 patients with NSCLC were analyzed. CD26 IHC expression was significantly higher in adenocarcinoma compared to squamous cell carcinoma (p < 0.0001). Patients with adenocarcinoma and CD26 expression had a better overall survival than patients without CD26 expression. The lack of CD26 expression was shown to be an independent risk factor for worse survival. CD26-expressing adenocarcinomas showed a higher expression of Vimentin and Elastin (p = 0.0027 and p < 0.0001, respectively), while E-cadherin expression was lower in this group of patients (p = 0.0021). In vitro, treatment with vildagliptin reduced the expression of Vimentin and the capacity for colony formation in H460 and LLC cell lines.
Summary and conclusion: The correlation of CD26 expression in lung adenocarcinomas and better patient survival, the antiproliferative effect on tumor cells by CD26 inhibition, and an altered EMT status give rise to the hypothesis that CD26 inhibitors impact the biology and clinical course of lung adenocarcinomas.

Keywords:  CD26; DPP4; EMT; adenocarcinoma; lung cancer

DOI:  https://doi.org/10.3389/fonc.2025.1552587
J Cancer Res Ther. 2025 Dec 26.

Inhibition of MDM2 by nutlin-3 decreased pyroptosis but increased apoptosis of lung carcinoma cells under 5-FU chemotherapy.

Tingting Hu, Hongyi Cai, Xiaoyu Duan, Yafei Zhuang.

   OBJECTIVES: MDM2 inhibition restores p53 function, and even mutant p53 can induce cancer cell apoptosis. Notably, apoptosis and pyroptosis may interconvert during chemotherapy. This study aimed to explore the role of the MDM2-p53 pathway in the regulation of GSDME-mediated pyroptosis in lung adenocarcinoma.
METHODS: Immunohistochemistry and Western blotting were employed to measure the expression levels of GSDMD, GSDME, cleaved PARP, and MDM2. Nutlin-3, an MDM2 inhibitor, was administered to 5-FU-treated wild-type A549 cells, wild-type HBE cells, GSDME-overexpressing HBE cells, and A549 cells overexpressing p53 codon 72 mutation.
RESULTS: GSDMD and GSDME were expressed in lung adenocarcinoma tissues, adjacent nontumor tissues, and noncancerous lung tissues, whereas only GSDME was expressed in A549 and HBE cells. After chemotherapy, the N-terminal fragment of GSDME was expressed in HBE and A549 cells. GSDME had a significantly lower protein level in HBE cells than in A549 cells ( P = 0.0092). GSDME overexpression markedly increased pyroptosis in A549 ( P = 0.01) and HBE cells ( P = 1.72 × 10 -6 ). Nutlin-3 significantly reduced cell viability and pyroptosis while increasing apoptosis in 5-FU-treated wild-type A549 cells, A549 cells with the p53 codon 72 mutation, and GSDME-overexpressing HBE cells. However, it exerted no significant effects on wild-type HBE cells.
CONCLUSIONS: GSDME-mediated pyroptosis plays a pivotal role in chemotherapy-induced cell death in lung adenocarcinoma. MDM2 inhibition, which switches pyroptosis to apoptosis, can be employed to regulate chemotherapy-induced pyroptosis in lung cancer cells and normal tissue cells.

Keywords:  Adenocarcinoma; GSDME; MDM2; cancer-adjacent tissues; non-small cell lung cancer; pyroptosis

DOI:  https://doi.org/10.4103/jcrt.jcrt_2060_24
J Transl Med. 2025 Dec 22.

CD155 reprograms glycolysis via the YAP/TEAD1-GLUT1 axis to promote lung adenocarcinoma progression and M2 macrophage polarization: a metabolic-immune target visualized by 18F-FDG PET/CT.

Zhiming Cheng, Shu Wang, Shuoyan Xu, Yuxiang Wang, Yao Diao, Bulin Du, Xuena Li, Yaming Li.

   BACKGROUND: CD155, an emerging immune checkpoint, contributes to tumor immune evasion and progression, but its roles in metabolic reprogramming and tumor-associated macrophages (TAMs) polarization in lung adenocarcinoma (LUAD) remain uncharacterized. This study combines molecular biology, metabolic imaging, and clinical data to elucidate CD155's dual role in driving LUAD progression through glycolytic rewiring and immunosuppressive TAMs polarization.
METHODS: Through immunohistochemistry (IHC) and 18F-FDG PET/CT imaging, we analyzed CD155 expression and its association with glycolysis in 80 LUAD patients. Functional assays and molecular studies revealed CD155-mediated regulation of tumor glycolysis and macrophage polarization via YAP/TEAD1-GLUT1 signaling. Xenograft models validated the in vivo findings, with 18F-FDG micro-PET imaging performing noninvasive metabolic profiling.
RESULTS: CD155 was significantly overexpressed in LUAD tissues and positively correlated with advanced TNM stage, lymph node metastasis and elevated 18F-FDG uptake. Mechanistically, CD155 interacts with YAP, reducing YAP phosphorylation at Ser127 to promote its nuclear translocation and TEAD1 activation, thereby upregulating GLUT1 transcription. This signaling axis enhanced glycolysis, thereby fueling LUAD proliferation and migration. Notably, CD155-induced lactate production and extracellular acidification drove macrophage polarization toward the immunosuppressive M2 phenotype. In vivo, CD155 silencing suppressed tumor glucose metabolism and growth, whereas overexpression accelerated tumor progression, both dynamically monitored through 18F-FDG PET visualization.
CONCLUSIONS: We identify a novel CD155/YAP/TEAD1/GLUT1 axis that reprograms LUAD metabolism and facilitates immunosuppressive tumor microenvironment formation. CD155 functions as a metabolic-immune hub in LUAD, and its targeting could simultaneously suppress tumor growth and restore antitumor immunity, offering dual therapeutic advantages. Clinically, 18F-FDG PET/CT represents a noninvasive biomarker for CD155-driven metabolic aggression, potentially guiding precision immunotherapy.

Keywords:  CD155; Glycolysis; Lung adenocarcinoma; Macrophage polarization; TEAD1; YAP

DOI:  https://doi.org/10.1186/s12967-025-07551-7