bims-meluca 2026-05-31 papers

Int J Mol Sci. 2026 May 15. pii: 4426. [Epub ahead of print]27(10):

Formation of Liver Metastases Is Accompanied by Accelerated Musculoskeletal Deficits in LLC Tumor Hosts.

Paola Ortiz Gonzalez, Anna M Miller, Luis F Cardona Polo, Lilian I Plotkin, Fabrizio Pin, Joshua R Huot.

Lung cancer is a leading cause of death worldwide and is often accompanied by declines in musculoskeletal health (i.e., cachexia). Despite affecting a majority of lung cancer patients, cachexia remains understudied and currently has no cure. We have previously demonstrated that liver metastases (LMs) exacerbate cachexia in murine models of colorectal cancer, and, while the liver represents a common site of metastases and is associated with poor prognosis in patients with lung cancer, whether LMs heighten musculoskeletal wasting in mice bearing lung cancer is unknown. Here, we aimed to characterize the impact of LMs on musculoskeletal health in a mouse model of lung cancer cachexia. C57BL/6J male mice were injected with LLC tumor cells either subcutaneously or intrasplenically (LMs) to mimic hepatic metastases (n = 6-9/group). Upon sacrifice, skeletal muscle, bone, and plasma were collected for morphological and molecular analyses. Consistently, compared to healthy controls, metastatic tumor hosts displayed greater reductions in muscle weights (~17%), in line with decreased muscle torque (~23%) and reduced muscle cross-sectional area (~10%). On a molecular level, skeletal muscle from mice bearing LMs had elevated levels of pStat3, Murf1, and Atrogin-1, suggesting enhanced protein catabolism. Similar to skeletal muscle, metastatic tumor hosts displayed greater losses in trabecular bone and increased skeletal fragility. Plasma proteomics identified 211 and 131 differentially expressed proteins in metastatic hosts compared to control animals and subcutaneous LLC hosts, respectively. Top regulated pathways in mice bearing LMs included neutrophil degranulation, BAG2 signaling, and cachexia signaling. Overall, our findings demonstrate that LMs are accompanied by accelerated musculoskeletal wasting and weakness in a mouse model of lung cancer cachexia. This work highlights the need for animal models that mimic advanced cancer, thus providing a better understanding of the mechanisms that mediate cachexia.

Keywords: bone; cachexia; lung cancer; muscle; musculoskeletal health

DOI: https://doi.org/10.3390/ijms27104426

Curr Oncol. 2026 Apr 22. pii: 241. [Epub ahead of print]33(5):

STK11 as an Emerging Biomarker in Non-Small Cell Lung Cancer.

Amit A Kulkarni, Adam Rock, Matthew Lee, Amanda Reyes, Manish R Patel, Robert A Kratzke, Ravi Salgia.

Immune checkpoint inhibitors (ICIs) have transformed non-small cell lung cancer (NSCLC) treatment; however, durable responses occur in only a subset of patients, underscoring the need for robust predictive biomarkers. Serine/threonine kinase 11 (STK11) is an emerging biomarker that portends poor prognosis and predicts therapeutic resistance. Loss of STK11 disrupts AMPK signaling, leading to unchecked mTOR activation, metabolic reprogramming, angiogenesis, and epithelial-mesenchymal transition, fostering tumor progression and immune evasion. STK11 mutations frequently co-occur with KRAS and KEAP1 alterations, exhibit low PD-L1 expression, an immunosuppressive tumor microenvironment that leads to the development of PD-1/PD-L1 resistance. Clinical studies consistently demonstrate inferior outcomes with ICIs in STK11-mutant NSCLC, particularly in the presence of KRAS and KEAP1 co-mutations. Dual checkpoint inhibition combining PD-1/PD-L1 and CTLA-4 blockade shows promise in overcoming resistance, results remain inconsistent, and prospective trials are ongoing. Beyond immunotherapy, STK11 mutations confer poor outcomes across targeted therapies, including KRAS G12C inhibitors, with KEAP1 co-mutation serving as a strong negative predictor of efficacy. In this review we present an overview of STK11 function and its role in tumor biology, highlight the prognostic and predictive potential of STK11 mutations in the context of NSCLC treatment and summarize the emerging treatment strategies.

Keywords: KEAP1; KRAS; LKB1; NSCLC; PD-L1; STK11; immune checkpoint inhibitors; immunotherapy resistance; metabolic reprogramming; targeted therapy

DOI: https://doi.org/10.3390/curroncol33050241

Sci Rep. 2026 May 25.

Expression of LIFR in tumor and SHOC2, YAP1 in plasma mRNA as potential biomarkers in KRAS G12C NSCLC.

Ana Giménez-Capitán, Daniel Olmo-Gónzalez, Elizabeth Martínez-Pérez, Andrés Aguilar-Hernández, María González-Cao, Roxana Reyes, Irene Moya, Víctor Albarrán, Ivana Sullivan, Joselyn Valarezo, Beatriz García, Ruth Román, Clara Mayo De Las Casas, Miguel Ángel Molina-Vila, Rafael Rosell.

Advanced non-small cell lung cancer (NSCLC) harboring KRAS G12C mutations can be treated with selective inhibitors, however progression-free survival remains limited. Resistance has been associated with co-mutations in TP53, STK11, and KEAP1, persistent plasma KRAS G12C, and activation of the MRAS-SHOC2-PP1C pathway with downstream YAP1 signaling. We evaluated the expression of MRAS-SHOC2-PP1C and YAP1-related genes in KRAS G12C mutant NSCLC. Messenger RNA levels of twenty genes were quantified using nCounter in tumor samples from 98 NSCLC patients, including KRAS G12C (n=23), KRAS non-G12C (n=24), and KRAS wild-type (n=51) cases. Longitudinal plasma samples from ten KRAS G12C patients treated with selective inhibitors were analyzed at baseline, day 3, week 6, and week 12. Eight genes (NFE2L2, NRAS, KRAS, ENO1, SHOC2, VCP1, LIFR, and MRAS) were differentially expressed in KRAS G12C compared with KRAS wild-type tumors (p<0.05). LIFR, KRAS, and MET were differentially expressed in KRAS non-G12C tumors. Among 30 KRAS-mutant patients, high LIFR expression was associated with improved survival. In plasma, twelve genes were consistently detected, and SHOC2, YAP1, LZTR1, RGS3, and ZDHHC7 were significantly upregulated at week 6. Low tumor LIFR expression was associated with poorer survival, supporting its potential as a prognostic biomarker and highlighting the feasibility of plasma-based gene expression monitoring.

Keywords: KRAS G12C inhibitors; LIFR; acquired resistance mechanisms; circulating plasma biomarkers; gene expression profiling; non-small cell lung cancer (NSCLC)

DOI: https://doi.org/10.1038/s41598-026-48898-1

Nutrients. 2026 May 18. pii: 1596. [Epub ahead of print]18(10):

Glutamine Starvation Induces Ferroptosis in NSCLC via AMPK/PDZD8-Mediated Ferritinophagy.

Hong Chen, Xiaoying Wu, Manting Zhu, Ying Cheng, Qing Feng.

Objectives: The dependence of non-small cell lung cancer (NSCLC) on glutamine has made targeting glutamine metabolism an attractive therapeutic approach. Dietary interventions are increasingly considered as adjuvant cancer therapies. This study aims to explore the relationship between glutamine starvation and ferroptosis in NSCLC and to elucidate the underlying molecular mechanisms. Methods: The effects of glutamine starvation were evaluated both in A549 and H460 NSCLC cell lines and in vivo using xenograft models in SCID mice. Assessments included cell viability, migration, clonogenic capacity, and the expression of key proteins. To gain mechanistic insight, AMPK was either overexpressed or inhibited, and key markers of ferritinophagy (including ULK1, BECN1, NCOA4, and LC3-II/I) and ferroptosis (such as ACSL4, GPX4, and xCT) were analyzed. Results: Glutamine starvation markedly suppressed tumor growth in both in vitro and in vivo settings, while also reducing cell migration and clonogenicity in cultured cells. This intervention activated AMPK, as indicated by increases in both total and phosphorylated forms, and upregulated PDZD8 expression. Mechanistically, AMPK activation played a critical role in driving ferritinophagy and ferroptosis-manipulation of AMPK consistently altered key markers of these processes. Furthermore, AMPK levels influenced PDZD8 protein expression. Notably, overexpressing PDZD8 alone was sufficient in promoting both ferritinophagy and ferroptosis, indicating that PDZD8 acts as a critical downstream mediator of AMPK in this pathway. Conclusions: Our findings reveal that glutamine starvation triggers ferroptosis in NSCLC via activation of ferritinophagy, mediated by the AMPK/PDZD8 signaling pathway. These results support the potential of dietary glutamine restriction as a novel therapeutic approach for NSCLC.

Keywords: AMPK; NSCLC; PDZD8; ferritinophagy; ferroptosis; glutamine starvation

DOI: https://doi.org/10.3390/nu18101596

Cells. 2026 May 13. pii: 891. [Epub ahead of print]15(10):

Myeloid Cell Leukemia 1 and Hexokinase 2 Directly Interact to Form a Glucose Metabolic Regulatory Axis.

Robert Lee, Alexus Acton, Madeline Holliday, Nicholas J Lennemann, William J Placzek.

Hexokinase 2 (HK2) catalyzes the first committed step of glucose metabolism-the conversion of glucose to glucose-6-phosphate-directing carbon flux into an array of metabolic pathways such as glycolysis, pentose phosphate pathways, amino acid biosynthesis, and others. Given its prominent role in glucose metabolism, it is critical we understand the regulation of HK2 to appreciate its role in normal physiological function as well as in disease states like cancers. In this study we sought to establish the ability of myeloid cell leukemia 1 (MCL1) to bind and regulate HK2 via its reverse Bcl-2 homology (rBH3) motifs. We employed a combination of biochemical and metabolic analysis in non-small cell lung cancer (NSCLC) cell models (H1299, A549, and NCI-H23) to establish a fundamental link between apoptosis and metabolic regulation. This demonstrates that MCL1 directly binds and enhances HK2 enzymatic activity through interactions with rBH3 on HK2. Consequently, we observe significant reductions in glucose-derived metabolites and impaired cellular metabolic plasticity with the disruption of the HK2-MCL1 interaction. These findings establish a novel mechanism by which anti-apoptotic proteins can directly regulate glucose metabolism.

Keywords: MCL1; NMR; cancer; hexokinase 2 (HK2); metabolism; metabolomics; non-small cell lung cancer (NSCLC)

DOI: https://doi.org/10.3390/cells15100891