bims-meluca 2025-12-21 papers

Support Care Cancer. 2025 Dec 19. 34(1): 46

Does pre-checkpoint inhibitor sarcopenia, visceral, or subcutaneous fat predict survival in non-small cell lung cancer patients?

Julia Kooser, Mellar Davis, Tian Guo, Erin Vanenkevort, Amanda Young, Nicole Koppenhaver, Braxton Lagerman, Mudit Gupta, Aalpen Patel, Mark Wojtowicz.

BACKGROUND: Sarcopenia and altered body composition have been associated with poor outcomes in cancer patients. We investigated whether skeletal muscle index (SMI), visceral fat area (VFA), and subcutaneous fat area (SFA) measured on CT scans predict survival in non-small cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitor therapy.
METHODS: This retrospective pilot study analyzed 46 NSCLC patients who had CT scans within 60 days of initiating checkpoint inhibitor therapy (93.5% pembrolizumab, 6.5% nivolumab) at a single tertiary care center. Body composition metrics were measured at the L3 vertebral level using TeraRecon software by a trained reader. Sarcopenia was defined using validated cutoffs (males < 45.4 cm2/m2, females < 34.4 cm2/m2). Cox proportional hazards models evaluated associations between body composition and survival, with analyses stratified by sex.
RESULTS: The cohort included 25 males (54.3%) and 21 females (45.7%), with median time from CT scan to checkpoint inhibitor initiation of 14 days (IQR: -47 to 18). One-year survival was 72.0% for males and 59.3% for females; two-year survival was 33.7% and 27.3%, respectively. Those who met the clinical criteria for sarcopenia did not statistically differ in survival compared to those who did not meet the clinical cut off (HR 1.21 (95% CI 0.63, 2.43). This finding remained consistent when males and females were examined separately and when the model was adjusted for timing to checkpoint inhibitor.
CONCLUSION: In this small pilot study, pre-treatment body composition metrics did not significantly predict survival in NSCLC patients receiving checkpoint inhibitors. However, the study was likely underpowered with wide confidence intervals, limiting definitive conclusions. These findings provide a methodological framework for larger multicenter studies to validate the prognostic utility of CT-derived body composition in this population.

Keywords: Body composition; Immune checkpoint inhibitor; Non-small cell lung cancer; Pembrolizumab; Sarcopenia; Skeletal muscle index; Subcutaneous fat; Visceral fat

DOI: https://doi.org/10.1007/s00520-025-10243-z

Clin Transl Med. 2025 Dec;15(12): e70554

Exosomal miR-3126-5p derived from cancer-associated fibroblasts facilitates glycolysis to accelerate NSCLC progression by targeting KLF13 to activate the SH2B1/IRS1 axis.

Zhenyu Zhang, Haicheng Ma, Yingying Zheng, Lina Wang, Chenghui Wang, Yuanyuan Liu, Hengxiao Lu, Shaoqiang Wang.

BACKGROUND: As a critical component of the tumour microenvironment, cancer-associated fibroblasts (CAFs) actively drive the malignant advancement of non-small-cell lung cancer (NSCLC); however, their underlying mechanisms continue to be poorly characterized. This work examined the role of CAFs-derived exosomal miR-3126-5p in the glycolysis of NSCLC cells.
METHODS: Glycolysis was evaluated by lactate production, glucose uptake, oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Cell proliferation and cycle were evaluated by CCK-8, EdU staining, and flow cytometry. Src homology 2B adaptor protein 1 (SH2B1) and insulin receptor substrate 1 (IRS1) protein interaction was tested by Co-IP and GST pull-down assay. ChIP, dual-luciferase reporter assay, and EMSA determined the binding of kruppel-like factor 13 (KLF13) to the SH2B1 promoter. Dual-luciferase reporter assay was applied to assess miR-3126-5p binding to KLF13 3'-UTR. In vivo growth of NSCLC was determined in the mouse xenograft and Lewis lung carcinoma models.
RESULTS: CAFs-derived exosomal miR-3126-5p was highly expressed in NSCLC tissues, and its elevated plasma level was significantly associated with poor prognosis of NSCLC patients. CAFs-derived exosomal miR-3126-5p facilitated glycolysis to accelerate the malignant progression of NSCLC cells. KLF13 exhibited reduced expression in NSCLC, while its overexpression suppressed NSCLC growth via repressing glycolysis. Exosomal miR-3126-5p targeted KLF13 3'-UTR to inhibit its expression in NSCLC cells. KLF13 transcriptionally inhibited SH2B1 expression to abolish the interaction between SH2B1 and IRS1 proteins, thus repressing PI3K/AKT pathway-mediated glycolysis. KLF13 knockdown counteracted the anti-cancer action of exosomal miR-3126-5p inhibition.
CONCLUSION: CAFs-derived exosomal miR-3126-5p accelerated NSCLC progression via inhibiting KLF13 expression, which transcriptionally activated SH2B1 to promote its interaction with IRS1, thereby promoting PI3K/AKT pathway-mediated glycolysis. Our findings position CAFs-secreted exosomal miR-3126-5p as a novel therapeutic intervention with potential in NSCLC management.
HIGHLIGHTS: CAFs-derived exosomal miR-3126-5p enhanced glycolysis of NSCLC cells via targeting KLF13. KLF13 led to transcriptional inhibition of SH2B1 in NSCLC cells. SH2B1 interplayed with IRS1 to facilitate glycolysis of NSCLC cells. IRS1 promoted glycolysis of NSCLC cells via the activation of PI3K/AKT pathway.

Keywords: KLF13; SH2B1; cancer‐associated fibroblasts; exosomal miR‐3126‐5p; glycolysis; non‐small‐cell lung cancer

DOI: https://doi.org/10.1002/ctm2.70554

Discov Oncol. 2025 Dec 13.

Endoplasmic reticulum stress-related genes play a role in the prognosis of lung adenocarcinoma.

Mingming Tang, Shi Zhang, Xingni Zhou, Zhigang Cai.

BACKGROUND: Lung adenocarcinoma (LUAD) has a high mortality rate. The signaling of endoplasmic reticulum (ER) stress sensor can regulate cancer progression. We aimed to investigate the relationship between ER stress-related genes and LUAD prognosis.
METHODS: Gene expression and clinical data of LUAD patients were downloaded from The Cancer Genome Atlas (TCGA) database. GSE68465 from Gene Expression Omnibus (GEO) was used for validation analysis. Two ER stress-related datasets were downloaded from MSigDB. ER stress-related genes which significantly correlated with the prognosis of LUAD were selected to construct ER score model. Patients were divided into two groups based on the median value of ER sore. The prognosis of patients in different groups was compared. Unsupervised hierarchical clustering analysis was used to identify different LUAD subtypes. Features with significantly correlation of prognosis were used to construct a nomogram. The expression of key ER stress-related genes in LUAD cells was experimentally validated.
RESULTS: Seven genes (EIF2AK3, IGFBP1, SHC1, GSK3A, EIF4G1, MBTPS2, and PSMC6) significantly associated with prognosis were used to construct the ER score model. The patients in the high ER score group had worse prognosis in both TCGA and GEO datasets. Patients with higher ER scores tended to have higher pathologic_T, pathologic_N, pathologic_M, and stage. There was a significant difference in prognosis between the two subtypes identified according to the model gene (p < 0.05). The nomogram constructed with stage, ER score and cluster showed a great performance for predicting prognosis. Experimental validation confirmed the downregulation of EIF2AK3 and the upregulation of IGFBP1, SHC1, GSK3A, EIF4G1, MBTPS2, and PSMC6 in LUAD cells.
CONCLUSION: The nomogram constructed by ER score and clinical features showed good predictive performance on LUAD. This study provided new insights into understanding the role of ER stress in LUAD.

Keywords: Endoplasmic reticulum stress; Immune; Lung adenocarcinoma; Nomogram; Prognosis

DOI: https://doi.org/10.1007/s12672-025-04240-1

Cell Death Discov. 2025 Dec 13.

NDR2 regulates non-small cell lung cancer cell migration under starvation by supporting autophagosome biogenesis through LC3 and ATG9A regulation.

Tiphaine Biojout, Emmanuel Bergot, Jasmine Taylor, Dimitri Leite Ferreira, Nathalie Colloc'h, Marc Riffet, Nicolas Elie, Maelle Guyot, Céline Bazille, Jérôme Levallet, Guénaëlle Levallet.

Non-small cell lung cancer (NSCLC) is characterized by the deregulation of the Hippo kinase NDR2 and high basal autophagic activity. NDR2 promotes autophagy-driven tumor growth in some cancers, but evidence in lung cancer is lacking. Human bronchial epithelial tumor cell (HBEC) lines H2030, H2030-BrM3, and H1299, with or without NDR2 depletion via siRNA or shRNA, were cultured for up to 24 h in the presence or absence of serum, and with or without the autophagosome-lysosome fusion inhibitor chloroquine (CQ). Autophagosome biogenesis, migration and Golgi apparatus functionality were analyzed. Serum deprivation of HBECs silences the expression of NDR1 but not NDR2. As shown by the increased expression of the autophagosome marker LC3-II, NDR2 participates to the formation and distribution of phagophores/autophagosomes in HBECs in an ATG9A-dependent manner. NDR2 is required for cargos degradation since its depletion disrupts lysosomal trafficking and/or fusion with autophagosomes. Finally, NDR2 silencing inhibits filopodia formation and cell polarization during HBEC migration under serum deprivation by disrupting Golgi repositioning to the leading edge, a process essential for cell migration. These data highlight NDR2's role in Golgi- and autophagy-regulated migration during starvation. Unlike NDR1, NDR2 is stabilized under starvation and promotes autophagy by regulating LC3 and ATG9A, thereby supporting NSCLC cell proliferation and migration. Routine staining for NDR2 and/or ATG9 could aid in diagnosing NSCLC with high migratory potential.

DOI: https://doi.org/10.1038/s41420-025-02889-9