bims-medica Biomed News
on Metabolism and diet in cancer
Issue of 2026–06–14
sixteen papers selected by
Brett Chrest, Wake Forest University
  1. ACSL4-driven ferroptosis susceptibility as a targetable vulnerability in monocytic acute myeloid leukemia.
  2. Single-Cell Imaging of Mitochondrial Metabolism and Remodeling in C2C12 Murine Skeletal Muscle Cells upon Differentiation.
  3. Extracellular flux analyses indicate low ATP yield and require refinement for accurate determination of maximal oxygen consumption rate.
  4. Organelle proteomics reveals novel metabolic vulnerabilities in FLT3-ITD cells.
  5. Venetoclax with intensive chemotherapy in acute myeloid leukemia.
  6. MARBL: A Live-Cell Method for Profiling Bioenergetic Heterogeneity by Noncanonical Methionine Labeling of the Cell Surface Proteome.
  7. Metformin Redirects Autophagy from Bulk Turnover to Mitochondrial Clearance.
  8. Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of interorganellar lipid cycling.
  9. Copper transport to mitochondria by SLC25A3 contributes to skeletal myoblast differentiation and is required for survival of differentiated myotubes.
  10. Cell size modulates ferroptosis susceptibility.
  11. Semaglutide-induced loss of skeletal muscle mass is blunted by co-administration of ketone esters.
  12. Proteome Responses to Acute Inhibition of De Novo Sphingolipid Synthesis Suggest Cancer Combination Therapies.
  13. Mitochondria tethered to the nucleus secure its energy supply.
  14. Real-world pharmacokinetics of venetoclax in patients with acute myeloid leukemia in Japan.
  15. TRAP1 ablation improves mitochondrial cristae and oxidative phosphorylation in pancreatic cancer stem cells.
  16. The phosphoenolpyruvate phosphotransferase system regulates cell length and width through semi-independent pathways.
  1. Front Oncol. 2026 ;16 1837940
    ACSL4-driven ferroptosis susceptibility as a targetable vulnerability in monocytic acute myeloid leukemia.
    Federico De Marchi, Michele Gottardi.
      Ferroptosis, an iron-dependent form of regulated cell death driven by lethal lipid peroxidation, has emerged as a targetable vulnerability in cancer. ACSL4 is the rate-limiting enzyme that dictates ferroptosis sensitivity by channeling polyunsaturated fatty acids into membrane phospholipids. In acute myeloid leukemia (AML), monocytic subtypes resist BCL2 inhibition with venetoclax, yet their metabolic dependencies remain poorly defined. Here, we integrated PRISM drug-sensitivity data (6,790 compounds) and DepMap CRISPR dependencies (18,435 genes) across 15 adult AML cell lines to map drug-gene co-dependencies. A multi-cohort validation strategy - filtering 50 discovery candidates (29 testable in BeatAML) through ex vivo drug-response data in 476 primary AML specimens and clinical outcomes in 140 adults with de novo AML (TCGA-LAML) - converged on a single axis linking SRC family kinase inhibition to ACSL4 expression. ACSL4-high blasts showed enhanced dasatinib sensitivity (r = -0.25, P = 4.3 x 10-8). A composite SRC/ACSL4 signature stratified overall survival (HR 1.27; 95% CI 1.10-1.47; P = 0.0014), remaining significant after age adjustment. Single-cell atlas projection localized this signature to the monocytic compartment. The SRC/ACSL4-high state displayed a ferroptosis gene expression profile characterized by co-upregulation of ACSL4, HMOX1, and LPCAT3 with failure to upregulate the principal ferroptosis defense axis GPX4/SLC7A11. Conversely, ACSL4-high blasts showed significant ex vivo resistance to venetoclax (r = 0.36, P = 2.5 x 10-12), linking the ferroptosis-primed monocytic state to BCL2 inhibitor failure. These findings nominate ACSL4-driven ferroptosis susceptibility as a lineage-specific vulnerability rendering monocytic AML selectively sensitive to SRC-directed therapy while resistant to BCL2 inhibition.
    Keywords:  ACSL4; SRC kinase; acute myeloid leukemia; dasatinib; ferroptosis; monocytic differentiation; venetoclax resistance
    DOI:  https://doi.org/10.3389/fonc.2026.1837940
  2. Int J Mol Sci. 2026 May 22. pii: 4689. [Epub ahead of print]27(11):
    Single-Cell Imaging of Mitochondrial Metabolism and Remodeling in C2C12 Murine Skeletal Muscle Cells upon Differentiation.
    Rozhin Penjweini, Alessandra Pasut, Branden Roarke, Katie A Link, Dan L Sackett, Jay R Knutson.
      As primary sites for oxygen consumption and energy production via oxidative phosphorylation (OXPHOS), mitochondria play a central role in the regulation of bioenergetics and generation of key metabolic intermediates for myogenic cell growth. Common methods to study mitochondria and their metabolism typically rely on population-level analyses, which can mask potential differences in individual cells. In this study, we used various imaging approaches to investigate the interplay between intracellular oxygenation, mitochondrial metabolism and dynamics in a model of myogenic differentiation. Fluorescence imaging of intracellular oxygen revealed that myogenic differentiation is accompanied by progressive shifts in intracellular oxygenation that depend upon and reflect changes in mitochondrial metabolism (i.e., higher oxygen consumption and adenosine triphosphate (ATP) production). By measuring intracellular oxygenation, we showed that mitochondrial metabolism reduces oxygen availability in the cytosol and the nucleus. Real-time redox imaging at the single-cell level further highlighted substantial metabolic heterogeneity and a shift toward OXPHOS as differentiation progressed. Morphological analyses revealed that during myogenic differentiation, mitochondria increase in size while becoming less mobile and overlapping less with microtubules. Overall, this study illustrates the value of combining complementary imaging approaches to provide a comprehensive single-cell perspective on mitochondrial metabolism, remodeling and spatial organization during myogenesis.
    Keywords:  mitochondrial metabolism; mitochondrial morphology and dynamics; single-cell imaging
    DOI:  https://doi.org/10.3390/ijms27114689
  3. Sci Rep. 2026 Jun 10. pii: 18344. [Epub ahead of print]16(1):
    Extracellular flux analyses indicate low ATP yield and require refinement for accurate determination of maximal oxygen consumption rate.
    Celine Ransy, Mathieu Boissan, Noureddine Hammad, Abdelouhab Bouaboud, Tarik Issad, Maud De Dieuleveult, Benoit Miotto, Manuela Ye, Eric Pasmant, Frédéric Bouillaud.
      The Agilent Seahorse XF Analyzer has become a central tool for investigating cellular oxidative metabolism. Most studies employ the Seahorse XF Cell Mito Stress Test, which measures the oxygen consumption rate (OCR) under sequential pharmacological modulation of mitochondrial respiration. This assay partitions basal OCR into its functional components and estimates maximal OCR through uncoupler-driven stimulation of respiration, with the resulting value interpreted as the spare respiratory capacity. However, maximal OCR is obtained only after complete inhibition of ATP synthesis by oxidative phosphorylation, and its reliable determination requires appropriate uncoupler titration. Studies have underscored the limitations of this approach. To evaluate its reliability, we examined 97 recent publications reporting 530 Cell Mito Stress Tests. Strikingly, 17% of assays yielded a maximal OCR lower than the basal OCR, raising concerns about the accuracy of the method. To improve maximal OCR determination, we introduce the Cell Stimulation Test, which - analogous to maximal VO₂ assessments in patients - stimulates respiration directly from the basal state across a broad (1-8x) range of uncoupler concentrations. Using the same Seahorse plate, we compared results from both assays. Combined application of the Cell Mito Stress Test and the Cell Stimulation Test enhances the accuracy of maximal OCR assessment and eliminates the need for prior optimization of uncoupler concentration. Our survey further indicates that oxygen consumption not coupled to ATP synthesis constitutes a substantial fraction of basal cellular OCR (median ≈50%), with an unexpectedly large contribution from OCR typically classified as non-mitochondrial. We briefly discuss the implications and limitations of this observation.
    Keywords:  Energy metabolism; Extracellular fluxes; Mitochondria; Oxygen; Respiration; Seahorse
    DOI:  https://doi.org/10.1038/s41598-026-46479-w
  4. Leukemia. 2026 Jun 09.
    Organelle proteomics reveals novel metabolic vulnerabilities in FLT3-ITD cells.
    Valeria Bica, Anna Francesca Pacilè, Martin Boettcher, Valentina Marano, Veronica Marabitti, Francesca Nazio, Mirko Cortese, Thomas Fischer, Livia Perfetto, Dimitrios Mougiakakos, Giorgia Massacci, Francesca Sacco.
      In acute myeloid leukemia (AML), the insertion site of internal tandem duplications (ITDs) within the FLT3 gene critically determines the sensitivity to tyrosine kinase inhibitors (TKIs). Despite recent advances, patients harboring ITDs in the tyrosine kinase domain (TKD) still lack effective therapeutic options. To elucidate the molecular basis underlying the differential TKI sensitivity of FLT3-ITD cells, we integrated high-resolution mass spectrometry-based (phospho)proteomics with subcellular fractionation. Our analysis revealed that midostaurin induces the subcellular redistribution of approximately 2500 proteins involved in crucial biological processes, including cell cycle control, autophagy, and metabolism. Functional analyses further demonstrated that the ITD insertion site determines the autophagy response to midostaurin and modulates mitochondrial metabolism, influencing organelle architecture and ATP production, even at steady state. Importantly, by integrating subcellular proteomic dataset with functional metabolic assays, we uncovered a lipid-dependent vulnerability of FLT3-ITD cells: lipid restriction enhances FLT3 trafficking to the plasma membrane, and markedly reduces cell viability, restoring midostaurin sensitivity of resistant FLT3-ITD cells. Together, our findings reveal that the FLT3-ITD insertion site orchestrates a coordinated remodeling of subcellular protein organization, autophagy, and metabolism, and identify lipid-mediated control of FLT3 compartmentalization as a therapeutically actionable mechanism to overcome TKI resistance in FLT3-ITD AML.
    DOI:  https://doi.org/10.1038/s41375-026-03000-6
  5. Chin Clin Oncol. 2026 May 28. pii: cco-2026-1-0005. [Epub ahead of print]
    Venetoclax with intensive chemotherapy in acute myeloid leukemia.
    Logan Shaver, Omer Jamy.
      
    Keywords:  7+3; Acute myeloid leukemia (AML); intensive chemotherapy (IC); venetoclax
    DOI:  https://doi.org/10.21037/cco-2026-1-0005
  6. bioRxiv. 2026 Jun 02. pii: 2026.06.01.729353. [Epub ahead of print]
    MARBL: A Live-Cell Method for Profiling Bioenergetic Heterogeneity by Noncanonical Methionine Labeling of the Cell Surface Proteome.
    Lillian R Delacruz, Ming Ye, Kendra A Libby, Keran Han, Chad J Munger, Yunping Qiu, Irwin J Kurland, Alison E Ringel.
      Heterogeneity is a hallmark of biological systems, where cell-to-cell variability supports adaptation to changing environments, but also enables maladaptive states such as drug resistance. Many sources of non-genetic variation, particularly bioenergetics and metabolism, remain difficult to measure in living cells and connect to functional outcomes. Here, we introduce MARBL (Methionine Analogues for Ratiometric Bioenergetics in Live cells), a method that encodes translationally-coupled energetic responses to metabolic stress as an internally normalized signal within the surface proteome of living cells. Applying MARBL to primary immune cells reveals that differences in baseline translational activity can underlie apparent metabolic vulnerabilities, underscoring the importance of ratiometric measurements. We demonstrate that MARBL can enrich pathogenic from non-pathogenic TH17 cells based on resilience to bioenergetic stress, which functionally distinguishes cells that produce IFNγ upon restimulation. Overall, MARBL offers a versatile platform to profile metabolic resilience in living cells and link bioenergetic state to cellular function.
    DOI:  https://doi.org/10.64898/2026.06.01.729353
  7. bioRxiv. 2026 Jun 06. pii: 2026.06.04.730191. [Epub ahead of print]
    Metformin Redirects Autophagy from Bulk Turnover to Mitochondrial Clearance.
    Thuraya M Mutawi, Shweta R Malvankar, Andrea Graziani, Udita Shah, Khanh Nguyen, David G Broadbent, Zachary Clark, Michaella J Rekowski, Susan M Lunte, Carlo Barnaba.
      Metformin is the most widely prescribed antidiabetic drug and an active candidate for repurposing in oncology. How it engages autophagy - a pathway central to both its metabolic and its anti-tumor effects - has remained unresolved, with reports of induction, suppression, and no effect. Here we show that metformin reroutes rather than induces or inhibits autophagy in human cancer cells: at therapeutic concentrations, it suppresses bulk cytosolic turnover by selectively blocking WIPI2-mediated phagophore tethering, while the ULK1 initiation complex relocates toward mitochondria and engages selective mitochondrial clearance. We trace this redirection to mitochondrial complex I inhibition, registered as a shift in the NAD + /NADH ratio before any change in the adenylate pool, and to a non-canonical reprogramming of the ULK1 complex that operates independently of mTORC1 and of the proposed PEN2-lysosomal route. AMPK is engaged in a subunit-specific manner that restrains ATG13 at initiation and enables WIPI2 displacement at maturation. The ULK1 complex is therefore the node at which metformin sets autophagic substrate selection, with direct implications for combination therapy in diabetes and cancer.
    DOI:  https://doi.org/10.64898/2026.06.04.730191
  8. bioRxiv. 2026 Jun 03. pii: 2026.05.30.724257. [Epub ahead of print]
    Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of interorganellar lipid cycling.
    Iuliia Karavaeva, Astrid Linde Basse, Samuel A J Trammell, Mohammed Faiz Hussain, Lasse Kruse Markussen, Jesper F Havelund, Marie Sophie Isidor, Hannah J Richter, Sabina Chubanava, Yann Deleye, Zafir Kaiser, Yachen Shen, Ditte Neess, Frederike Sass, Fabian Finger, Lidia Argemi Muntadas, David Tandio, Tao Ma, Elahu Gosney Sustarsic, Hannes Embring, Cecilie Kynding Kristensen, Rebecca L McIntyre, Genesee J Martinez, Anna Sofie Husted, Matthew J Emmett, Zachary A Kipp, Mikkel Frost, Mark P Jedrychowski, Michel van Weeghel, Homa Majd, Ekaterina Zhuravleva, Robert W McGarrah, Kaja Plucinska, Mohit K Midha, Andreas Prokesch, Paul Cohen, James G Granneman, Patrick Seale, Riekelt H Houtkooper, Jacob B Hansen, Steven P Gygi, Thue W Schwartz, Matthew Paul Gillum, Terry D Hinds, Raymond Edward Soccio, Phillip J White, Edmund R S Kunji, Thomas Moritz, Jonas T Treebak, Susanne Mandrup, Brice Emanuelli, Lawrence Kazak, Nils J Færgeman, Mitchell A Lazar, Zachary Gerhart-Hines.
      Adipocyte lipid metabolism is coordinated by circadian rhythms, diet, and environmental temperature. Yet how these diverse signals are molecularly integrated remains unknown. Here we show that clock, diet, and temperature cues converge on the orphan mitochondrial transporter, SLC25A34, to orchestrate thermogenic cycling of lipid synthesis and oxidation. During sleep, the clock suppresses Slc25a34 transcription through REV-ERBα. Waking, lipid-rich diets, or cold exposure abolish this repression, allowing lipolytic signals to stimulate Slc25a34 expression via PPARα. SLC25A34 then imports oxaloacetate into mitochondria to accelerate the export of substrates used for acetyl-CoA production in the cytosol. This feeds into cytosolic lipid synthesis and transcriptional induction of mitochondrial biogenesis, which collectively promote mitochondrial lipid oxidation. Thus, SLC25A34 confers circadian, dietary, and environmental control of thermogenic metabolism through interorganellar lipid cycling.
    DOI:  https://doi.org/10.64898/2026.05.30.724257
  9. bioRxiv. 2026 Jun 07. pii: 2026.06.03.729837. [Epub ahead of print]
    Copper transport to mitochondria by SLC25A3 contributes to skeletal myoblast differentiation and is required for survival of differentiated myotubes.
    Alexandra M Perez, Jason D Fivush, Bailey M Cordill, Nathan Ferguson, Yu Zhang, Allison T Mezzell, Ushodaya Mattam, Omar Chaudhry, Karleigh G Porter, Saanvi Maadaadi, Dina Secic, Megan Bischoff, Karthickeyan Chella Krishnan, Rhett Kovall, Tom Cunningham, Maria Czyzyk-Krzeska, Katherine E Vest.
      Differentiation of skeletal muscle is associated with increased mitochondrial biogenesis and reliance of oxidative phosphorylation (OXPHOS). The terminal enzyme complex in the electron transport chain, cytochrome c oxidase (COX), requires copper for its assembly and activity, and copper delivery to mitochondria is essential for OXPHOS. However, when mitochondrial copper becomes essential during skeletal myoblast differentiation is not known. Here, we show that genetic deficiency of the mitochondrial copper and phosphate carrier SLC25A3 induced prior to myoblast differentiation leads to the formation of smaller myotubes, but SLC25A3 deficiency induced in mature myotubes leads to cell death and detachment. Both phenotypes are recapitulated upon genetic knockdown of COX17, a critical assembly protein for both COX copper cofactors, or by chemical inhibition of COX. Importantly, myotube death caused by SLC25A3 deficiency is rescued by copper supplementation or expression of an SLC25A3 variant that transports copper but not phosphate. Taken together these data support a model wherein copper transport by SLC25A3 and copper delivery to COX is critical for survival in mature myotubes.
    DOI:  https://doi.org/10.64898/2026.06.03.729837
  10. Elife. 2026 Jun 10. pii: RP111544. [Epub ahead of print]15
    Cell size modulates ferroptosis susceptibility.
    Evgeny Zatulovskiy, Magdalena B Murray, Shuyuan Zhang, Scott J Dixon, Jan M Skotheim.
      Size is a fundamental property of cells that influences many aspects of their physiology. This is because cell size sets the scale for all subcellular components and drives changes in the composition of the proteome. Given that large and small cells differ in their biochemical composition, we hypothesized that they should also differ in how they respond to signals and make decisions. Here, we investigated how cell size affects the susceptibility of human cells to cell death. We found that large cells are more resistant to ferroptosis caused by system xc- inhibition. Ferroptosis is a type of cell death characterized by the iron-dependent accumulation of toxic lipid peroxides. This process is opposed by cysteine-dependent lipid peroxide detoxification mechanisms. We found that larger cells exhibit higher concentrations of the cysteine-containing metabolite glutathione and lower concentrations of membrane lipid peroxides. Mechanistically, this can be explained by the fact that larger cells had lower concentrations of an enzyme that enriches cellular membranes with peroxidation-prone polyunsaturated fatty acids, ACSL4, and increased concentrations of the glutathione-producing enzymes glutamate-cysteine ligase and glutathione synthetase, the iron-chelating protein ferritin, and the lysosomal protease cathepsin B, which can catabolize cysteine-rich extracellular proteins to produce additional cystine for fueling the synthesis of glutathione. Taken together, our results highlight the significant impact of cell size on cellular function and survival, revealing a size-dependent vulnerability to ferroptosis that could influence therapeutic strategies based on this cell death pathway.
    Keywords:  biochemistry; cell biology; cell death; cell size; chemical biology; erastin2; ferroptosis; glutathione; heterogeneous response; human; scaling
    DOI:  https://doi.org/10.7554/eLife.111544
  11. JCI Insight. 2026 Jun 09. pii: e201810. [Epub ahead of print]
    Semaglutide-induced loss of skeletal muscle mass is blunted by co-administration of ketone esters.
    Yasser Abuetabh, Mya A Schmidt, Masaaki Naganuma, Ramana Vaka, Mahmoud A El-Ghiaty, Shelly Braun, Ethan A Kwan, Matthieu Cp Zolondek, Darius Sahid, Laibah Khan, Rajat K Shandal, Ashley L Trudeau, Yaning Li, Sufyan O Malik, Qiuyu Sun, Danica K Roth, Daniela Y Morales-Llamas, Jody L Levasseur, Mourad Ferdaoussi, Richard P Fahlman, Jason Rb Dyck.
      While glucagon-like peptide-1 receptor agonists (GLP-1RAs) like semaglutide are effective in treating obesity, up to 45% of the resulting weight loss can be attributed to skeletal muscle loss. Given the critical role of skeletal muscle in health and mobility, this may have long-term adverse consequences. Herein we investigated whether oral ketone ester supplementation could prevent semaglutide-induced muscle loss and explored the underlying molecular mechanisms. Obese, glucose-intolerant mice received vehicle, semaglutide, or semaglutide plus a β-hydroxybutyrate-generating ketone ester for three weeks. Body composition, muscle strength, and endurance were assessed longitudinally. Semaglutide monotherapy reduced lean mass, impaired muscle strength, and suppressed mitochondrial gene expression while elevating atrophy-related genes in skeletal muscle samples. Co-administration with ketone ester preserved skeletal muscle mass and function without compromising fat loss. Mechanistically, ketone ester co-treatment prevented semaglutide-induced changes in mitochondrial and atrophy-related gene expression, suggesting mitochondrial defects and impaired ketone metabolism contribute to GLP-1RA-induced muscle loss. Together, these findings demonstrate that ketone ester supplementation can maintain muscle mass and performance during semaglutide-driven weight loss. These preclinical findings support ketone therapy as a promising strategy to counteract the sarcopenia-promoting effects of GLP-1RAs and warrant clinical evaluation to assess its translational potential.
    Keywords:  Metabolism; Muscle biology; Obesity
    DOI:  https://doi.org/10.1172/jci.insight.201810
  12. Cancers (Basel). 2026 Jun 02. pii: 1827. [Epub ahead of print]18(11):
    Proteome Responses to Acute Inhibition of De Novo Sphingolipid Synthesis Suggest Cancer Combination Therapies.
    Thi Thu Trang Luu, Dakai Zhang, Khaggeswar Bheemanapally, Masihuz Zaman, Zhiping Wu, Yang Liu, Xiaoqin Wu, Hyun-Eui Kim, Lei Zheng, Besim Ogretmen, Junmin Peng, Guangwei Du.
      Background: Sphingolipids are essential structural and signaling lipids that support membrane integrity and govern cell fate decisions. While the consequences of chronic sphingolipid inhibition have been extensively explored, the immediate cellular responses to acute suppression of sphingolipid synthesis remain poorly defined. Methods: We analyzed subcellular proteomic changes following an acute reduction in sphingolipid levels induced by myriocin, an inhibitor of de novo sphingolipid synthesis. We then evaluated the cytotoxicity of co-treatment with myriocin and inhibitors of the altered pathways in cancer cells. Results: We found that de novo sphingolipid synthesis is sensitive to myriocin, an inhibitor of serine palmitoyltransferase (SPT), and can be efficiently inhibited within 4 h of treatment. Cells respond to reduced sphingolipid levels by rapidly remodeling their proteome. Mass spectrometry analysis revealed changes in the abundance of hundreds of proteins across the membrane, cytosolic, and nuclear fractions. Gene set enrichment analysis revealed alterations in the proteome across several pathways involved in protein and lipid homeostasis and stress responses, including upregulation of cholesterol homeostasis and lysosome. Co-treatment with myriocin and cholesterol synthesis or lysosomal function inhibitors synergistically reduced cancer cell viability by promoting apoptosis rather than other forms of programmed cell death. Conclusions: Together, our work provides insights into how cells rapidly rewire the abundance of certain protein classes in response to reduced sphingolipid levels and identifies signaling and metabolic pathways that can be exploited for therapeutic intervention.
    Keywords:  cancer; cholesterol synthesis; combination therapy; de novo sphingolipid synthesis; lysosome; myriocin; proteome
    DOI:  https://doi.org/10.3390/cancers18111827
  13. Nature. 2026 Jun;654(8119): 605-606
    Mitochondria tethered to the nucleus secure its energy supply.
    Philippa Clarke, Sophie Trefely.
      
    Keywords:  Cell biology; Developmental biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-026-01587-5
  14. Blood Neoplasia. 2026 Aug;3(3): 100234
    Real-world pharmacokinetics of venetoclax in patients with acute myeloid leukemia in Japan.
    Minoru Kanaya, Yuji Mukai, Goichi Yoshimoto, Mirei Kobayashi, Sayaka Kajikawa, Toma Suzuki, Naoki Miyashita, Shinpei Harada, Takashi Ishio, Emi Yokoyama, Koh Izumiyama, Makoto Saito, Masanobu Morioka, Akio Mori, Toshihiro Matsukawa, Masahiro Onozawa, Mitsuru Moriyama, SungGi Chi, Kosuke Doki, Takanori Teshima, Yosuke Minami, Masato Homma, Takeshi Kondo.
      Venetoclax (VEN) combined with azacitidine (AZA) or low-dose cytarabine (LDAC) has significantly improved outcomes for older patients with acute myeloid leukemia (AML). However, severe cytopenia often leads to treatment interruptions. Previous literature has reported that Asian patients tend to have higher plasma VEN concentrations and are more prone to severe neutropenia. We hypothesized that VEN pharmacokinetics (PK) influence these adverse events in the Japanese population. In a prospective observational study (UMIN000047371) involving 76 patients, we monitored VEN PK (trough, maximum plasma concentration, and area under the plasma concentration-time curve from 0 to 12 hours [AUC0-12]). Our analysis of an 81-sample PK data set revealed that samples taken 6 hours after VEN dose offered the best correlation to AUC0-12 (r = 0.945). Importantly, in patients who achieved composite complete remission, a positive correlation was found between the duration of grade 3 neutropenia and VEN AUC0-12 (r = 0.338; P = .028). We further investigated potential factors influencing VEN PK and neutropenia, specifically considering tumor burden and renal function. Samples from patients with pretreatment white blood cell (WBC) counts of <3000/μL and an estimated glomerular filtration rate (eGFR) of <60 mL/min exhibited significantly higher VEN AUC0-12 levels (P = .037) than other groups. These patients also demonstrated a significantly more extended period of grade 3 neutropenia (P = .037). These results suggest that VEN PK could be crucial for predicting neutrophil recovery after VEN-containing regimens in AML. Specifically, patients with low pretreatment WBC counts and low eGFR may represent a risk factor for higher VEN concentrations and, consequently, prolonged neutropenia.
    DOI:  https://doi.org/10.1016/j.bneo.2026.100234
  15. Cancer Drug Resist. 2026 ;9 17
    TRAP1 ablation improves mitochondrial cristae and oxidative phosphorylation in pancreatic cancer stem cells.
    Giulia Ambrosini, Elisa Dalla Pozza, Ilaria Cristanini, Sara Vinco, Enrica Cappellozza, Barbara Cisterna, Claudio Laquatra, Andrea Rasola, Emanuela Bottani, Ilaria Dando.
      Aim: Cancer stem cells (CSCs) in pancreatic ductal adenocarcinoma (PDAC) display high metabolic plasticity, supporting tumor aggressiveness and therapeutic resistance. Here, we investigated the role of the mitochondrial chaperone TRAP1 in regulating mitochondrial architecture, metabolism, and adhesion in CSCs. Methods: We studied an in vitro model of CSCs using Panc1 cells and the corresponding stable TRAP1-knockout cells (TRAP1-KO). Molecular techniques used were quantitative polymerase chain reaction (qPCR), Western blot, transmission electron microscopy, and Seahorse technology. Results: CSCs showed increased TRAP1 expression after 2 weeks of culture, reflecting a preferential metabolic shift toward glycolysis. TRAP1 deletion impaired the ability of CSCs to form compact spheroids without altering canonical CSC traits, such as reduced proliferation, increased stem marker expression, and enhanced chemoresistance. We demonstrate that TRAP1 deletion increases CDH1, an effect that was reversed by succinate supplementation, indicating that the TRAP1-succinate-CDH1 axis controls adhesion-related properties. Ultrastructural analyses revealed profound mitochondrial remodeling in the absence of TRAP1: parental cells displayed enlarged, elongated mitochondria with wider cristae, whereas CSCs developed fragmented mitochondria with thinner cristae and tighter crista junctions. These alterations were closely associated with the differential regulation of mitochondrial fission factor (MFF). Functionally, loss of TRAP1 enhanced oxidative phosphorylation, leading to increased mitochondrial adenosine triphosphate (ATP) production, elevated maximal respiration, and reduced proton leak. Conclusion: Collectively, these findings identify TRAP1 as a critical regulator of mitochondrial organization, respiratory efficiency, and CDH1-mediated adhesion in PDAC CSCs, highlighting metabolic and structural vulnerabilities that may be exploited therapeutically to destabilize CSC homeostasis and enhance treatment response.
    Keywords:  CDH1; Cancer stem cells; TRAP1; mitochondria; oxidative phosphorylation; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.20517/cdr.2025.229
  16. Mol Biol Cell. 2026 Jun 11. mbcE26030129
    The phosphoenolpyruvate phosphotransferase system regulates cell length and width through semi-independent pathways.
    Jacob Surber, Randy Morgenstein.
      It has been known for over 80 years that bacterial cell size is affected by growth conditions. Cells grown in nutrient rich medium are larger and wider than those grown in nutrient poor medium. Yet even after decades of research it is still not fully known how metabolism and cell size are coregulated. In this work, we describe a new source of metabolic control over Escherichia coli cell size, the phosphoenolpyruvate phosphotransferase system (PTS). The PTS is used to phosphorylate sugars upon entry into the cell. We found that mutations in this system result in both shorter and thinner cells and that the regulation of both dimensions of cell size appears to come from two separate mechanisms. The first mechanism regulates cell length through the production of cAMP, while the second mechanism regulates cell width through control of the levels of PEP or pyruvate in the cell.
    DOI:  https://doi.org/10.1091/mbc.E26-03-0129
This page is being maintained by Thomas Krichel. It was last updated on 2026‒06‒14 at 15:43.