bims-meluca 2026-10-04 papers

Cancer Discov. 2026 Oct 01. 16(10): 1964-1966

Activity over Abundance: ADAMTSL4 Unlocks Latent TGFβ1 in Cancer Cachexia.

Cancer cachexia is increasingly recognized as a coordinated, tumor-induced, unsustainable alteration in interorgan communication. Machado and colleagues identify a new molecular mechanism that promotes cachexia, in which tumor-secreted ADAMTSL4 drives tissue wasting by promoting local activation of latent TGFβ1, revealing post-secretory control of ligand activation as a potential therapeutic vulnerability in cancer cachexia. See related article by Machado et al., p. 2172.

DOI: https://doi.org/10.1158/2159-8290.CD-26-1661

bioRxiv. 2026 Sep 24. pii: 2026.09.23.752387. [Epub ahead of print]

Metabolic-epigenetic coupling between leucine catabolism and glycolysis drives CDK4/6 inhibitor resistance.

Michael Uj Oliphant, Klarisa Norton, Kiran Kurmi, Howard Yang, Shakchhi Joshi, Jonah Lee, Nina Kozlova, Taru Muranen, John G Clohessy, Marcia Haigis, Senthil K Muthuswamy.

Resistance to CDK4/6 inhibitors limits the durability of therapy for ER+ breast cancer. Despite the identification of mechanisms that regulate resistance, the metabolic adaptations that enable therapeutic escape remain poorly understood. Here, we identify a metabolic-epigenetic circuit that drives resistance by coordinately rewiring amino acid and glucose metabolism. CDK4/6 inhibitor-resistant ER+ tumor cells upregulate the leucine transporter SLC7A5, enhancing leucine uptake. SLC7A5 overexpression is sufficient to confer palbociclib resistance across ER+ cell lines, patient-derived organoids and xenografts. Stable isotope tracing in cell lines and in xenograft tumors revealed that leucine is catabolized through BCAT2 and HMGCL to increase acetyl-CoA levels, and elevated acetyl-CoA promotes H3K27 acetylation at the GLUT1 promoter, upregulating GLUT1 expression and glycolytic activity. Disrupting leucine transport, catabolism, or availability suppresses GLUT1 expression and restores therapeutic sensitivity in resistant models. In patients receiving palbociclib-based therapy, high SLC7A5 expression and coordinated SLC7A5-GLUT1 co-expression are associated with shorter progression-free survival. Together, these findings define a metabolic- epigenetic mechanism linking branched-chain amino acid catabolism to glycolysis and identify a biomarker-associated metabolic vulnerability in advanced ER+ breast cancer.
Statement of Significance: Resistance to CDK4/6 inhibitors is nearly universal in ER+ breast cancer. We identify a metabolic- epigenetic circuit in which acetyl-coA derived from leucine catabolism promotes epigenetic changes at the GLUT1 promoter, thereby increasing glucose uptake and driving glycolysis. Disrupting leucine transport, catabolism, or availability suppresses this program and restores drug sensitivity, identifying crosstalk between amino acid metabolism and glycolysis in regulating drug resistance. High expression of the leucine transporter, SLC7A5, is associated with shorter progression-free survival, revealing a biomarker-associated metabolic vulnerability.

DOI: https://doi.org/10.64898/2026.09.23.752387

Cell Mol Gastroenterol Hepatol. 2026 Sep 28. pii: S2352-345X(26)00178-5. [Epub ahead of print] 101900

Ferroptosis regulates metabolic inflammation-driven tumorigenesis in obesity-related gastric cancer.

Mizuki Tanabe, Kaname Uno, Toru Tamahara, Naoki Asano, Seizo Koshiba, Keisuke Kusano, Koya Ogasawara, Yumiko Kaise, Masahiro Saito, Tomoyuki Koike, Ritsuko Shimizu, Atsushi Masamune.

BACKGROUND AND AIMS: The incidence of gastric cardia adenocarcinoma (GCA) has increased with increasing prevalence of metabolic syndrome (MetS). Peroxisome proliferator-activated receptor-delta (PPAR-δ) emerged as a key target in MetS and carcinogenesis. We aimed to elucidate its role in GCA progression.
METHODS: Male K19-Wnt1/C2mE mice were fed a control or high-fat diet (HFD) with or without the PPAR-δ agonist GW-501516 or the PPAR-δ antagonist GSK-3787 (GSK). The involvement of nuclear factor erythroid 2-related factor 2 (Nrf2) in the PPAR-δ-regulated, metabolism-driven tumorigenesis was examined by comparing wild-type and Nrf2-deficient conditions.
RESULTS: In HFD+GSK-treated K19-Wnt1/C2mE mice with metabolic endotoxemia, granular-nodular tumors at the squamocolumnar junction (SCJ) were greater than those in the other groups. Intratumor expression of the NAD(P)H quinone dehydrogenase 1 (NQO1) and glutathione peroxidase 4 (GPx4) proteins increased and the plasma levels of dysbiosis-related metabolites for tumor energy metabolism increased. In HFD+GSK-treated Nrf2-deficient mice, tumors shrank with decreases in NQO1 and GPx4 proteins expression and increases in the malondialdehyde level and GSSG/GSH ratio, and the plasma levels of metabolites for energy metabolism and ferroptosis resistance decreased. Suppression of PPAR-δ signaling in AGS cells treated with GSK or a small interfering RNA (siRNA) inhibited ferroptosis by increasing solute carrier family 7 member 11 (SLC7A11) expression and activating NRF2 signaling. Transfection with NRF2 siRNA decreased the GSK-induced upregulation of SLC7A11, and NRF2 directly regulates SLC7A11 transcription by binding to its promoter.
CONCLUSIONS: Cotreatment with HFD and GSK may promote SCJ tumor progression by suppressing ferroptosis through intratumoral NRF2 signaling and dysbiosis-related metabolites, indicating a negative role of PPAR-δ signaling on MetS-related SCJ tumorigenesis.

Keywords: ferroptosis; gastric cardia adenocarcinoma; metabolic syndrome; nuclear factor erythroid 2-related factor 2; peroxisome proliferator-activated receptor delta

DOI: https://doi.org/10.1016/j.jcmgh.2026.101900

Front Oncol. 2026 ;16 1900448

SIRT2 is associated with prognosis, ferroptosis susceptibility, and immune infiltration in lung adenocarcinoma.

Wei Zhang, Li-Sha Ren, Huan Bai, Ying-Ying Mu, Yue Qian, Hongyu Chen.

Objective: Lung adenocarcinoma (LUAD) is a highly aggressive malignancy originating from the bronchial epithelium or glandular tissues and represents the most rapidly increasing subtype of lung cancer worldwide. Its high incidence and mortality rates contribute to an overall unfavorable prognosis. Therapeutic options for patients with advanced-stage LUAD remain limited, emphasizing the urgent importance of identifying reliable prognostic biomarkers and novel therapeutic targets. Silent information regulator 2 (SIRT2), a member of the mammalian sirtuin family, has been implicated in multiple cancer types; however, its functional relevance in LUAD has not yet been comprehensively defined.
Methods: Data from TCGA and GEO were employed to evaluate SIRT2 expression patterns in LUAD. Functional enrichment approaches were applied to infer the biological pathways potentially regulated by SIRT2. Molecular docking and Gene Set Cancer Analysis (GSCA) were used to examine how SIRT2 expression and drug sensitivity are related, and to identify potential small-molecule interactors. Key candidate targets and compounds were subsequently subjected to in silico docking validation. The bioinformatic predictions were further verified through in vitro functional assays and Western blotting using A549 LUAD cells.
Results: SIRT2 expression was markedly downregulated in LUAD tissues, and low SIRT2 levels were closely associated with adverse clinical prognostic features, including pathological stage, gender and primary treatment response. Reduced SIRT2 expression correlated with poorer overall, progression-free, and disease-specific survival. Functional enrichment indicated that SIRT2 is involved in multiple core signaling pathways implicated in LUAD progression. Furthermore, SIRT2 expression was strongly associated with ferroptosis-related pathways and estimated immune cell infiltration. Experimental validation in A549 LUAD cells revealed that SIRT2 is linked to suppressed malignant cellular phenotypes and reduced expression of the ferroptosis suppressor GPX4.
Conclusions: Collectively, these findings support SIRT2 as a potential prognostic biomarker for LUAD. The molecular networks and pathways uncovered here advance our understanding of SIRT2 biology and lay a foundation for further research. Additional studies focusing on immune-related signatures correlated with SIRT2 may facilitate the development of novel immunotherapeutic approaches for LUAD.

Keywords: SIRT2; biomarkers; ferroptosis; lung adenocarcinoma; prognosis; tumor-immune infiltration

DOI: https://doi.org/10.3389/fonc.2026.1900448