bims-meluca 2026-03-29 papers

Cells. 2026 Mar 12. pii: 506. [Epub ahead of print]15(6):

Loss of PIK3CA Allows In Vitro Growth but Not In Vivo Progression of KRAS Mutant Lung Adenocarcinoma in a Syngeneic Orthotopic Implantation Model.

Abigail L Booth, Giuseppe Caso, Barbara Rosati, Ya-Ping Jiang, Wei-Xing Zong, Richard Z Lin, Harold Bien.

Constitutively active KRAS mutations are highly prevalent in lung cancers, but the direct role of its downstream phosphatidylinositol 3-kinase (PI3K) pathway in tumor progression remains unclear. A previous study established the requirement for PIK3CA, the alpha catalytic isoform, in lung tumor development in mouse models with an intact Trp53 tumor suppressor. In this study, we further investigated the requirement of PIK3CA for tumor growth both in vitro and in vivo. We first generated a "KPA" cell line by genetically deleting Pik3ca from a murine lung adenocarcinoma "KP" cell line harboring oncogenic KrasG12D and lacking Trp53. We also examined the requirement for STK11, a tumor suppressor and metabolic regulator frequently co-mutated with KRAS in lung cancer. We found that Pik3ca is not required for cell survival and growth in vitro, even under anchorage-independent conditions, but reduced the growth rate by 15%. We next orthotopically implanted KP and KPA cells into syngeneic mice and found that PIK3CA is absolutely required for tumor progression, even in the absence of Trp53. Implantation of KP cells, or a "KPS" cell line lacking the Stk11 gene, led to rapid tumor growth and death of all host animals. In contrast, mice implanted with KPA cells all survived with no detectable lung tumors. The gene expression profiles from cultured cell lines suggest oxidative stress as a potential vulnerability of KPA cells. Indeed, we found KPA cells were more sensitive to hydrogen peroxide and diethyl maleate-induced oxidative stress as compared to KP and KPS cells. Together, these results indicate that PIK3CA is not required for lung cancer cell growth induced by mutant KRAS in vitro but is essential for in vivo progression and growth.

Keywords: KRAS; LUAD; PIK3CA; STK11; lung cancer; orthotopic model

DOI: https://doi.org/10.3390/cells15060506

Cells. 2026 Mar 13. pii: 515. [Epub ahead of print]15(6):

Reliable Radiologic Skeletal Muscle Area Assessment-A Biomarker for Cancer Cachexia Diagnosis.

Sabeen Ahmed, Nathan Parker, Margaret Park, Daniel Jeong, Lauren C Peres, Evan W Davis, Jennifer B Permuth, Erin M Siegel, Matthew B Schabath, Yasin Yilmaz, Ghulam Rasool.

Loss of skeletal muscle mass in cancer cachexia is associated with poorer survival, reduced treatment tolerance, and diminished quality of life. Routine oncology computed tomography (CT) can yield skeletal muscle area (SMA) and skeletal muscle index (SMI) for early cachexia assessment and prognostication, but manual annotation is labor intensive and existing automated tools often show inconsistent reliability. We developed SMAART-AI (Skeletal Muscle Assessment-Automated and Reliable Tool based on AI), a fully automated pipeline that localizes the third lumbar (L3) vertebral level, segments skeletal muscle, and quantifies prediction uncertainty to flag potentially unreliable outputs. Performance and reliability were evaluated across gastroesophageal, pancreatic, colorectal, and ovarian cancer cohorts, benchmarking against expert annotations and existing tools. SMAART-AI achieved a Dice score of 97.80% ± 0.93% in gastroesophageal cancer and a median SMA deviation of 2.48% from expert annotations across pancreatic, colorectal, and ovarian cohorts. Uncertainty scores correlated strongly with prediction error, enabling identification of high-error cases to support trustworthy deployment. Integrating the SMA/SMI with clinical features and body mass index (BMI) improved survival prediction (concordance index was +2.19% for colorectal, +9.82% for pancreatic, and +2.58% for ovarian cancer) and supported cachexia detection (70.00% accuracy; F1 80.00%). Overall, SMAART-AI provides an uncertainty-aware, clinically translatable framework for scalable CT-based muscle assessment and improved oncologic prognostication.

Keywords: artificial intelligence; cancer cachexia; machine learning; radiographic biomarker; reliability; robustness; uncertainty

DOI: https://doi.org/10.3390/cells15060515

Trends Endocrinol Metab. 2026 Mar 26. pii: S1043-2760(26)00041-X. [Epub ahead of print]

Endocrine control of one-carbon metabolism in cachexia.

Yongrui Hai, Xuejing Duan, Gaofei Wei.

Cancer cachexia lacks effective therapies due to an incomplete understanding of its upstream drivers. A recent study by Morigny et al. identifies one-carbon metabolism as a conserved endocrine-metabolic program that links tumor signals to skeletal muscle hypermetabolism and systemic energy imbalance, highlighting methyl-donor pathways as actionable targets for treating cachexia.

Keywords: IL-6; cancer cachexia; glucose hypermetabolism; muscle atrophy; one-carbon metabolism

DOI: https://doi.org/10.1016/j.tem.2026.02.006

Cell Death Dis. 2026 Mar 21.

Lactylation stabilizes PD-L1 to promote tumor immune evasion and cell growth.

Lijun Liang, Yiqi Zong, Jinghao Huang, Yixuan Chen, Nuotong Xu, Pengyu Yan, Hai Song, Ming Wu.

Programmed death-ligand 1 (PD-L1) plays a critical role in tumor immune evasion, yet the mechanisms that regulate its expression, specifically the metabolic control of its stability and function, remain elusive. In this study, we demonstrate that lactate, a key metabolite in the tumor microenvironment, upregulates PD-L1 expression via lysine lactylation (Kla) of PD-L1 at residue K280 within its intracellular domain. This modification stabilizes PD-L1 by inhibiting E3 ligase HUWE1 binding, ubiquitination, and subsequent proteasomal degradation. We identified alanyl-tRNA synthetase 1 (AARS1) as the lactyltransferase that utilizes lactate as a lactyl-donor and is responsible for PD-L1 K280 lactylation. Functionally, PD-L1 lactylation promotes tumor immune evasion by impairing CD8 + T cell-mediated cytotoxicity and accelerates tumor growth in vivo. Furthermore, sodium lactate (NaLa) administration enhances the efficacy of anti-PD-L1 immunotherapy in preclinical models. Clinically, PD-L1 K280 lactylation correlates with advanced non-small cell lung cancer stages and poor patient survival, highlighting its potential as a diagnostic biomarker. Our findings unveil a novel lactate-PD-L1 regulatory axis and propose lactylation as a therapeutic target to augment the efficacy of the immune checkpoint blockade.

DOI: https://doi.org/10.1038/s41419-026-08589-1