bims-medica 2025-12-07 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–12–07
twenty papers selected by
Brett Chrest, Wake Forest University

Pathway coessentiality mapping reveals complex II is required for de novo purine biosynthesis in acute myeloid leukaemia.
Drink Responsibly: Cancer Cells also Like Sugary Drinks.
Recurrent Breast Cancer Cells Depend on De novo Pyrimidine Biosynthesis to Suppress Ferroptosis.
Targeting distinct amino acid metabolic vulnerabilities in IDH-mutant and IDH-wildtype gliomas.
Oxidative pentose phosphate pathway is required for T cell activation and antitumor immunity.
Mitochondrial formate dehydrogenase links mitochondrial and cytosolic one carbon metabolism via a one-carbon shunt.
Fructose-containing sugars and metabolic risk: a systematic review and meta-analysis.
De Novo Hepatic Pyrimidine Synthesis Regulates Systemic Energy Homeostasis.
TP53-dependent antitumor effects of DHODH Inhibition in nasopharyngeal carcinoma.
Decay of driver mutations shapes the landscape of intestinal transformation.
Sustained reductions in valine and isoleucine mediate anti-cancer pharmacological effects of inhibiting amino acid transporter LAT1 in cancer cells.
Order in which cancer-driving mutations occur affects the chance of tumour development.
Polarized Distribution of Lipid Droplets with Long Acyl Chains and Unsaturation are Hallmarks of Human Intestinal Enteroid Differentiation.
Stroma-driven horizontal transfer of TCA-related proteins mediates metabolic plasticity and imatinib resistance in chronic myeloid leukemia.
Glutamine deficiency enhances nuclear localization of TCA cycle enzymes and epigenetic modifications, impairing myogenesis.
Vacuolar-type H+-ATPase-mediated extra-organellar buffering resolves mitochondrial dysfunction.
Ozonization for MALDI-2 MS imaging of carbon-carbon double bond positional isomers of phosphatidylethanolamines in biological tissues.
Rebuilding the Marrow In Vitro: Translational Advances in the 3D Modeling of Blood Cancers.
High concentrations of L-lysine cause mitochondrial damage and necrosis in isolated pancreatic acinar cells.
Platelet bioenergetics correlate with skeletal muscle respiration in a murine model of type II diabetes.

Nat Metab. 2025 Dec 05.

Pathway coessentiality mapping reveals complex II is required for de novo purine biosynthesis in acute myeloid leukaemia.

Amy E Stewart, Derek K Zachman, Pol Castellano-Escuder, Lois M Kelly, Ben Zolyomi, Michael D I Aiduk, Christopher D Delaney, Ian C Lock, Claudie Bosc, John Bradley, Shane T Killarney, J Darren Stuart, Paul A Grimsrud, Olga R Ilkayeva, Christopher B Newgard, Navdeep S Chandel, Alexandre Puissant, Kris C Wood, Matthew D Hirschey.

Understanding how cellular pathways interact is crucial for treating complex diseases like cancer. Individual gene-gene interaction studies have provided valuable insights, but may miss pathways working together. Here we develop a multi-gene approach to pathway mapping which reveals that acute myeloid leukaemia (AML) depends on an unexpected link between complex II and purine metabolism. Through stable-isotope metabolomic tracing, we show that complex II directly supports de novo purine biosynthesis and that exogenous purines rescue AML cells from complex II inhibition. The mechanism involves a metabolic circuit where glutamine provides nitrogen to build the purine ring, producing glutamate that complex II metabolizes to sustain purine synthesis. This connection translates into a metabolic vulnerability whereby increasing intracellular glutamate levels suppresses purine production and sensitizes AML cells to complex II inhibition. In a syngeneic AML mouse model, targeting complex II leads to rapid disease regression and extends survival. In individuals with AML, higher complex II gene expression correlates with resistance to BCL-2 inhibition and worse survival. These findings establish complex II as a central regulator of de novo purine biosynthesis and a promising therapeutic target in AML.

DOI: https://doi.org/10.1038/s42255-025-01410-x
Cancer Res. 2025 Dec 02.

Drink Responsibly: Cancer Cells also Like Sugary Drinks.

Fabio Zani, Julianna Blagih.

Sugar-sweetened beverages (SSBs), which contain both glucose and fructose, have been linked to an increased incidence of colorectal cancer (CRC). Their effects on CRC progression, however, are unclear. In their recent work, Feng and colleagues investigated how exposure to SSBs affects CRC metastasis. They discovered that several CRC cell lines showed enhanced migration when exposed to glucose and fructose together, compared to cells exposed to glucose or fructose alone. Similarly, in mouse models of CRC liver metastasis, mice fed with both glucose and fructose developed more liver metastases, suggesting that SSBs promote CRC spread. Leveraging on metabolomic analyses, they discovered that in the presence of both glucose and fructose, the enzyme SORD converts fructose to sorbitol, regenerating NAD⁺ from NADH. Deleting SORD reduced the NAD+/NADH ratio and CRC cell migration and metastasis. Restoring the NAD⁺/NADH ratio rescued migration, suggesting that SORD-driven NAD⁺ regeneration promotes metastatic behaviour. Furthermore, they demonstrated that increased NAD⁺/NADH levels have a profound effect on cell metabolism, supporting glycolysis, the TCA cycle, and the mevalonate pathway. Interestingly, pharmacologic inhibition of the mevalonate pathway with statins reduced cell migration and liver metastasis in mice consuming SSBs. Together, these findings demonstrate that SSBs enhance CRC metastasis through SORD-dependent metabolic reprogramming. By regenerating NAD⁺ and glycolysis and the mevalonate pathway, SORD links SSB consumption to increased tumor cell migration and metastatic potential.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-5296
bioRxiv. 2025 Nov 17. pii: 2025.11.17.688927. [Epub ahead of print]

Recurrent Breast Cancer Cells Depend on De novo Pyrimidine Biosynthesis to Suppress Ferroptosis.

Kelley R McCutcheon, Josh Wu, Yasemin Ceyhan Ozdemir, Brock J McKinney, Sharan Srinivasan, Ayaha Itokawa, Oliver J Newsom, Anna Vigil, Douglas B Fox, Lucas B Sullivan, James V Alvarez.

Breast cancer recurrence remains a major clinical challenge, often associated with therapy resistance and altered metabolic states. To define metabolic vulnerabilities of recurrent disease, we performed a CRISPR knockout screen targeting 421 metabolic genes in paired primary and recurrent HER2-driven breast cancer cell lines. While both primary and recurrent tumors shared dependencies on core metabolic pathways, recurrent tumors exhibited selective essentiality for the de novo pyrimidine synthesis pathway, including Cad , Dhodh , and Ctps . Pharmacologic inhibition of the rate-limiting enzyme DHODH with BAY-2402234 selectively impaired the growth of recurrent tumor cells, while primary tumor cells were relatively resistant. BAY treatment robustly inhibited pyrimidine synthesis in all lines, but only recurrent cells underwent iron-dependent lipid peroxidation and ferroptotic cell death. Lipidomic profiling revealed enrichment of polyunsaturated ether phospholipids in recurrent cells, which may predispose them to ferroptosis. A sensitizer CRISPR screen in primary cells further identified nucleotide salvage and lipid metabolic pathways as modifiers of DHODH inhibitor sensitivity. Stable isotope tracing and nutrient depletion experiments showed that primary cells can compensate for DHODH inhibition through nucleotide salvage, whereas recurrent cells exhibit impaired salvage capacity, likely due to reduced expression of Slc28 / Slc29 nucleoside transporters. Together, these findings reveal that breast cancer recurrence is associated with increased dependence on de novo pyrimidine synthesis to suppress ferroptosis, highlighting a therapeutically actionable metabolic vulnerability in recurrent disease.

DOI: https://doi.org/10.1101/2025.11.17.688927
Acta Neuropathol Commun. 2025 Nov 29.

Targeting distinct amino acid metabolic vulnerabilities in IDH-mutant and IDH-wildtype gliomas.

Shigeo Ohba, Akiyoshi Hirayama, Takao Teranishi, Keisuke Hitachi, Hisateru Yamaguchi, Kazuhiro Murayama, Manabu Natsumeda, Kensuke Tateishi, Kunihiro Tsuchida, Hiroaki Wakimoto, Hideyuki Saya, Russell Pieper, Yuichi Hirose.

  Lower grade gliomas frequently harbor mutations in isocitrate dehydrogenase (IDH), which define biologically distinct tumor subtypes. Although IDH-mutant and IDH-wildtype gliomas share similar histological morphology, they display markedly different metabolic profiles that may be exploited for targeted therapy. In this study, we investigated therapeutic approaches tailored to these metabolic differences. Using capillary electrophoresis-mass spectrometry, we compared the metabolomes of engineered IDH-wildtype and IDH-mutant glioma cell models. IDH-mutant cells exhibited elevated asparagine levels and reduced glutamine and glutamate levels compared with IDH-wildtype cells. These differences were corroborated in vivo by proton magnetic resonance spectroscopy of 130 patients with diffuse gliomas, showing lower glutamine and glutamate in IDH-mutant tumors. Pharmacological depletion of asparagine with L-asparaginase, which converts asparagine to aspartate, preferentially inhibited the growth of IDH-wildtype glioma cells, and this effect was potentiated by inhibition of asparagine synthetase. In contrast, inhibition of glutamate dehydrogenase 1 (GLUD1), the enzyme catalyzing the conversion of glutamate to α-ketoglutarate, selectively suppressed proliferation of IDH-mutant glioma cells by inducing reactive oxygen species accumulation and apoptosis. In vivo, L-asparaginase suppressed tumor growth in xenografted IDH-wildtype gliomas, whereas GLUD1 inhibition significantly reduced tumor growth in IDH-mutant glioma xenografts. These findings reveal distinct amino acid metabolic vulnerabilities defined by IDH mutation status and identify L-asparaginase and GLUD1 inhibition (via R162) as promising, mutation-specific therapeutic strategies. L-asparaginase demonstrated potent antitumor activity against IDH-wildtype gliomas, while GLUD1 inhibition selectively suppressed IDH-mutant gliomas both in vitro and in vivo. These results highlight the clinical potential of targeting amino acid metabolism in gliomas and provide a strong rationale for translating these mutation-specific approaches into future clinical trials.

Keywords:  Asparagine; Cancer metabolism; Glioma; Glutaminolysis; Isocitrate dehydrogenase

DOI:  https://doi.org/10.1186/s40478-025-02193-8
Proc Natl Acad Sci U S A. 2025 Dec 09. 122(49): e2516288122

Oxidative pentose phosphate pathway is required for T cell activation and antitumor immunity.

Zihong Chen, Kellen L Olszewski, Rolf-Peter Ryseck, Xincheng Xu, Jacob A Boyer, Christian G Peace, Yihui Shen, Caroline R Bartman, Lydia Lynch, Joshua D Rabinowitz.

  Glucose is catabolized by two major metabolic pathways, glycolysis and the oxidative pentose phosphate pathway (oxPPP). The oxPPP generates nicotinamide adenine dinucleotide phosphate (NADPH) at two steps, glucose-6-phosphate dehydrogenase (G6PD), the most common enzyme deficiency in humans, and 6-phosphogluconate dehydrogenase (PGD). Previous literature suggests that G6PD supports but PGD limits T cell-mediated immunity. Here, we use T cell-specific knockout mouse models to show that both enzymes are required for antitumor immunity and response to immunotherapy. PGD knockout depletes mature T cells systemically, while G6PD loss does not reduce basal T cell populations but results in apoptosis upon activation. Such apoptosis is not reversed by major downstream products of the oxPPP, including antioxidants, nucleosides, or fatty acids. Instead, T cells are partially rescued by removal of media cystine, whose reduction requires NADPH. G6PD loss induces an oxidative stress response that upregulates cystine import, which together with low NADPH leads to fatal disulfide stress. Overall, these results highlight an essential role for the oxidative pentose phosphate pathway in cystine homeostasis and T cell-mediated immunity.

Keywords:  NADPH; T cell activation; T cell antitumor immunity; disulfide stress; oxidative pentose phosphate pathway

DOI:  https://doi.org/10.1073/pnas.2516288122
Plant Physiol. 2025 Dec 05. pii: kiaf623. [Epub ahead of print]

Mitochondrial formate dehydrogenase links mitochondrial and cytosolic one carbon metabolism via a one-carbon shunt.

Marc-Sven Roell, Franziska Kuhnert, Philipp Westhoff, Sompop Saeheng, Sanja Roje, Andreas P M Weber.

The transfer of one-carbon (C1) units is an integral part of cellular metabolism and is essential for the biosynthesis of nucleotides, amino acids, and cofactors, as well as for cellular methylation reactions. Within the plant cell, mitochondria are considered the hubs of one-carbon metabolism; however, the mechanisms and fluxes that distribute C1 units from the mitochondria throughout the cell are unknown. Formate, the anion of formic acid, is an intermediate of C1 metabolism and is converted to C1-tetrahydrofolate intermediates (C1 folates) or oxidized to CO2 by formate dehydrogenase. The presence of formate dehydrogenase in plant cells challenges the formate exchange between mitochondria and the cytosol, a basic principle of eukaryotic cellular and organellar C1 metabolism. Based on the biochemical and physiological characterization of Arabidopsis (Arabidopsis thaliana) formate dehydrogenase 1 (FDH1), we propose an FDH1-regulated C1 shunt linking mitochondrial and cytosolic C1 metabolism by formate exchange. Finally, we give a perspective on a cellular serine/formate shuttle that allows the distribution and transfer of C1 units according to the redox state within the compartments.

DOI: https://doi.org/10.1093/plphys/kiaf623
Food Nutr Res. 2025 ;69

Fructose-containing sugars and metabolic risk: a systematic review and meta-analysis.

Prasetya Guntari, Astina Junaida, Palupi Eny, Namkieat Pichamon, Jiamjarasrangsi Wiroj, Sapwarobol Suwimol.

   Background: Fructose-containing sugars are widely consumed, yet their metabolic effects remain debated.
Objective: This meta-analysis aimed to evaluate the impact of different fructose-containing sugars on glycaemic control, lipid profiles, and uric acid levels in adults.
Methods: A total of 17 study codes from seven clinical trials were included, with intervention durations ranging from 7 h to 49 days. Interventions were classified as fructose, fructose-glucose mixtures (F/G), honey, or sucrose. Comparators varied and included unsweetened beverages, artificial sweeteners, and habitual diets. Meta-analyses using random-effects models assessed outcomes including fasting blood glucose (FBG), serum insulin, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), very low-density lipoprotein cholesterol (VLDL-c), and uric acid. Effect sizes were reported as Hedges' g.
Results: Fructose-glucose mixtures intake significantly increased FBG (Hedges' g = 0.474, P = 0.002) and serum insulin (Hedges' g = 0.592, P < 0.001), while fructose, honey, and sucrose showed no significant effects. Monosaccharide intake modestly increased insulin (P = 0.006). Fructose and sucrose alone did not affect TC, but their combined intake resulted in a significant increase (Hedges' g = 0.412, P = 0.009). No significant changes were observed in LDL-c, VLDL-c, or pooled metabolic outcomes. Fructose intake was strongly associated with increased uric acid (Hedges' g = 1.628, P < 0.001), and pooled analysis of fructose, F/G, and honey also showed a significant increase (Hedges' g = 0.550, P = 0.028).
Conclusion: The short-term consumption of added sugars - fructose, sucrose, and F/G mixtures - had minimal effects on FBG, insulin, triglycerides (TG), non-esterified fatty acids (NEFAs), high-density lipoprotein cholesterol (HDL-c), and VLDL-c. However, significant increases in TC and LDL-c were observed, particularly with fructose and sucrose, indicating adverse effects on lipid metabolism. Some fructose interventions, especially those using high-fructose corn syrup, also showed marked increases in uric acid. While acute metabolic changes were limited, these findings suggest that regular intake of added sugars may elevate cardiometabolic risk. Long-term studies are warranted to clarify chronic effects and inform dietary guidelines.

Keywords:  fructose; glycaemic response; meta-analysis; serum insulin; uric acid

DOI:  https://doi.org/10.29219/fnr.v69.11062
bioRxiv. 2025 Nov 18. pii: 2025.11.18.689117. [Epub ahead of print]

De Novo Hepatic Pyrimidine Synthesis Regulates Systemic Energy Homeostasis.

Ling Fu, Pradnya H Patil, Pengfei Zhang, Ignacio Norambuena-Soto, Qiutang Xiong, Yin Wang, Chelsea Jang, Kevin Wang, Yunqian Peng, Lu Ding, Patrick Fueger, Lihua Jin, Wendong Huang, Philip L Lorenzi, Lin Tan, Markus Kalkum, Philipp E Scherer, Zhao V Wang, Yingfeng Deng.

Fasting blood uridine is increased in obesity and type 2 diabetes (T2D), but the significance of hepatic uridine biosynthesis to the etiology of both remains elusive. We found that de novo pyrimidine synthesis in the liver is reduced by fasting and diet-induced obesity, while suppression of hepatic pyrimidine synthesis promotes obesity and insulin resistance. The metabolic sequalae of hepatic pyrimidine synthesis suppression, however, is not associated with altered plasma uridine concentration. Instead, it is associated with an increased hepatic glucose production and a decreased hepatic insulin clearance, two key functions of hepatocytes in regulating systemic energy homeostasis. We found that enhanced gluconeogenesis is the primary reason for increased hepatic glucose production. Moreover, uridine, which was maintained stable in the circulation by adipose tissue and the liver, preferentially shut down pyrimidine synthesis in hepatocytes but not adipocytes at blood concentrations that occur with fasting. Remarkably, uridine, at fasting levels, increases gluconeogenesis further in hepatocytes when de novo pyrimidine synthesis is suppressed, indicating a synergistical action of uridine and its biosynthesis pathway in promoting hepatic glucose production, a mechanism highly relevant to the pathophysiology of insulin resistance in obesity. Theologically, maintenance of blood uridine within the narrow range protects mammals from high-rate spontaneous tumorigenesis. Since obesity promotes an increase in blood uridine from adipocytes, suppressing uridine synthesis in hepatocytes becomes a critical response to lower spontaneous tumorigenesis. Pyrimidine synthesis suppression in hepatocytes, however, promotes gluconeogenesis and ultimately triggers obesity and T2D. These findings suggest a new paradigm for the etiology of metabolic deterioration in diet-induced obesity, in which perturbations in uridine promotes obesity and T2D.

DOI: https://doi.org/10.1101/2025.11.18.689117
Discov Oncol. 2025 Nov 30.

TP53-dependent antitumor effects of DHODH Inhibition in nasopharyngeal carcinoma.

Xingchen Dong, Yaoting Zhang, Zhicun Zhang, Ting Liu, Dongsheng Gu.

  Nucleic acid metabolism reprogramming has emerged as a common feature of cancer; however, its role in nasopharyngeal carcinoma (NPC) remains largely unexplored. This study investigated the expression patterns of nucleic acid metabolism pathways in NPC and evaluated the therapeutic potential of targeting these pathways. Via bioinformatics analysis of multiple NPC datasets, we identified significant upregulation of nucleic acid metabolism pathways in tumor tissues compared with normal nasopharyngeal epithelium. Notably, increased activity of pyrimidine biosynthesis pathways was strongly correlated with poor disease-free survival in NPC patients. Dihydroorotate dehydrogenase (DHODH), which is a rate-limiting enzyme in de novo pyrimidine synthesis, was selected as a therapeutic target. The DHODH inhibitor BAY2402234 demonstrated potent antiproliferative effects on the NPC cell lines C666-1 and NPC/HK-1 at nanomolar concentrations, with IC50 values of 4.71 nM and 3.51 nM being observed 48 h, respectively. BAY2402234 treatment significantly suppressed cell migration and invasion while inducing apoptosis. Transcriptome analysis revealed that BAY2402234 treatment led to extensive gene expression remodeling with significant activation of the TP53 signaling pathway. Functional validation experiments confirmed the essential role of TP53 in mediating the antitumor effects of BAY2402234, as siRNA-mediated TP53 knockdown substantially attenuated drug efficacy. Importantly, the low mutation rate of TP53 in NPC suggests that BAY2402234 may be particularly effective in this cancer type. These findings provide the first comprehensive evidence that nucleic acid metabolism plays a crucial role in NPC progression and that the targeting of DHODH represents a promising therapeutic strategy, particularly via TP53-dependent mechanisms.

Keywords:  Cancer metabolism; DHODH inhibitor; Nasopharyngeal carcinoma; Nucleic acid metabolism; TP53 signaling

DOI:  https://doi.org/10.1007/s12672-025-03857-6
Nature. 2025 Dec 03.

Decay of driver mutations shapes the landscape of intestinal transformation.

Filipe C Lourenço, Iannish D Sadien, Kim Wong, Sam Adler, Ashley Sawle, Leonor Schubert Santana, Lee Hazelwood, Giada Giavara, Anna M Nicholson, Matthew D Eldridge, Noori Maka, Gerard Lynch, Stephen T McSorley, Joanne Edwards, Richard Kemp, David J Adams, Douglas J Winton.

Colorectal cancer (CRC) has traditionally been thought to develop through stepwise mutation of the APC tumour suppressor and other driver genes, coupled with expansion of positively selected clones. However, recent publications show that many premalignant lesions comprise multiple clones expressing different mutant APC proteins1-4. Here, by mediating transformation on different mouse backgrounds containing mutations in Kras or other common CRC driver genes, we establish that the presence of diverse priming events in the normal mouse intestinal epithelium can change the transformation and clonal-selection landscape, permitting the fixation of strong driver mutations in Apc and Ctnnb1 that are otherwise lost due to negative selection. These findings, combined with our demonstration of mutational patterns consistent with similar priming events in human CRC, suggest that the order in which driver mutations occur in intestinal epithelium can determine whether clones are positively or negatively selected and can shape subsequent tumour development.

DOI: https://doi.org/10.1038/s41586-025-09762-w
Cancer Metab. 2025 Dec 02. 13(1): 46

Sustained reductions in valine and isoleucine mediate anti-cancer pharmacological effects of inhibiting amino acid transporter LAT1 in cancer cells.

Kou Nishikubo, Ryuichi Ohgaki, Hiroki Okanishi, Minhui Xu, Yoshikatsu Kanai.

   BACKGROUND: L-type amino acid transporter 1 (LAT1; SLC7A5), which preferentially transports large neutral amino acids (LNAAs), is highly upregulated in various cancers and represents a promising therapeutic target. The first-in-class LAT1-specific inhibitor, nanvuranlat (JPH203, KYT-0353), has exhibited potent anti-cancer effects and is under clinical evaluation. However, alterations in the amino acid availability in cancer cells underlying its pharmacological activities remain to be elucidated.
METHODS: Amino acids in nanvuranlat-treated cancer cells were measured by high-performance liquid chromatography. LAT1 knockdown was performed using siRNA. To mimic LAT1 inhibition, cancer cells were incubated in culture media lacking specific LNAA(s) reduced by nanvuranlat. The consequences of these treatments were compared by cell-based assays, including analyses of amino acid contents, cell growth, amino acid-related signaling pathways, cell cycle, ATP production rate, and transcriptomes by RNA sequencing. Metabolome of nanvuranlat-treated and untreated cells was compared by mass spectrometry. The effects of nanvuranlat on amino acid composition were also examined in three-dimensional cancer cell spheroids.
RESULTS: Both pharmacological and genetic inhibition of LAT1 preferentially and continuously reduced valine, isoleucine, and tryptophan in pancreatic cancer MIA PaCa-2 cells. Nanvuranlat induced similar alterations in intracellular amino acids in multiple cancer cell lines. Depletion of these amino acids from culture media selectively lowered their intracellular concentrations, recapitulating the effects of nanvuranlat on cell growth, amino acid-related mTORC1/GAAC signaling pathways, and cell cycle. Deprivation of valine or isoleucine exhibited more pronounced impacts than tryptophan in all assays. As a novel pharmacological action of nanvuranlat mediated by the reductions in valine and isoleucine, we revealed downregulation of multiple genes in the TCA cycle and respiratory chain, accompanied by a decreased mitochondrial ATP production rate. Consistently, metabolomics revealed broad decreases in the TCA cycle intermediates by LAT1 inhibition. Nanvuranlat also similarly influenced the amino acid levels in cancer cell spheroids.
CONCLUSIONS: Reductions in valine and isoleucine in cancer cells primarily account for the multifaceted anti-cancer pharmacological activities of LAT1 inhibition by nanvuranlat. This study establishes the molecular basis for LAT1-targeted therapy and highlights growth-promoting processes in cancer cells that can be exploited pharmacologically by modulating the availability of specific amino acids.

Keywords:  Amino acids; Cell cycle; GAAC pathway; Inhibitor; LAT1; Metabolomics; Mitochondrial ATP production; RNA sequencing; Transporter; mTORC1 pathway

DOI:  https://doi.org/10.1186/s40170-025-00415-0
Nature. 2025 Dec 03.

Order in which cancer-driving mutations occur affects the chance of tumour development.



Keywords:  Cancer; Genetics

DOI:  https://doi.org/10.1038/d41586-025-03748-4
Anal Chem. 2025 Dec 04.

Polarized Distribution of Lipid Droplets with Long Acyl Chains and Unsaturation are Hallmarks of Human Intestinal Enteroid Differentiation.

Patrik K Johansson, Yueming Liu, Katarina C Klett, Sarah C Heilshorn, Annika Enejder.

Cell polarization and differentiation require increased energy mobilization and cell membrane synthesis, whereby mitochondria and lipid droplets (LDs) play key roles. However, how these metabolic organelles organize at the subcellular level to efficiently meet energy demands in human intestinal organoids is unclear. To address this, we introduce coherent anti-Stokes Raman scattering (CARS) microscopy multiplexed with confocal fluorescence microscopy to spatially map LDs and mitochondria throughout cell differentiation in human intestinal enteroids. The results show an overall decrease in LDs over time, though less pronounced for cells positive for proliferation or stemness markers. The LD depletion was observed in the apical region, resulting in a polarized distribution to the basal side. A similar mitochondrial polarization pattern was also observed in differentiated enteroids. Spectral CARS further shows that LDs postdifferentiation contain lipids with signatures of longer acyl chains and a higher degree of unsaturation. These observations demonstrate that polarized metabolic and lipid supply infrastructures are formed to support intestinal cell differentiation in organoid cultures.

DOI: https://doi.org/10.1021/acs.analchem.5c02648
Cell Commun Signal. 2025 Dec 02.

Stroma-driven horizontal transfer of TCA-related proteins mediates metabolic plasticity and imatinib resistance in chronic myeloid leukemia.

Piotr Chroscicki, Nikodem Kasak, Dorota Dymkowska, Laura Turos-Korgul, Dominik Cysewski, Vira Chumak, Dawid Stepnik, Monika Kusio-Kobialka, Agata Kominek, Magdalena Lebiedzinska-Arciszewska, Alicja Krop, Joanna Szczepanowska, Mariusz Wieckowski, Tomasz Stoklosa, Krzysztof Zablocki, Katarzyna Piwocka.

   BACKGROUND: Alterations in cancer cell metabolism have recently gained considerable attention as a possible cause of adaptation and resistance to therapy. However, the underlying molecular mechanisms, particularly in leukemia resistance occurring in the bone marrow microenvironment, remain unclear. Here, we explore the role of direct stroma-leukemia interactions and transfer of membrane vesicles along with proteins as a mechanism of stroma-driven protection.
METHODS: K562 CML leukemia cells and primary CD34 + CML blasts were cultured alone or co-cultured with HS-5 stromal cells to mimic the bone marrow microenvironment conditions. Imatinib treatment was used experimentally as it is a standard first-line treatment in CML. Assessment of vesicles transfer, metabolic parameters, mitochondrial function phenotyping, Trans-SILAC proteomics and metabolomics, together with apoptosis assessment, verified the influence of stroma on metabolic plasticity, protein transfer and adaptation to imatinib in leukemic cells. Trans-system evaluated necessity of direct cell-cell contact. Data from single-cell atlas of diagnostic CML bone marrow were used to correlate gene expression profiles with clinical outcome. Telaglenastat was used to validate the clinical potential of our findings.
RESULTS: Stromal cells enhanced metabolic plasticity and oxidative capacity in leukemia, thereby protecting against metabolic decline and oxidative stress caused by imatinib. Direct stroma-leukemia contact was necessary for vesicles transfer, metabolic rearrangement and protection from imatinib-induced apoptosis. This was accompanied with shift towards OXPHOS activity, associated with increased utilization of non-glucose substrates. We found the presence of stromal TCA-related proteins in leukemic cells, associated with higher TCA cycle dynamics and activity, increased glutamine and reduced oxidative stress. The gene expression profiles correlated with clinical resistance to TKIs. Targeting the glutamine-TCA axis by telaglenastat in combination with imatinib reversed the stroma-driven protection, leading to increased apoptosis.
CONCLUSION: This study describes a novel mechanism of direct bone marrow-mediated protection of leukemic cells from imatinib/TKI, related to transfer of metabolic proteins leading to higher activity of TCA cycle, metabolic plasticity and adaptation. Targeting the stroma-driven TCA cycle-related metabolism combined with imatinib presents a promising strategy to achieve therapeutic efficacy to overcome bone marrow microenvironment-mediated protection in CML.

Keywords:  Bone marrow stroma; Glutamine; Imatinib; Leukemia microenvironment; Metabolic plasticity; Mitochondria; Proteome; Resistance; TCA; TNTs

DOI:  https://doi.org/10.1186/s12964-025-02564-7
Am J Physiol Cell Physiol. 2025 Dec 05.

Glutamine deficiency enhances nuclear localization of TCA cycle enzymes and epigenetic modifications, impairing myogenesis.

Angad Yadav, Susan Schmitt, Wenxia Ma, James A Mobley, Anna Elizabeth Thalacker-Mercer.

  Extracellular glutamine (Gln) is essential for muscle progenitor cell (MPC) function and skeletal muscle regeneration / development, especially under physiological stress like aging or catabolic conditions. Gln availability regulates MPC proliferation by modulating intracellular metabolic and epigenetic states. Gln deficiency reduces cell viability, induces G0/G1 cell cycle arrest, and downregulates MyoD expression, collectively inhibiting myogenesis in human primary myoblasts (HSMM) and mouse C2C12 cells. Mechanistically, Gln deficiency enhances nuclear localization of TCA cycle enzyme, KGDHC, components (i.e., DLST and OGDH), elevates histone succinylation, and reduces chromatin accessibility at the myogenic regulatory regions (MyoD1 locus). These changes establish a direct link between Gln availability and an epigenetic-metabolic axis crucial for myogenic gene regulation. Thus, extracellular Gln acts as a key regulator of MPC proliferation through metabolic mediated control of chromatin state.

Keywords:  Chromatin accessibility; Glutamine metabolism; Succinylation; TCA cycle compartmentalization; myogenesis

DOI:  https://doi.org/10.1152/ajpcell.00568.2025
Nat Commun. 2025 Dec 03.

Vacuolar-type H+-ATPase-mediated extra-organellar buffering resolves mitochondrial dysfunction.

Geoffray Monteuuis, Ryan Awadhpersad, Daan van der Kolk, Sachin K Singh, Tuula A Nyman, Alina Malyutina, Nicola Zamboni, Kari Moisio, Juhana Juutila, Ville Hietakangas, Sara Seneca, Christopher J Carroll, Christopher B Jackson.

Mitochondrial dysfunction underlies a wide range of human diseases, including primary mitochondrial disorders, neurodegeneration, cancer, and ageing. To preserve cellular homeostasis, organisms have evolved adaptive mechanisms that coordinate nuclear and mitochondrial gene expression. Here, we use genome-wide CRISPR knockout screening to identify cell fitness pathways that support survival under impaired mitochondrial protein synthesis. The strongest suppressor of aberrant mitochondrial translation defects - besides a compendium of known mitochondrial translation quality control factors - is the loss of the vacuolar-type H+-ATPase (v-ATPase), a key regulator of intracellular acidification, nutrient sensing, and growth signaling. We show that partial v-ATPase loss reciprocally modulates mitochondrial membrane potential (ΔΨm) and cristae structure in both cancer cell lines and mitochondrial disease patient-derived models. Our findings uncover an extra-organellar buffering mechanism whereby partial v-ATPase inhibition mitigates mitochondrial dysfunction by altering pH homeostasis and driving metabolic rewiring as a protective response that promotes cell fitness.

DOI: https://doi.org/10.1038/s41467-025-66656-1
Anal Chim Acta. 2026 Jan 08. pii: S0003-2670(25)01208-5. [Epub ahead of print]1382 344814

Ozonization for MALDI-2 MS imaging of carbon-carbon double bond positional isomers of phosphatidylethanolamines in biological tissues.

Dominika Bezdeková, Michal Hendrych, Jan Schwenzfeier, Jens Soltwisch, Klaus Dreisewerd, Petr Vlček, Jan Preisler, Antonín Bednařík.

   BACKGROUND: Offline on-tissue ozonization combined with subsequent matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) offers a robust approach for spatial differentiation of carbon-carbon double bond (db) positional isomers of phospholipids across various tissue types. However, isomeric imaging of certain physiologically important lipid classes, such as phosphatidylethanolamines (PEs), remains challenging due to the comparatively low abundance of the produced ozonide ions. In this work, we therefore employed MALDI with laser post-ionization (MALDI-2) to boost PE ozonide signals and obtain new biological insights by its application on biological tissue samples.
RESULTS: Analysis of PE standard and PE in model tissue showed that MALDI-2 process does not significantly contribute to the in-source fragmentation of fragile ozonides produced offline unless very high post-ionization laser energies are employed. The capabilities of the developed method were demonstrated on MALDI-2 MSI mapping of positional PE isomers in whole-body sections of mouse embryos, as well as in human colorectal cancer tissue biopsies. For example, we identified three positional db isomers of PE 34:1 (Δ7, Δ9, and Δ11) and four isomers of PE 36:1 (Δ5, Δ7, Δ9, and Δ11) that exhibited distinct spatial distributions, particularly across different organs of the mouse embryo. A noteworthy observation was also the accumulation of all identified PE isomers in the brown fat tissue (BAT) regardless of the double-bond position. Within the colorectal carcinoma sample, particular enhancement of PE 36:1 (Δ9) isomer was found in the tumor tissue.
SIGNIFICANCE: The combination of offline tissue section ozonization with MALDI-2 laser post-ionization opens a way for isomeric imaging of less abundant or poorly ionized lipids in MALDI and holds potential for elucidating the biological roles of lipid db isomers in healthy and cancer metabolism. Thanks to the offline nature of the reaction, the technique does not require any instrumental modifications of the MALDI mass spectrometer, which makes it readily adoptable.

Keywords:  Lipid double-bond positional isomers; MALDI & MALDI-2 MS imaging; Mouse embryonal and pup tissue samples; On-tissue reactions; Ozonization

DOI:  https://doi.org/10.1016/j.aca.2025.344814
Onco (Basel). 2025 Dec;pii: 51. [Epub ahead of print]5(4):

Rebuilding the Marrow In Vitro: Translational Advances in the 3D Modeling of Blood Cancers.

Giovannino Silvestri, Aditi Chatterjee.

  Hematological malignancies such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), lymphomas, and multiple myeloma remain difficult to model ex vivo because conventional two-dimensional (2D) cultures and murine systems fail to reproduce the spatial, metabolic, vascular, and immune complexity of human bone marrow and lymphoid niches. Recent advances in three-dimensional (3D) platforms-including spheroids, engineered organoid-like marrow models, and microfluidic niche-on-a-chip systems-now allow for a more physiological replication of stromal, endothelial, and immune interactions that drive resistance and relapse. In this review, we introduce explicit definitions distinguishing spheroids, organoid-like constructs, true hematopoietic organoids, and microfluidic devices to establish a unified framework for hematologic 3D modeling. We synthesize applications across AML, CML, lymphoma, and myeloma, highlighting mechanistic insights, strengths, and limitations unique to each disease. Finally, we outline a translational roadmap that integrates bioprinting, perfusable vasculature, immune reconstitution, and AI-driven analytics toward next-generation patient-specific platforms. These innovations position 3D marrow-mimetic systems as essential tools for precision oncology in blood cancers.

Keywords:  3D bioprinting; 3D marrow-mimetic systems; AML; CML; bone marrow niche; immunotherapy; microfluidics; organoids; precision medicine; tumor microenvironment

DOI:  https://doi.org/10.3390/onco5040051
Sci Rep. 2025 Dec 03.

High concentrations of L-lysine cause mitochondrial damage and necrosis in isolated pancreatic acinar cells.

Eszter T Végh, Zsolt Balla, Ágnes Dágó, Ola Salamah, Brigitta Tóth, Jason Elperin, Steven Speakman, Natalia Shalbueva, Petra Pallagi, Zsolt Rázga, Lóránd Kiss, Anna Gukovskaya, Zoltán Rakonczay.

  Intraperitoneal administration of high doses of basic amino acids, such as L-lysine (L-Lys), L-arginine (L-Arg) or L-ornithine (L-Orn) induces acute pancreatitis in rodents. Although the exact mechanism of their action is not fully understood, the role of mitochondria has been implicated. We aimed to investigate the effects of basic amino acids, particularly L-Lys, on isolated pancreatic acinar cells. Isolated mouse or rat pancreatic acinar cells were treated with high concentrations (10-60 mM) of L-Lys, L-Arg or L-Orn. The morphology of acinar mitochondria was observed by electron microscopy. The function of mitochondria was assessed by mitochondrial membrane potential (∆Ψm) and cellular ATP level measurements. Changes in intracellular Ca2+ concentration ([Ca2+]i), trypsin activity and cellular viabilities were also determined. Treatment of acinar cells with L-Lys caused mitochondrial swelling. L-Lys and L-Arg markedly decreased ∆Ψm after 6 h of treatment, whereas L-Orn had a less pronounced effect than L-Lys or L-Arg. Intracellular ATP levels were also reduced by basic amino acids. L-Lys did not alter [Ca2+]i and did not induce early trypsinogen activation. Furthermore, L-Lys administration primarily caused acinar necrosis. Overall, L-Lys primarily damaged pancreatic acinar mitochondria and caused necrotic cell death without affecting the initial [Ca2+]i.

Keywords:  Acute pancreatitis; Basic amino acids; L-arginine; L-lysine; L-ornithine; Pancreatic acinar cells

DOI:  https://doi.org/10.1038/s41598-025-29890-7
Front Mol Biosci. 2025 ;12 1639882

Platelet bioenergetics correlate with skeletal muscle respiration in a murine model of type II diabetes.

Mia S Wilkinson, Emily J Ferguson, Justin Bureau, Roan A L Haggerty-Goede, Dalia M Miller, Michelle Kuriakose, Jennifer L M H Veeneman, Patricia D A Lima, Chris McGlory, Kimberly J Dunham-Snary.

  Mitochondrial bioenergetic research in skeletal muscle is limited by the need for biopsies. We executed a proof-of-concept study to evaluate whether blood platelets could serve as a minimally invasive surrogate for skeletal muscle mitochondrial respiration in mice. Using Seahorse extracellular flux analysis, platelet respiration was measured in healthy C57BL/6J and leptin receptor-null db/db mice, while high-resolution respirometry (Oroboros O2k) assessed mitochondrial function in white gastrocnemius muscle of the same animals. A critical component of this study was extensive methodological optimization for platelet bioenergetics analysis in mice. We provide comprehensive methodological details and guiding principles for performing Seahorse bioenergetic assays on mouse platelets. Our foundational findings also suggest platelet mitochondria can reflect tissue-level mitochondrial health, pointing to a potential "liquid biopsy" approach for assessing metabolic status. Multiple key metrics of respiration showed significant correlations between platelets and muscle in the same animals, indicating that platelet bioenergetic profiles mirror the metabolic status of skeletal muscle in healthy and genetically diabetic mice. This work lays the conceptual and methodological foundation for future studies in human metabolic diseases where muscle bioenergetic dysfunction is implicated but current methods are not implementable for clinical surveillance. This study provides foundational proof-of-concept in healthy and diabetic mice, motivating validation in human studies as the next step toward biomarker development and precision medicine strategies.

Keywords:  bioenergetics; metabolism; mitochondria; platelets; skeletal muscle

DOI:  https://doi.org/10.3389/fmolb.2025.1639882