bims-medica 2026-08-09 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2026–08–09
eighteen papers selected by
Brett Chrest, Wake Forest University

Illuminating spatial dynamics of glutamine metabolism with a sensitive genetically encoded biosensor.
Microenvironmental arginine restriction sensitizes pancreatic cancers to polyunsaturated fatty acids by suppression of lipid synthesis.
Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.
Intensive multimodal ketogenic metabolic therapy in glioblastoma: A clinical trial.
Mannose supports lung cancer metabolism during glycolytic limitation.
Profiling of Yeast Saccharomyces cerevisiae Mitochondrial AMPylome Reveals a Regulation of OXPHOS Coupling through ATP Synthase Subunit Delta.
Quantitative In Vivo Imaging of ATP Dynamics in Drosophila Using the Ratiometric Biosensor QUEEN.
A covalent PFKL activator suppresses tumor growth.
Triglyceride Storage is Upregulated in Different Mouse Non-Melanoma Skin Cancer Cell Lines.
Targeting a novel metabolic vulnerability of non-small cell lung cancer to fatty acid oxidation surmounts chemoresistance.
Pre-cancerous blood cells prematurely age the bone marrow to fuel cancer risk.
Cancer prevalence in primary mitochondrial disease patients and their families.
A tumour-derived organoid biobank maps cancer gene dependencies.
Hyperpolarized [2-13C]Pyruvate Identifies a Mitochondria-Active Hepatocellular Carcinoma Phenotype With Vulnerability to Mitochondrial Inhibition.
Lysosomal metabolism in pancreatic cancer and its crosstalk with host physiology.
Palmitate promotes liver metastases by decreasing neutrophil antitumour behaviour.
Stromal cell senescence augments haematopoietic cell fitness in clonal haematopoiesis.
Proton motive force as a driver of persister sensitization by adenosine.

RSC Chem Biol. 2026 Jul 13.

Illuminating spatial dynamics of glutamine metabolism with a sensitive genetically encoded biosensor.

Jack M Scully, Michael J Sun, Siddharth Das, Nataly J Arias, Edmund D Kapelczak, Tiffany D Robinson, Katie G Vineall, Teagan S Dean, Tara TeSlaa, Ajit S Divakaruni, Danielle L Schmitt.

Glutamine is the most abundant amino acid in serum, used as a key nutrient by cells for protein synthesis, energy production, carbon and nitrogen metabolism, and cellular redox balance. The use of glutamine in the cell is highly compartmentalized, but the dynamics of glutamine metabolism across organelles and individual cells are not fully understood. To illuminate subcellular glutamine dynamics, we developed a green fluorescent protein-based intracellular glutamine optical reporter, iGlo. We find iGlo is sensitive and specific for glutamine and can be used to measure glutamine uptake, production, and consumption with high spatiotemporal resolution in multiple cell types. Furthermore, multiplexed imaging of iGlo with a lactate biosensor in single cells reveals the temporal crosstalk between glucose and glutamine metabolism to maintain energy homeostasis. Thus, iGlo enables the sensitive and precise study of compartmentalized glutamine dynamics and represents a new and enhanced tool for studying the spatiotemporal dynamics and regulation of metabolism.

DOI: https://doi.org/10.1039/d6cb00164e
Elife. 2026 Aug 05. pii: RP106492. [Epub ahead of print]14

Microenvironmental arginine restriction sensitizes pancreatic cancers to polyunsaturated fatty acids by suppression of lipid synthesis.

Patrick B Jonker, Mumina Sadullozoda, Guillaume Cognet, Juan J Apiz Saab, Kelly H Sokol, Violet X Wu, Deepa Kumari, Colin Sheehan, Mete E Ozgurses, Darby Agovino, Grace Croley, Lindsey N Dzierozynski, Chufan Cai, Leah M Ziolkowski, Smit A Patel, Althea Bock-Hughes, Kay F Macleod, Hardik Shah, Jonathan L Coloff, Evan C Lien, Alexander Muir.

  Nutrient limitation is a characteristic feature of poorly perfused tumors. In contrast to well-perfused tissues, nutrient deficits in tumors impose metabolic constraints on cancer cells. The metabolic constraints created by the tumor microenvironment can lead to vulnerabilities in cancers. Identifying the metabolic constraints of the tumor microenvironment and the vulnerabilities that arise in cancers can provide new insight into tumor biology and identify promising anti-neoplastic targets. To identify how the microenvironment constrains the metabolism of pancreatic tumors, we challenged pancreatic cancer cells with microenvironmental nutrient levels and analyzed changes in cellular metabolism. We found that arginine limitation in pancreatic tumors perturbs saturated and monounsaturated fatty acid synthesis by suppressing the lipogenic transcription factor SREBP1, in part via activation of the amino acid sensor GCN2. Synthesis of these fatty acids is critical for maintaining a balance of saturated, monounsaturated, and polyunsaturated fatty acids (PUFAs) in cellular membranes. Because of microenvironmental constraints on fatty acid synthesis, pancreatic cancer cells and tumors are unable to maintain lipid homeostasis when exposed to PUFAs, leading to cell death by ferroptosis. In sum, arginine restriction in the tumor microenvironment constrains lipid metabolism in pancreatic cancers, which renders these tumors vulnerable to polyunsaturated-enriched fats.

Keywords:  biochemistry; cancer; cancer biology; chemical biology; diet; human; metabolism; mouse; stress; synthetic lethality; tumor microenvironment

DOI:  https://doi.org/10.7554/eLife.106492
Cell Metab. 2026 Aug 05. pii: S1550-4131(26)00324-4. [Epub ahead of print]

Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.

Ang Jia, Xiaowen Zhang, Ji-Hao Zhou, Yongcan Ma, Jing Wang, Yongbo Gong, Wenjie Song, Hangcheng Hu, Yufei Yu, Haixia Yang, Youli Lu, Linzhang Huang, Xingrong Du, Chunmei Chang, Shanshan Pei, Peng Li, Craig T Jordan, Tong-Jin Zhao, Haobin Ye.

DOI: https://doi.org/10.1016/j.cmet.2026.07.026
Neurooncol Adv. 2026 Jan-Dec;8(1):8(1): vdag165

Intensive multimodal ketogenic metabolic therapy in glioblastoma: A clinical trial.

Matthew C L Phillips, Ziad Thotathil, Nur Azri Bin Haji Mohd Yasin, Charles de Groot, Alvin Tan, Marion Kuper-Hommel, Lee-Ann Creagh, Eric Ji, Nichola Naidoo, Mariska van Essen, Fouzia Ziad, Ben G Moon, Chris Frampton, Michael B Jameson.

   Background: Glioblastoma (GBM), isocitrate dehydrogenase (IDH)-wildtype, has a median overall survival of 11-14 months despite standard treatment. Ketogenic metabolic interventions that lower the glucose ketone index (GKI) may improve outcomes. We evaluated the feasibility, tolerability, and potential clinical benefit of integrating standard treatment with an intensive multimodal metabolic therapy program (MTP) in newly diagnosed IDH-wildtype GBM.
Methods: Patients received standard chemoradiation and adjuvant chemotherapy alongside an MTP comprising prolonged fasting, time-restricted feeding, and a ketogenic diet. The primary outcome was the proportion sustaining a mean daily GKI ≤6 during chemoradiation. Secondary outcomes included GKI control throughout chemotherapy, body weight, body mass index, adverse events, performance, exercise, quality of life, and survival, compared with contemporary controls using unadjusted hazard ratios (HRs) and 95% confidence intervals (CIs).
Results: Among 32 eligible patients, 18 commenced chemoradiation with the MTP (intention-to-treat), and 15 completed it (per-protocol). In the intention-to-treat population, 15 of 18 patients (83%) sustained a mean daily GKI ≤6 during chemoradiation. Among per-protocol patients, the GKI was 1.88 ± 0.56 during chemoradiation and 2.53 ± 0.86 throughout chemotherapy. Intentional weight loss averaged 17%, normalizing body mass index. MTP-related adverse events were mild or moderate. Exercise activity and quality of life improved. Median overall survival was 21.5 months versus 14.7 months in controls (HR = 0.42, 95% CI 0.18-0.97, P = .027), with 3-year survival of 27% versus 7%.
Conclusions: Intensive multimodal metabolic therapy was feasible, well-tolerated, and associated with improved exercise activity, quality of life, and survival outcomes, including higher 3-year survival.

Keywords:  fasting; glioblastoma; glucose ketone index; ketogenic diet; metabolic therapy

DOI:  https://doi.org/10.1093/noajnl/vdag165
EMBO Rep. 2026 Aug 07.

Mannose supports lung cancer metabolism during glycolytic limitation.

Theresa Haitzmann, Niklas B Thompson, Hardik Shah, Katharina Schindlmaier, Joseph Jelwan, Thomas O Eichmann, Nia G Hammond, Maia G Clare, Robert B Cameron, Brandon Faubert, Katharina Leithner.

Cancer cells frequently show elevated glucose consumption to support proliferation and survival. This led to the assumption that glycolytic inhibitors could be effective in cancer treatment. However, barriers to clinical implementation remain. Adaptive strategies, such as metabolizing alternative nutrients, may play a role. Here, we investigated the use of an understudied sugar, mannose, in lung cancer cells and xenografts. Stable isotope tracing reveals enhanced contribution of mannose to GDP-mannose and GDP-fucose, key glycosylation precursors, upon treatment with the glycolytic inhibitor 2-deoxyglucose (2-DG) or glucose starvation in vitro. Mannose restores the glucose-withdrawal-induced decrease of GDP-mannose and GDP-fucose pools, and partially rescues proliferation upon 2-DG treatment or glucose deprivation. 13C6-mannose infusion in patient-derived xenograft mice reveals a considerable contribution of mannose to GDP-mannose and GDP-fucose in tumors, which is further enhanced by 2-DG. In normal lungs, the pathway is only partially active. Mannose is also shuttled towards glycolysis in lung tumors in vivo and glucose-deprived cells in vitro. In conclusion, mannose utilization for glycosylation precursor synthesis represents an adaptive strategy in lung cancer cells under metabolic stress.

DOI: https://doi.org/10.1038/s44319-026-00874-6
J Proteome Res. 2026 Aug 07. 25(8): 3965-3986

Profiling of Yeast Saccharomyces cerevisiae Mitochondrial AMPylome Reveals a Regulation of OXPHOS Coupling through ATP Synthase Subunit Delta.

Chiranjit Panja, Aneta Wiesyk, Suchismita Masanta, Katarzyna Niedzwiecka, Emilia Baranowska, Dominik Cysewski, Marta Sipko, Anna Anielska-Mazur, Agata Malinowska, Roza Kucharczyk.

  Protein adenylation (AMPylation) is a post-translational modification in which an adenosine monophosphate (AMP) group is covalently attached to target proteins by AMPylases using ATP as a donor. In metazoans, two conserved AMPylase families are known: FIC-domain proteins and SelO. The yeast Saccharomyces cerevisiae lacks a FIC-domain enzyme; its only known AMPylase is the mitochondrial SelO homologue, Fmp40, involved in redox signaling. We conducted the first comprehensive screen for AMPylated proteins in the mitochondrial proteome of S. cerevisiae analyzing both wild-type and fmp40Δ cells using quantitative mass spectrometry. We identified 124 AMPylated mitochondrial proteins in wild-type and 41 in fmp40Δ mitochondria, suggesting the existence of additional AMPylase(s) in yeast. Among the modified targets, seven ATP synthase subunits were AMPylated, many at sites also phosphorylated, underscoring complex PTM regulation of the enzyme. We demonstrated that substitutions of one such residue, serine 29 in the δ subunit (Atp16), to alanine or glutamic acid, altered ATP synthase activity and oxidative phosphorylation coupling under both fermentative and respiratory conditions. This regulation is crucial for maintaining mitochondrial membrane potential. Our study provides the first catalog of AMPylated mitochondrial proteins in yeast, establishing a foundation for future studies on mitochondrial AMPylation.

Keywords:  AMPylation; ATP synthase; Fmp40; mitochondria; yeast

DOI:  https://doi.org/10.1021/acs.jproteome.5c01273
Dev Growth Differ. 2026 Aug;68(6): e70065

Quantitative In Vivo Imaging of ATP Dynamics in Drosophila Using the Ratiometric Biosensor QUEEN.

Yuhan Luo, Sayaka Sekine, Naoto Kasahara, Hiroyuki Uechi, Takafumi Toyohara, Takaaki Abe, Erina Kuranaga.

  Genetically encoded ATP biosensors enable monitoring of cellular energy status, but their application in multicellular organisms remains limited. QUEEN is a ratiometric ATP biosensor consisting of a bacterial ATP-binding protein fused to a circularly permuted fluorescent protein and has been primarily validated in cultured cells. Here, we generated transgenic Drosophila melanogaster lines expressing QUEEN-7μ, enabling tissue-specific expression through the GAL4/UAS system. We characterized its performance in motor neurons and muscles. QUEEN-7μ responses were validated using pharmacological and genetic perturbations of mitochondrial function. Mitochondrial inhibition decreased the QUEEN-7μ ratio, consistent with reduced ATP levels, whereas acute treatment with mitochonic acid-5 (MA-5), a small molecule that enhances mitochondrial ATP synthesis, increased the QUEEN-7μ ratio, with a larger effect at higher concentration. Consistently, genetic manipulations, including the mitochondrial Complex I knockdown and Mitofilin/MIC60 overexpression, produced corresponding decreases and increases in the QUEEN-7μ ratio. These results establish QUEEN-7μ as a reliable ratiometric ATP reporter for quantitative in vivo analysis in Drosophila. This system provides a versatile platform for investigating energy metabolism and mitochondrial function in Drosophila.

Keywords:   Drosophila melanogaster ; ATP biosensor; QUEEN; energy metabolism; in vivo imaging; mitochondrial function; ratiometric sensor

DOI:  https://doi.org/10.1111/dgd.70065
Nat Chem Biol. 2026 Aug 05.

A covalent PFKL activator suppresses tumor growth.

Xiaoding Jiang, Eric M Lynch, Congcong Lyu, Crystal N Wilson, Lauren E Salay, Hayden T Hess, Scott N Lyons, Mu-Jie Lu, Shuangyu Luo, Gibae Kim, Hsin-Ru Chan, Wesley J Wolfe, Lauren G Zacharias, Thomas P Mathews, Yi-Chih Lin, Bradley A Webb, Justin M Kollman, Xiaolu A Cambronne, Ku-Lung Hsu.

Glycolysis fuels vital cellular functions, and its dysregulation has been implicated in cancer, neurodegeneration, antibiotic resistance and diabetes. The glycolytic dependency of cancer, known as the Warburg effect, represents a key vulnerability for development of targeted anticancer agents; however, the development of such agents remains challenging owing to metabolic heterogeneity and resistance. Here we developed a covalent phosphofructokinase-1 liver type (PFKL) activator that couples glycolytic activation with delivery of a cytotoxic carnitine palmitoyltransferase 2 (CPT2)-targeting payload to cancer cells in vitro and in vivo. The electrophile-drug conjugate site-specifically and proteome-wide selectively modifies K677 in the allosteric effector site to stabilize the R-state tetramer of PFKL, while concomitantly releasing a CPT2-selective inhibitor to destabilize cell metabolism. The delivery mechanism of electrophile-drug conjugates is analogous to that of antibody-drug conjugates, but differentiated by their selective covalent targeting of intracellular proteins.

DOI: https://doi.org/10.1038/s41589-026-02289-9
MicroPubl Biol. 2026 ;2026

Triglyceride Storage is Upregulated in Different Mouse Non-Melanoma Skin Cancer Cell Lines.

Shannon Nowotarski, Ryan Cunnane, Marissa Catteau, Justin DiAngelo.

Links between tumorigenesis and lipid metabolism have been observed in various cancers, but whether lipid metabolism is altered in skin cancers is not well understood. Here we show that two different mouse skin cancer cell lines accumulate more triglycerides when compared to normal keratinocytes. This suggests that lipid metabolism is altered in mouse skin cancer tumor progression and may have implications for the regulation of lipid metabolism in non-melanoma skin cancer in humans.

DOI: https://doi.org/10.17912/micropub.biology.002182
Drug Resist Updat. 2026 Aug 02. pii: S1368-7646(26)00113-5. [Epub ahead of print]89 101462

Targeting a novel metabolic vulnerability of non-small cell lung cancer to fatty acid oxidation surmounts chemoresistance.

Simona Fontana, Dimas Carolina Belisario, Claudia Giannotta, Luca Alessandri, Sabrina Digiovanni, Angelo Meoli, Francesco Passiglia, Alessandra Merlini, Giulianmichela Di Palma, Martina Perin, Francesca Napoli, Maddalena Arigoni, Muhlis Akman, Elisa Balmas, Costanzo Costamagna, Iris Chiara Salaroglio, Joanna Kopecka, Alessandro Bertero, Luisella Righi, Massimo Massaia, Raffaele Calogero, Silvia Novello, Giorgio Vittorio Scagliotti, Yehuda G Assaraf, Chiara Riganti.

   AIMS: Non-small cell lung cancer (NSCLC) patients treated with platinum drugs develop chemoresistance. C/EBPβ has alternative translational LAP and LIP isoforms which impact cancer chemoresistance by modulating ABC efflux transporter expression and activity. Differential alternative translation of LAP:LIP reprograms metabolism in murine embryonic fibroblasts; however, little is known in cancer. To target possible metabolic vulnerabilities, we herein investigated whether LAP/LIP rewires NSCLC cell metabolism towards a chemoresistant phenotype.
METHODS: LAP- or LIP-overexpressing NSCLC cells were screened for anticancer drug sensitivity, DNA damage and ABC exporter expression and function. Metabolome/lipidome analyses and functional metabolic assays were performed to identify possible chemosensitizing agents. Tumor growth, mass spectrometry imaging and single-cell RNA-sequencing were determined in Hu-CD34+NSG xenografts.
RESULTS: LAP induced chemoresistance by increasing ABCB1/ABCC1/ABCC2 levels, activity and oxidative DNA damage. Furthermore, LAP altered metabolome and lipidome composition of plasma membrane and mitochondria, and upregulated HADHA and CPT1A, key enzymes in fatty acid oxidation (FAO). The high metabolic flux through FAO and oxidative phosphorylation increased mitochondrial ATP levels, thereby fueling these ATP-driven multidrug efflux pumps. Conversely, LIP displayed the opposite effect. CPT1A knock-out or catalytically-inactive mutant, FAO inhibition with etomoxir or trimetazidine, surmounted chemoresistance. In LAPhigh chemoresistant immune-xenografts, etomoxir redistributed fatty acids within tumor immune-microenvironment (TIME), metabolically reprogrammed NK cells and enhanced their anti-tumor activity.
CONCLUSION: Increased LAP:LIP ratio induced chemoresistance in NSCLC tumors by instigating a FAO-dependence, unveiling a metabolic vulnerability. FAO inhibition emerges as a novel chemosensitization strategy operating via rewiring tumor and TIME metabolism.

Keywords:  C/EBP-β; Cisplatin resistance; Fatty acid oxidation; Non-small cell lung cancer

DOI:  https://doi.org/10.1016/j.drup.2026.101462
Nat Cell Biol. 2026 Aug 06.

Pre-cancerous blood cells prematurely age the bone marrow to fuel cancer risk.

DOI: https://doi.org/10.1038/s41556-026-02032-5
Ther Adv Rare Dis. 2026 Jan-Dec;7:7 26330040261471914

Cancer prevalence in primary mitochondrial disease patients and their families.

Shrey Dalwadi, Nicole M Engelhardt, Colleen C Muraresku, Kelsey Keith, Kathleen D Valverde, Katherine L Nathanson, Marni J Falk.

   Background: While somatic mitochondrial dysfunction occurs in diverse cancers, the association between oncogenesis and germline mitochondrial gene pathogenic variants remains unclear. Further, few clinical observations have been reported of cancer occurring in primary mitochondrial disease (PMD) patients.
Objectives: To improve understanding of the potential modulating role for PMD gene disorders in cancer prevalence.
Design: 727 individuals, including 100 with PMD, from 97 unrelated families were retrospectively surveyed to assess their history of individual cancer occurrence.
Methods: We evaluated survey responses by characterizing the cancer prevalence among the study cohort and comparing to the general U.S. population via the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) database. Odds ratio calculation was performed to determine the association of survey responses and cancer prevalence.
Results: Although overall cancer prevalence in PMD probands and their families was elevated compared to the NCI SEER rate (8800 vs 5600 cases per 100,000), odds ratio calculation determined that PMD did not significantly increase the likelihood of developing cancer, with a non-significant trend observed toward less cancer occuring in PMD that needs to be explored in further studies. Cancer prevalence was significantly correlated with advanced age. Significantly reduced prevalence of prostate cancer was seen across the entire cohort. Surprisingly, while low absolute prevalence (n = 3), a 9-fold increased odds ratio of cancer was seen in POLG patients relative to those with other causes of PMD.
Conclusion: No evidence of increased cancer odds was identified in a cohort of PMD patients and their close relatives. Interestingly, a possible inverse association, which did not reach statistical significance, was suggested between mitochondrial disease status and cancer odds. Future prospective investigations in larger PMD kindreds are warranted to validate and evaluate potential mechanistic relations between cancer prevalence and PMD.

Keywords:  POLG; cancer; mitochondria; primary mitochondrial disease

DOI:  https://doi.org/10.1177/26330040261471914
Nature. 2026 Aug 05.

A tumour-derived organoid biobank maps cancer gene dependencies.

OCCAMS Consortium

Cancer cell lines remain foundational for research and drug discovery, yet they incompletely capture tumour diversity, lack linked patient context, and have undergone adaptation to culture. Tumour organoids are three-dimensional cultures derived from patient tissue that offer a powerful complement to cell lines1. Here we derived and characterized 256 clinically annotated tumour organoids directly from colorectal, oesophageal, ovarian, pancreatic and gastric cancers as renewable, genetically stable models. Extensive characterization of each model and matched patient tumour samples included whole-genome and transcriptome sequencing, and genome-wide CRISPR-Cas9 screens across 162 organoids mapped gene dependencies. Integrative analyses revealed genomic and clinical markers of dependency across common and rare subtypes, identified organoid-specific essential genes, and revealed targetable vulnerabilities following tumour evolution in paired pre- and post-treatment samples. In colorectal cancer, functional and pharmacological interrogation of the EGFR-RAS-MAPK axis uncovered differential effects of KRAS variant alleles. This open, publicly available resource provides a systematic map of gene dependencies in patient-derived organoids, expanding the model diversity and mechanistic insight needed to advance precision oncology.

DOI: https://doi.org/10.1038/s41586-026-10830-y
NMR Biomed. 2026 Sep;39(9): e70360

Hyperpolarized [2-13C]Pyruvate Identifies a Mitochondria-Active Hepatocellular Carcinoma Phenotype With Vulnerability to Mitochondrial Inhibition.

Qianhui Dou, Sophia M Mirrione, Karen Dos Santos, Samuel R Calos, Aaron K Grant, Yi-Fen Yen, Leo L Tsai.

Hepatocellular carcinoma (HCC) exhibits metabolic heterogeneity that is not fully characterized by glycolysis-focused spectroscopic profiling. This study investigated whether in vitro hyperpolarized (HP) [2-13C]pyruvate NMR spectroscopy can identify a mitochondria-active HCC phenotype and assess its association with sensitivity to mitochondrial metabolic inhibition. HP [2-13C]pyruvate NMR spectroscopy was used to evaluate mitochondrial metabolism in McA-RH7777 HCC cells, with N1S1 cells serving as a glycolysis-dominant reference. Cell viability following treatment with the glutaminase inhibitor BPTES and the mitochondrial metabolic inhibitor CPI-613 was assessed by MTT assay, and metabolic changes following CPI-613 treatment were further evaluated using HP [2-13C]pyruvate. HP [2-13C]pyruvate demonstrated enhanced pyruvate-to-glutamate conversion in McA-RH7777 cells, whereas N1S1 showed minimal glutamate labeling. CPI-613 treatment resulted in a dose-dependent reduction in cell viability, while BPTES produced limited effects. Although pyruvate-to-glutamate conversion did not significantly decrease following CPI-613 treatment, pyruvate-to-lactate conversion increased, indicating metabolic adaptation. These findings demonstrate that HP [2-13C]pyruvate enables functional identification of a mitochondria-active HCC phenotype characterized by enhanced pyruvate-to-glutamate conversion. This approach may facilitate metabolic subtype classification, help identify tumors susceptible to mitochondrial metabolic inhibition, and enable non-invasive monitoring of treatment-induced metabolic adaptation.

DOI: https://doi.org/10.1002/nbm.70360
Genes Dev. 2026 Aug 06.

Lysosomal metabolism in pancreatic cancer and its crosstalk with host physiology.

Caleb Cheng, Rüya Pakkan, Arul M Chinnaiyan, Costas A Lyssiotis.

  Pancreatic ductal adenocarcinoma (PDAC) grows within a highly fibrotic, pressurized microenvironment that collapses vasculature and restricts delivery of oxygen and circulating nutrients. To survive this metabolic stress, PDAC cells activate lysosome-centered nutrient acquisition and recycling programs, including macroautophagy, RAS-driven macropinocytosis, and receptor-mediated endocytosis, that traffic intracellular and extracellular cargo to lysosomes for degradation and metabolite export. These pathways are reinforced by oncogenic signaling and MiT/TFE-dependent lysosomal biogenesis, and they support core outputs of tumor metabolism such as iron bioavailability, amino acid and nucleotide pools, lipid homeostasis, and immune evasion. Lysosomal programs in nonmalignant compartments (fibroblasts, stellate cells, and immune cells) further shape nutrient exchange, matrix production, and whole-body metabolism, positioning the lysosome as a key node at the tumor-host interface. Although genetic and pharmacologic blockade of autophagy/lysosome function can produce potent antitumor effects in preclinical models, clinical trials with lysosomotropic agents have shown limited benefit, highlighting challenges in target engagement, biomarkers, and rational combination strategies. Here we review current tools and concepts for interrogating lysosomal flux in PDAC, integrate emerging insights from systemic metabolism and dietary interventions, and outline therapeutic opportunities for more effectively exploiting lysosome dependence in pancreatic cancer.

Keywords:  lysosome metabolism; pancreatic cancer; tumor host metabolism

DOI:  https://doi.org/10.1101/gad.353702.126
Nat Metab. 2026 Aug 05.

Palmitate promotes liver metastases by decreasing neutrophil antitumour behaviour.

Anke Vandekeere, Juan Fernández-García, Yiming Peng-Winkler, Miguel Martín Pérez, Ming Liu, Sara Isabel Fernandes, Janine Theile, Philipp Willnow, Sanne Verheul, Gitte Zels, Anirudh Pabba, Christine Desmedt, Cornelis Verhoef, Patricia Altea-Manzano, Salvador Aznar Benitah, Ilaria Elia, Ilaria Malanchi, Sarah-Maria Fendt.

Liver metastases are frequent and challenging to treat owing to the liver's metabolically active and immune-tolerant environment. However, how cancer cells exploit nutrient availability in the liver to evade immune surveillance remains unknown. Here we show that cancer cells use the palmitate availability in the liver to impair the neutrophil antitumour function. Mechanistically, we find that breast and colorectal cancer cells metastasizing to the liver, but not the lung, require the palmitoyltransferase 17 (DHHC17, gene name ZDHHC17) to stabilize laminin-511 enabling its secretion. In turn, neutrophils in the liver metastasis environment respond to laminin-511 by decreasing their cancer cell-killing capacity. Consistently, silencing ZDHHC17 in cancer cells decreases liver metastases only in the presence of neutrophils, while metastasis growth is restored in ZDHHC17-silenced metastases upon injection of laminin-511 or inhibition of neutrophil degranulation. Taken together, we find that liver palmitate not only supports tumour intrinsic processes but also enables immune evasion.

DOI: https://doi.org/10.1038/s42255-026-01582-0
Nat Cell Biol. 2026 Aug 06.

Stromal cell senescence augments haematopoietic cell fitness in clonal haematopoiesis.

Jayna J Mistry, Kira A Young, Anna Navarro Figueredo, Gibran Edun, Alicia G Aguilar-Navarro, Patricia A Colom Díaz, Maria Telpoukhovskaia, Inés Fernández Maestre, Sheng F Cai, Katharina S Götze, Anastasia N Tikhonova, Ross L Levine, Jennifer J Trowbridge.

Microenvironment remodelling impacts tumour growth and metastasis, but whether remodelling promotes pre-malignant clonal fitness remains unknown. Here, using single-cell RNA-sequencing of the bone-marrow microenvironment in a mouse model of DNMT3A-mutant clonal haematopoiesis (CH), we identify mesenchymal stromal cells (MSCs) in a molecular state of cellular senescence. Elevated bone-marrow MSC senescence is also observed in humans with CH driven by several common somatic mutations. MSC senescence is induced by mutant haematopoietic cells in a contact-independent manner through production of soluble factors including TNF-α and IL-6. These cytokines activate a Stat3-driven pathway that is necessary and sufficient for MSC senescence induction. Genetic or pharmacological depletion of senescent non-haematopoietic cells reduces the burden of CH and delays progression to myeloid neoplasia. Our findings show that microenvironment remodelling modifies pre-malignant clonal fitness and identifies disruption of the crosstalk between pre-malignant cells and their niche as a cancer prevention strategy.

DOI: https://doi.org/10.1038/s41556-026-02025-4
J Biol Chem. 2026 Aug 07. pii: S0021-9258(26)02289-1. [Epub ahead of print] 113417

Proton motive force as a driver of persister sensitization by adenosine.

Noah T Thompson, David A Kitzenberg, Alexander S Dowdell, Rebecca L Roer, J Scott Lee, Corey S Worledge, Sean P Colgan, Daniel J Kao.

  Antibiotic tolerance and persistence contribute to the emergence of antimicrobial resistance, yet strategies to reverse these phenotypes remain limited. Our previous work revealed that the naturally occurring nucleoside adenosine can reverse antibiotic tolerance in diverse bacterial strains by modulating cellular energetics. Here, we define the mechanism underlying this potentiation, identifying adenosine metabolism as a driver of cytoplasmic alkalinization and proton motive force (PMF) generation. Using RNA sequencing, metabolite assays, and pH-sensitive fluorescent reporters, we show that adenosine is catabolized by purine nucleoside phosphorylase (deoD) to yield ribose-1-phosphate, which enters the pentose phosphate pathway. This metabolic flux stimulates the electron transport chain, leading to proton translocation, increased cytoplasmic pH, and enhanced PMF. Disruption of key metabolic enzymes (deoD, deoB, tktAB) or the inhibition of enolase abolishes both alkalinization and antibiotic sensitization. Using a respiratory-deficient mutant, we demonstrate that aerobic respiration is the primary driver of alkalinization and gentamicin potentiation, although adenosine can partially increase membrane potential independently of oxidative phosphorylation. These findings support a model in which adenosine metabolism promotes aminoglycoside uptake via PMF-driven transport, sensitizing tolerant bacteria to killing. Our work implicates the ribose moiety of adenosine as a key metabolic lever for reversing tolerance. Broader exploration of nucleoside-based adjuvants across bacterial species and antibiotic classes may reveal generalizable strategies to enhance antibiotic efficacy against recalcitrant infections.

Keywords:  adenosine; antibiotics; bacterial metabolism; energetics; tolerance

DOI:  https://doi.org/10.1016/j.jbc.2026.113417