bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2025–05–04
forty papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Mitochondrial Ca2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity.
  2. A RAS(ON) multi-selective inhibitor combination therapy triggers long-term tumor control through senescence-associated tumor-immune equilibrium in PDAC.
  3. Cancer-Associated Cachexia: Bridging Clinical Findings with Mechanistic Insights in Human Studies.
  4. Dissecting the Heterogeneity of Senescent Cells Through CITE-seq Integration.
  5. Hypoxia Induces Extensive Protein and Proteolytic Remodeling of the Cell Surface in Pancreatic Adenocarcinoma (PDAC) Cell Lines.
  6. GIPR agonism and antagonism decrease body weight and food intake via different mechanisms in male mice.
  7. Decipher the single-cell level responses to chemotherapy in pancreatic ductal adenocarcinoma by a cross-time context graph model.
  8. Intracellular metabolic gradients dictate dependence on exogenous pyruvate.
  9. Cytosolic NADK is conditionally essential for folate-dependent nucleotide synthesis.
  10. N-acetyl-l-cysteine averts ferroptosis by fostering glutathione peroxidase 4.
  11. Cancer Cell Identification via Lysosomal Membrane Microviscosities Using a Green-Emitting BODIPY Molecular Rotor.
  12. MTMR regulates KRAS function by controlling plasma membrane levels of phospholipids.
  13. 3D virtual biopsy of in vivo pH and metabolism using PRESS and semi-LASER MRS of hyperpolarized 13C nuclei.
  14. Direct Inhibition of RAS Reveals the Features of Oncogenic Signaling Driven by RAS G12 and Q61 Mutations.
  15. Competing signaling pathways controls electrotaxis.
  16. Reliable Radiologic Skeletal Muscle Area Assessment - A Biomarker for Cancer Cachexia Diagnosis.
  17. GDF15 drives de novo lipogenesis and contributes to ovarian cancer metastasis.
  18. Ribosomal rebellion: When protein factories drive cancer progression.
  19. Prediabetes and Pancreatic Cancer Risk.
  20. ESMO Clinical Practice Guideline Express Update on the management of metastatic pancreatic cancer.
  21. Single cell spatial proteomics maps human liver zonation patterns and their vulnerability to fibrosis.
  22. Resistance exercise combined with protein supplementation for skeletal muscle mass in people with pancreatic cancer undergoing neoadjuvant chemotherapy: Study protocol for the REBUILD trial.
  23. Deep tissue imaging of cancer in the infrared.
  24. Mitochondrial CCN1 drives ferroptosis via fatty acid β-oxidation.
  25. Local Clustering and Global Spreading of Receptors for Optimal Spatial Gradient Sensing.
  26. Proximity Labeling of Cell Surface Proteins via Cell Surface Remodeling.
  27. Myosin-Independent Amoeboid Cell Motility.
  28. Mitochondria - the CEO of the cell.
  29. Cell cycle duration determines oncogenic transformation capacity.
  30. NAD kinase essentiality in cancer: in real life, it is all about folates.
  31. FABP4-tastic Pancreatic Stellate Cells Coddle KITL to Uphold Inherent Microenvironmental Tumor Suppression.
  32. Hemoglobin S Promotes Glycemic Dysregulation in a Mouse Model of Human Sickle Cell Disease.
  33. PSAT1 impairs ferroptosis and reduces immunotherapy efficacy via GPX4 hydroxylation.
  34. SPAC: a scalable, integrated enterprise platform for end-to-end single cell spatial analysis of multiplexed tissue imaging.
  35. Protein diffusion controls how single cells respond to electric fields.
  36. Post-transcriptional regulator HuR promotes immune evasion in pancreatic ductal adenocarcinoma.
  37. B4GALT5 inhibits CD8+ T-cell response by downregulating MHC-I level through ERAD pathway in PDAC.
  38. Identifying the specific lipid biomarkers and LYPLA1 as a novel candidate in intramuscular fat deposition of Erhualian pigs.
  39. Regional differences in progenitor metabolism shape brain growth during development.
  40. Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling.
  1. Cell Rep. 2025 Apr 24. pii: S2211-1247(25)00398-5. [Epub ahead of print]44(5): 115627
    Mitochondrial Ca2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity.
    Jillian S Weissenrieder, Jessica Peura, Usha Paudel, Nikita Bhalerao, Natalie Weinmann, Calvin Johnson, Maximilian Wengyn, Rebecca Drager, Emma Elizabeth Furth, Karl Simin, Marcus Ruscetti, Ben Z Stanger, Anil K Rustgi, Jason R Pitarresi, J Kevin Foskett.
      Endoplasmic reticulum to mitochondria Ca2+ transfer is important for cancer cell survival, but the role of mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCU) in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Here, we show that increased MCU expression is associated with malignancy and poorer outcomes in patients with PDAC. In isogenic murine PDAC models, Mcu deletion (McuKO) ablated mitochondrial Ca2+ uptake, which reduced proliferation and inhibited self-renewal. Orthotopic implantation of MCU-null tumor cells reduced primary tumor growth and metastasis. Mcu deletion reduced the cellular plasticity of tumor cells by inhibiting epithelial-to-mesenchymal transition (EMT), which contributes to metastatic competency in PDAC. Mechanistically, the loss of mitochondrial Ca2+ uptake reduced the expression of the key EMT transcription factor Snail and secretion of the EMT-inducing ligand TGF-β. Snail re-expression and TGF-β treatment rescued deficits in McuKO cells and restored their metastatic ability. Thus, MCU may present a therapeutic target in PDAC to limit cancer-cell-induced EMT and metastasis.
    Keywords:  CP: Cancer; CP: Metabolism; EMT; MCU; PDAC; calcium signaling; cancer; epithelial-to-mesenchymal transition; metabolism; mitochondria; pancreas; uniporter
    DOI:  https://doi.org/10.1016/j.celrep.2025.115627
  2. Cancer Discov. 2025 Apr 29.
    A RAS(ON) multi-selective inhibitor combination therapy triggers long-term tumor control through senescence-associated tumor-immune equilibrium in PDAC.
    Caroline Broderick, Riccardo Mezzadra, Exequiel M Sisso, Felix Mbuga, Rashi Raghulan, Almudena Chaves Perez, Amanda Kulick, Lingyan Jiang, Jingjing Jiang, Yu-Jui Ho, Janelle Simon, Eric Rosiek, Eric Chan, Aveline Filliol, Ronan Chaligne, Elisa de Stanchina, Ximo Pechuan-Jorge, Andrea Schietinger, Mallika Singh, Scott W Lowe.
      Pharmacological inhibition of oncogenic RAS represents an attractive strategy to target pancreatic ductal adenocarcinoma (PDAC), an almost ubiquitously RAS-driven disease. However, initial responses to targeted monotherapy inhibition of active RAS can be followed by relapses, potentially driven by the persistence of drug-tolerant tumor cells. To target these 'persister' cells, we investigated strategies to increase their immune visibility in mouse models of PDAC. We show that combining a RAS(ON) multi-selective inhibitor with the CDK4/6 inhibitor palbociclib drives persister cells into a senescent-like state, which coincides with improved tumor control and substantial remodeling of the tumor microenvironment. Combining RAS(ON) and CDK4/6 inhibition with a CD40 agonist results in durable regressions and CD4 T cell-dependent tumor-immune equilibrium. Our studies reveal a combinatorial approach that circumvents resistance to RAS(ON) inhibitor monotherapy in preclinical models and demonstrate a mechanism by which therapy-induced senescence can be reinforced by the immune system, resulting in durable tumor control.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-1425
  3. Cancer Discov. 2025 Apr 29. OF1-OF26
    Cancer-Associated Cachexia: Bridging Clinical Findings with Mechanistic Insights in Human Studies.
    Kexin Koh, Rachel Scott, Elizabeth M Cespedes Feliciano, Tobias Janowitz, Marcus D Goncalves, Eileen P White, Barry J A Laird, Kerstin Haase, Mariam Jamal-Hanjani.
       SIGNIFICANCE: CAC represents a significant clinical unmet need. Despite its high prevalence and associated mortality and morbidity, there are currently no globally approved effective therapies. This review provides a comprehensive overview of human studies aimed at defining CAC clinically and identifying mediators underlying it that are revealing effective health interventions. Furthermore, we highlight ongoing international efforts to advance our understanding of CAC.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-0293
  4. Methods Mol Biol. 2025 ;2908 99-109
    Dissecting the Heterogeneity of Senescent Cells Through CITE-seq Integration.
    Kotb Abdelmohsen, Krystyna Mazan-Mamczarz, Dimitrios Tsitsipatis, Martina Rossi, Rachel B Munk, Myriam Gorospe.
      Cellular senescence, a state of persistent growth arrest following cell damage, is associated with aging and age-related diseases. Understanding cell heterogeneity within senescent populations is crucial for developing therapies to mitigate senescence-associated pathologies. The protocol described here outlines an integrated approach to exploit the presence of cell surface proteins on subsets of senescent cells to study their heterogeneity at the single-cell level. After identifying senescence-associated surface proteins by mass spectrometry (MS) and then performing cellular indexing of transcriptomes and epitopes sequencing (CITE-seq) single-cell analysis, we were able to identify unique transcriptomic programs associated with specific surface protein markers expressed in some senescent cells but not in others. We illustrate the utility of this approach by investigating the complex heterogeneity of senescent cell populations. However, this methodology can be applied to other biological scenarios where cells with unique transcriptomic profiles can be studied individually, thanks to the presence of specific cell surface proteins that distinguish them from other cells within the same population.
    Keywords:  CITE-seq; Cell cycle; Multiomics; Proteome; Senescence; Single-cell transcriptome; Surface proteins; Transcriptome
    DOI:  https://doi.org/10.1007/978-1-0716-4434-8_7
  5. J Proteome Res. 2025 May 01.
    Hypoxia Induces Extensive Protein and Proteolytic Remodeling of the Cell Surface in Pancreatic Adenocarcinoma (PDAC) Cell Lines.
    Irene Lui, Kaitlin Schaefer, Lisa L Kirkemo, Jie Zhou, Rushika M Perera, Kevin K Leung, James A Wells.
      The tumor microenvironment (TME) plays a crucial role in cancer progression. Hypoxia is a hallmark of the TME and induces a cascade of molecular events that affect cellular processes involved in metabolism, metastasis, and proteolysis. In pancreatic ductal adenocarcinoma (PDAC), tumor tissues are extremely hypoxic. Here, we leveraged mass spectrometry technologies to examine hypoxia-induced alterations in the abundance and proteolytic modifications to cell surface and secreted proteins. Across four PDAC cell lines, we discovered extensive proteolytic remodeling of cell surface proteins involved in cellular adhesion and motility. Looking outward at the surrounding secreted space, we identified hypoxia-regulated secreted and proteolytically shed proteins involved in regulating the humoral immune and inflammatory response, and an upregulation of proteins involved in metabolic processing and tissue development. Combining cell surface N-terminomics and secretomics to evaluate the cellular response to hypoxia enabled us to identify significantly altered candidate proteins which may serve as potential biomarkers and therapeutic targets in PDAC. Furthermore, this approach provides a blueprint for studying dysregulated extracellular proteolysis in other cancers and inflammatory diseases.
    Keywords:  Cancer-regulated proteolysis; Cell surface N-terminomics; Hypoxia; Protein shedding; Secretomics; Tumor microenvironment
    DOI:  https://doi.org/10.1021/acs.jproteome.4c01037
  6. Nat Metab. 2025 Apr 29.
    GIPR agonism and antagonism decrease body weight and food intake via different mechanisms in male mice.
    Robert M Gutgesell, Ahmed Khalil, Arkadiusz Liskiewicz, Gandhari Maity-Kumar, Aaron Novikoff, Gerald Grandl, Daniela Liskiewicz, Callum Coupland, Ezgi Karaoglu, Seun Akindehin, Russell Castelino, Fabiola Curion, Xue Liu, Cristina Garcia-Caceres, Alberto Cebrian-Serrano, Jonathan D Douros, Patrick J Knerr, Brian Finan, Richard D DiMarchi, Kyle W Sloop, Ricardo J Samms, Fabian J Theis, Matthias H Tschöp, Timo D Müller.
      Agonists and antagonists of the glucose-dependent insulinotropic polypeptide receptor (GIPR) enhance body weight loss induced by glucagon-like peptide-1 receptor (GLP-1R) agonism. However, while GIPR agonism decreases body weight and food intake in a GLP-1R-independent manner via GABAergic GIPR+ neurons, it remains unclear whether GIPR antagonism affects energy metabolism via a similar mechanism. Here we show that the body weight and food intake effects of GIPR antagonism are eliminated in mice with global loss of either Gipr or Glp-1r but are preserved in mice with loss of Gipr in either GABAergic neurons of the central nervous system or peripherin-expressing neurons of the peripheral nervous system. Single-nucleus RNA-sequencing shows opposing effects of GIPR agonism and antagonism in the dorsal vagal complex, with antagonism, but not agonism, closely resembling GLP-1R signalling. Additionally, GIPR antagonism and GLP-1R agonism both regulate genes implicated in synaptic plasticity. Collectively, we show that GIPR agonism and antagonism decrease body weight via different mechanisms, with GIPR antagonism, unlike agonism, depending on functional GLP-1R signalling.
    DOI:  https://doi.org/10.1038/s42255-025-01294-x
  7. Cancer Lett. 2025 Apr 26. pii: S0304-3835(25)00317-9. [Epub ahead of print] 217751
    Decipher the single-cell level responses to chemotherapy in pancreatic ductal adenocarcinoma by a cross-time context graph model.
    Xinqi Li, Yueze Liu, Feihan Zhou, Wenbo Guo, Guangyu Chen, Jinxin Tao, Jingmin Huang, Jiangdong Qiu, Hao Chen, Bo Ren, Lei You, Yanan Shi, Gang Yang, Taiping Zhang, Jin Gu, Yupei Zhao.
      Gemcitabine is commonly used for pancreatic ductal adenocarcinoma (PDAC), one of the most lethal cancer types. However, the drug resistance is a critical challenge for improving the PDAC chemotherapy. Here, we applied single-cell RNA sequencing (scRNA-seq) on PDAC patient-derived xenograft (PDX) models to study the complex cellular responses related to the gemcitabine resistances. To reconstruct dynamic tumor cell responses from these static scRNA-seq snapshots, we proposed scConGraph, a scalable bi-layer graph model that can efficiently integrate cross-time context information. Based on scConGraph, we observed that stemness and endoplasmic reticulum stress contribute to intrinsic resistance. As for acquired resistance, cancer cells may resist or evade gemcitabine treatment by activating the cell cycle, entering quiescence, or inducing epithelial-mesenchymal transition. Notably, GDF15 exhibited recurrent and significant upregulations among acquired-resistance cell subpopulations. Experimental validation confirmed that inhibiting GDF15 sensitizes tumor cells to gemcitabine, suggesting a potential target for gemcitabine-induced chemoresistance.
    Keywords:  Pancreatic ductal adenocarcinoma; chemoresistance; intratumor heterogeneity; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.canlet.2025.217751
  8. Nat Metab. 2025 Apr 28.
    Intracellular metabolic gradients dictate dependence on exogenous pyruvate.
    Benjamin T Jackson, Angela M Montero, Sangita Chakraborty, Julia S Brunner, Paige K Arnold, Anna E Bridgeman, Pavlina K Todorova, Katrina I Paras, Lydia W S Finley.
      During developmental transitions, cells frequently remodel metabolic networks, including changing reliance on metabolites such as glucose and glutamine to fuel intracellular metabolic pathways. Here we used embryonic stem (ES) cells as a model system to understand how changes in intracellular metabolic networks that characterize cell state transitions affect reliance on exogenous nutrients. We find that ES cells in the naive ground state of pluripotency increase uptake and reliance on exogenous pyruvate through the monocarboxylate transporter MCT1. Naive ES cells, but not their more committed counterparts, rely on exogenous pyruvate even when other sources of pyruvate (glucose, lactate) are abundant. Pyruvate dependence in naive ES cells is a consequence of their elevated mitochondrial pyruvate consumption at the expense of cytosolic NAD+ regeneration. Indeed, across a range of cell types, increased mitochondrial pyruvate consumption is sufficient to drive demand for extracellular pyruvate. Accordingly, restoring cytosolic NAD+ regeneration allows naive ES cells to tolerate pyruvate depletion in diverse nutrient microenvironments. Together, these data demonstrate that intracellular metabolic gradients dictate uptake and reliance on exogenous pyruvate and highlight mitochondrial pyruvate metabolism as a metabolic vulnerability of naive ES cells.
    DOI:  https://doi.org/10.1038/s42255-025-01289-8
  9. Nat Metab. 2025 May 02.
    Cytosolic NADK is conditionally essential for folate-dependent nucleotide synthesis.
    Kyle M Flickinger, Carlos A Mellado Fritz, Kimberly S Huggler, Gina M Wade, Gavin R Chang, Kathryn C Fox, Judith A Simcox, Jason R Cantor.
      Nicotinamide adenine dinucleotide kinase (NADK) catalyses the phosphorylation of NAD+ to produce NAD phosphate, the oxidized form of NADPH, a cofactor that serves a critical role in driving reductive metabolism. Cancer cells co-express two distinct NAD kinases that differ by localization (NADK, cytosol; NADK2, mitochondria). CRISPR screens performed across hundreds of cancer cell lines indicate that both are dispensable for growth in conventional culture media. By contrast, NADK deletion impaired cell growth in human plasma-like medium. Here we trace this conditional NADK dependence to the availability of folic acid. NADPH is the preferred cofactor of dihydrofolate reductase (DHFR), the enzyme that mediates metabolic activation of folic acid. We find that NADK is required for enabling cytosolic NADPH-driven DHFR activity sufficient to maintain folate-dependent nucleotide synthesis under low folic acid conditions. Our results reveal a basis for conditional NADK essentiality and suggest that folate availability determines whether DHFR activity can be sustained by alternative electron donors such as NADH.
    DOI:  https://doi.org/10.1038/s42255-025-01272-3
  10. Cell Chem Biol. 2025 Apr 28. pii: S2451-9456(25)00100-X. [Epub ahead of print]
    N-acetyl-l-cysteine averts ferroptosis by fostering glutathione peroxidase 4.
    Jiashuo Zheng, Weijia Zhang, Junya Ito, Bernhard Henkelmann, Chenxi Xu, Eikan Mishima, Marcus Conrad.
      N-acetyl-l-cysteine (NAC) is a medication and a widely used antioxidant in cell death research. Despite its somewhat obscure mechanism of action, its role in inhibiting ferroptosis is gaining increasing recognition. In this study, we demonstrate that NAC treatment rapidly replenishes the intracellular cysteine pool, reinforcing its function as a prodrug for cysteine. Interestingly, its enantiomer, N-acetyl-d-cysteine (d-NAC), which cannot be converted into cysteine, also exhibits a strong anti-ferroptotic effect. We further clarify that NAC, d-NAC, and cysteine all act as direct reducing substrates for GPX4, counteracting lipid peroxidation. Consequently, only GPX4-rather than system xc-, glutathione biosynthesis, or ferroptosis suppressor protein 1-is necessary for NAC and d-NAC to prevent ferroptosis. Additionally, we identify a broad range of reducing substrates for GPX4 in vitro, including β-mercaptoethanol. These findings provide new insights into the mechanisms underlying the protective effects of NAC and other potential GPX4-reducing substrates against ferroptosis.
    Keywords:  FSP1; GPX4; GSH; NAC; cysteine; d-NAC; ferroptosis; system x(c)(−); xCT; β-ME
    DOI:  https://doi.org/10.1016/j.chembiol.2025.04.002
  11. JACS Au. 2025 Apr 28. 5(4): 2004-2014
    Cancer Cell Identification via Lysosomal Membrane Microviscosities Using a Green-Emitting BODIPY Molecular Rotor.
    Ru Ta Bagdonaitė, Rokas Žvirblis, Jelena Dodonova-Vaitku Nienė, Artu Ras Polita.
      Lysosomes are dynamic, membrane-bound organelles that play key roles in cellular waste disposal, macromolecule recycling, and signaling. Disruptions in lysosomal function and lipid composition are implicated in a wide range of diseases including lysosomal storage disorders, fatty liver disease, atherosclerosis, and cancer. Imaging of the lysosomal lipid composition has the potential to not only enhance the understanding of lysosome-related diseases and their progression but also help identify them. In this work, we present a novel viscosity-sensitive, green-emitting BODIPY probe that can distinguish between ordered and disordered lipid phases and selectively internalize into the lysosomal membranes of live cells. Through the use of fluorescence lifetime imaging microscopy, we demonstrate that lysosomal membranes in multiple cancer cells exhibit significantly higher microviscosities compared to noncancer cells. The differences in lysosomal microviscosities provide an effective approach for identifying cancer cells and indicate that malignant cells may possess more oxidized and saturated lysosomal lipid membranes. Furthermore, we demonstrate the utility of viscosity-sensitive probes in quantifying the compositional changes in lysosomal membranes by investigating the effects of lysosome-permeabilizing cationic amphiphilic drugs (CADs), sertraline, and astemizole. Our results reveal that despite their functional similarities, these CADs exert opposite effects on lysosomal microviscosities in both cancerous and noncancerous cells, suggesting that different mechanisms may contribute to the CAD-induced lysosomal damage and leakage.
    DOI:  https://doi.org/10.1021/jacsau.5c00253
  12. J Cell Biol. 2025 Jul 07. pii: e202403126. [Epub ahead of print]224(7):
    MTMR regulates KRAS function by controlling plasma membrane levels of phospholipids.
    Taylor E Lange, Ali Naji, Ransome van der Hoeven, Hong Liang, Yong Zhou, Gerald R V Hammond, John F Hancock, Kwang-Jin Cho.
      KRAS, a small GTPase involved in cell proliferation and differentiation, frequently gains activating mutations in human cancers. For KRAS to function, it must bind the plasma membrane (PM) via interactions between its membrane anchor and phosphatidylserine (PtdSer). Therefore, depleting PM PtdSer abrogates KRAS PM binding and activity. From a genome-wide siRNA screen to identify genes regulating KRAS PM localization, we identified a set of phosphatidylinositol (PI) 3-phosphatases: myotubularin-related proteins (MTMR) 2, 3, 4, and 7. Here, we show that silencing MTMR 2/3/4/7 disrupts KRAS PM interactions by reducing PM PI 4-phosphate (PI4P) levels, thereby disrupting the localization and operation of ORP5, a lipid transfer protein maintaining PM PtdSer enrichment. Concomitantly, silencing MTMR 2/3/4/7 elevates PM PI3P levels while reducing PM and total PtdSer levels. We also observed MTMR 2/3/4/7 expression is interdependent. We propose that the PI 3-phosphatase activity of MTMR is required for generating PM PI, necessary for PM PI4P synthesis, promoting the PM localization of PtdSer and KRAS.
    DOI:  https://doi.org/10.1083/jcb.202403126
  13. Magn Reson Med. 2025 May 01.
    3D virtual biopsy of in vivo pH and metabolism using PRESS and semi-LASER MRS of hyperpolarized 13C nuclei.
    Wolfgang Gottwald, Luca Nagel, Martin Grashei, Sebastian Bauer, Nadine Setzer, Florian Gaksch, Sandra Sühnel, Jason G Skinner, Rickmer Braren, Irina Heid, Geoffrey J Topping, Franz Schilling.
       PURPOSE: To develop and evaluate sequences for multi-voxel magnetic resonance spectroscopy using hyperpolarized molecules.
    METHODS: A standard single voxel PRESS sequence was extended to acquire multiple voxels consecutively. Its SNR was compared against a 2D FID-CSI with both 1H and hyperpolarized 13C nuclei in phantoms and in a healthy mouse at 7T. This sequence was also used to determine tumor pH and metabolic activity in an endogenous murine pancreatic ductal adenocarcinoma model. Furthermore, a semi-LASER sequence, using adiabatic full passage RF pulses for refocusing, was implemented. Multi-voxel PRESS and semi-LASER were then compared in healthy mice for measuring metabolic activity and pH using hyperpolarized [1-13C]pyruvate and [1,5-13C2]Z-OMPD, respectively.
    RESULTS: Multi-voxel PRESS and semi-LASER detected 13C metabolites in mouse kidneys and endogenous pancreatic ductal adenocarcinoma (PDAC) tumors with SNR comparable to that of standard 2D FID-CSI. They enable fast MRS with a high spectral resolution that is highly customizable to recover spectra from regions not coverable by a single CSI slice.
    CONCLUSION: For the first time, we show hyperpolarized MRS using multi-voxel PRESS and semi-LASER sequences for hyperpolarized 13C-labeled molecules. By implementing a semi-LASER sequence using adiabatic full passage refocusing pulses, RF saturation was reduced. Semi-LASER allows flexible overlapping of voxel refocusing planes, while for PRESS, signal from these regions is attenuated.
    Keywords:  13C hyperpolarization; MR‐spectroscopy; pH; pyruvate; semi‐LASER
    DOI:  https://doi.org/10.1002/mrm.30544
  14. Cancer Discov. 2025 Apr 28. OF1-OF18
    Direct Inhibition of RAS Reveals the Features of Oncogenic Signaling Driven by RAS G12 and Q61 Mutations.
    Michelangelo Marasco, Dinesh Kumar, Santiago Garcia Borrego, Tessa Seale, Giulia Maddalena, Riccardo Mezzadra, Kylie Belanger, Soren Cole, Brayan Perez, Wei Luan, Radha Mukherjee, Ilinca Aricescu, Vladimir Markov, Yuxin Zhu, Sabrina Arena, Alberto Bardelli, Elisa de Stanchina, Scott W Lowe, Richard A Burkhart, Jacquelyn W Zimmerman, Rona Yaeger, Scott E Kopetz, Neal Rosen, Sandra Misale.
       SIGNIFICANCE: RAS inhibition in multiple tumor types reveals the difference between G12 mutants and Q61 mutants in their cooperation with upstream regulators and downstream effectors to promote oncogenic signaling. Our findings provide the rationale for combinatorial approaches and contribute to explaining the nonuniform distribution of RAS mutations, de novo and at resistance.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0614
  15. iScience. 2025 May 16. 28(5): 112329
    Competing signaling pathways controls electrotaxis.
    S Kulkarni, F Tebar, C Rentero, M Zhao, P Sáez.
      Understanding how cells follow exogenous cues is a key question for biology, medicine, and bioengineering. Growing evidence shows that electric fields represent a precise and programmable method to control cell migration. Most data suggest that the polarization of membrane proteins and the following downstream signaling are central to electrotaxis. Unfortunately, how these multiple mechanisms coordinate with the motile machinery of the cell is still poorly understood. Here, we develop a mechanistic model that explains electrotaxis across different cell types. Using the zebrafish proteome, we identify membrane proteins directly related to migration signaling pathways that polarize anodally and cathodally. Further, we show that the simultaneous and asymmetric distribution of these membrane receptors establish multiple cooperative and competing stimuli for directing the anodal and cathodal migration of the cell. Using electric fields, we enhance, cancel, or switch directed cell migration, with clear implications in promoting tissue regeneration or arresting tumor progression.
    Keywords:  Biophysics; Cell biology; Mechanobiology
    DOI:  https://doi.org/10.1016/j.isci.2025.112329
  16. medRxiv. 2025 Apr 25. pii: 2025.04.21.25326162. [Epub ahead of print]
    Reliable Radiologic Skeletal Muscle Area Assessment - A Biomarker for Cancer Cachexia Diagnosis.
    Sabeen Ahmed, Nathan Parker, Margaret Park, Daniel Jeong, Lauren Peres, Evan W Davis, Jennifer B Permuth, Erin Siegel, Matthew B Schabath, Yasin Yilmaz, Ghulam Rasool.
      Cancer cachexia is a common metabolic disorder characterized by severe muscle atrophy which is associated with poor prognosis and quality of life. Monitoring skeletal muscle area (SMA) longitudinally through computed tomography (CT) scans, an imaging modality routinely acquired in cancer care, is an effective way to identify and track this condition. However, existing tools often lack full automation and exhibit inconsistent accuracy, limiting their potential for integration into clinical workflows. To address these challenges, we developed SMAART-AI (Skeletal Muscle Assessment-Automated and Reliable Tool-based on AI), an end-to-end automated pipeline powered by deep learning models (nnU-Net 2D) trained on mid-third lumbar level CT images with 5-fold cross-validation, ensuring generalizability and robustness. SMAART-AI incorporates an uncertainty-based mechanism to flag high-error SMA predictions for expert review, enhancing reliability. We combined the SMA, skeletal muscle index, BMI, and clinical data to train a multi-layer perceptron (MLP) model designed to predict cachexia at the time of cancer diagnosis. Tested on the gastroesophageal cancer dataset, SMAART-AI achieved a Dice score of 97.80% ± 0.93%, with SMA estimated across all four datasets in this study at a median absolute error of 2.48% compared to manual annotations with SliceOmatic. Uncertainty metrics - variance, entropy, and coefficient of variation - strongly correlated with SMA prediction errors (0.83, 0.76, and 0.73 respectively). The MLP model predicts cachexia with 79% precision, providing clinicians with a reliable tool for early diagnosis and intervention. By combining automation, accuracy, and uncertainty awareness, SMAART-AI bridges the gap between research and clinical application, offering a transformative approach to managing cancer cachexia.
    DOI:  https://doi.org/10.1101/2025.04.21.25326162
  17. Biochim Biophys Acta Mol Basis Dis. 2025 Apr 23. pii: S0925-4439(25)00216-9. [Epub ahead of print]1871(6): 167868
    GDF15 drives de novo lipogenesis and contributes to ovarian cancer metastasis.
    Chenxi Wang, Zhengjie Ou, Hongming Deng, Ying Zhang, Xiaoyang Li, Xiaobing Wang, Dan Zhao.
      Ovarian cancer is frequently diagnosed at an advanced stage, characterized by extensive metastasis. Recent studies indicate that metastatic and primary tumors exhibit similar mutational landscape, suggesting that non-mutational factors significantly contribute to the metastatic process. Enhanced lipid metabolism has been implicated across various stages of cancer progression, making the targeting of metabolic vulnerabilities a promising therapeutic strategy. In this study, we demonstrate that growth differentiation factor 15 (GDF15), a member of the TGF-β superfamily, which has been Indicated to be associated with several metabolic diseases, is significantly elevated in the serum of ovarian cancer patients, particularly in metastatic lesions compared to primary tumors. Elevated GDF15 levels correlate with reduced overall survival and progression-free survival. Furthermore, we found that GDF15 facilitates tumor metastasis by regulating de novo lipogenesis through the PI3K/AKT signaling pathway. These findings suggest that targeting GDF15-mediated lipid metabolism could provide a novel therapeutic approach to inhibit ovarian cancer metastasis.
    Keywords:  GDF15; Lipogenesis; Ovarian cancer metastasis; PI3K/AKT pathway
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167868
  18. Cancer Cell. 2025 Apr 18. pii: S1535-6108(25)00136-9. [Epub ahead of print]
    Ribosomal rebellion: When protein factories drive cancer progression.
    Qiushuang Wu, Sohail F Tavazoie.
      In Cancer Cell, two studies unveil mechanisms by which co-option of the protein synthesis machinery promotes cancer progression and potential therapeutic interventions. Kuzuoglu-Ozturk et al. show that eIF4A-mediated enhancement of oncogenic transcript translation initiation drives cancer progression, while Weller et al. demonstrate how aberrant transfer RNA (tRNA) modification disrupts translational fidelity to produce neoantigens.
    DOI:  https://doi.org/10.1016/j.ccell.2025.03.035
  19. Pancreas. 2025 May 01. 54(5): e501
    Prediabetes and Pancreatic Cancer Risk.
    Kuan-Fu Liao, Shih-Wei Lai.
      
    DOI:  https://doi.org/10.1097/MPA.0000000000002454
  20. ESMO Open. 2025 Apr;pii: S2059-7029(25)00397-7. [Epub ahead of print]10(4): 104528
    ESMO Clinical Practice Guideline Express Update on the management of metastatic pancreatic cancer.
    ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org
      
    Keywords:  FOLFIRINOX; NALIRIFOX; gemcitabine; guideline; metastatic pancreatic cancer; systemic treatment
    DOI:  https://doi.org/10.1016/j.esmoop.2025.104528
  21. bioRxiv. 2025 Apr 13. pii: 2025.04.13.648568. [Epub ahead of print]
    Single cell spatial proteomics maps human liver zonation patterns and their vulnerability to fibrosis.
    Caroline A M Weiss, Lauryn A Brown, Lucas Miranda, Paolo Pellizzoni, Shani Ben-Moshe, Sophia Steigerwald, Kirsten Remmert, Jonathan Hernandez, Karsten Borgwardt, Florian A Rosenberger, Natalie Porat-Shliom, Matthias Mann.
      Understanding protein distribution patterns across tissue architecture is crucial for deciphering organ function in health and disease. Here, we applied single-cell Deep Visual Proteomics to perform spatially-resolved proteome analysis of individual cells in native tissue. We combined this with a novel strategic cell selection pipeline and a continuous protein gradient mapping framework to investigate larger clinical cohorts. We generated a comprehensive spatial map of the human hepatic proteome by analyzing hundreds of individual hepatocytes from 18 individuals. Among more than 2,500 proteins per cell about half exhibited zonated expression patterns. Cross-species comparison with mouse data revealed conserved metabolic functions and human-specific features of liver zonation. Analysis of fibrotic samples demonstrated widespread disruption of protein zonation, with pericentral proteins being particularly susceptible. Our study provides a comprehensive resource of human liver organization while establishing a broadly applicable framework for spatial proteomics analyses along tissue gradients.
    DOI:  https://doi.org/10.1101/2025.04.13.648568
  22. PLoS One. 2025 ;20(5): e0322192
    Resistance exercise combined with protein supplementation for skeletal muscle mass in people with pancreatic cancer undergoing neoadjuvant chemotherapy: Study protocol for the REBUILD trial.
    Paola Gonzalo-Encabo, John Gardiner, Mary K Norris, Rebekah L Wilson, Amber J Normann, Danny Nguyen, Nathan Parker, Darryl Tjogas, Lauren K Brais, Jeffrey A Meyerhardt, Michael H Rosenthal, Brian M Wolpin, Hajime Uno, Christina M Dieli-Conwright.
       BACKGROUND: Pancreatic cancer patients' prognosis may be limited by two conditions, cachexia and sarcopenia. Resistance exercise and protein supplementation are safe non-pharmacological strategies that may increase or preserve skeletal muscle mass within this population. Therefore, the primary aim of this study is to examine the feasibility of a home-based virtually supervised resistance exercise intervention, with or without protein supplementation in pancreatic cancer patients initiating neoadjuvant chemotherapy. This intervention may also maintain skeletal muscle mass and improve plasma biomarkers associated with muscle tissue wasting, physical function and psychological measures.
    METHODS: We aim to recruit 45 patients with locally advanced pancreatic cancer initiating neoadjuvant chemotherapy. Patients will be randomized to receive either Resistance Exercise (RE) (n = 15), Resistance Exercise and Protein Supplementation (RE + PS) (n = 15), or Attention Control (AC) (n = 15). Patients randomized to RE or RE + PS will receive 16-weeks of home-based virtually supervised resistance exercise. The AC will receive a 16-week stretching program. Primary and secondary outcomes will be measured at baseline and after 16 weeks during study visits.
    DISCUSSION: The REBUILD trial is the first randomized controlled trial that combines resistance exercise with daily protein supplementation during neoadjuvant chemotherapy in pancreatic cancer patients. Our novel home-based virtually supervised exercise intervention seeks to mitigate barriers to participation in this vulnerable population. Furthermore, results of this trial will address important research gaps associated with pancreatic cancer-related cachexia, a condition closely connected with poor prognosis and mortality.
    DOI:  https://doi.org/10.1371/journal.pone.0322192
  23. Nat Rev Cancer. 2025 Apr 28.
    Deep tissue imaging of cancer in the infrared.
    Ali Yasin Sonay.
      
    DOI:  https://doi.org/10.1038/s41568-025-00823-w
  24. Dev Cell. 2025 Apr 18. pii: S1534-5807(25)00206-0. [Epub ahead of print]
    Mitochondrial CCN1 drives ferroptosis via fatty acid β-oxidation.
    Wanxin Guo, Congcong Zhang, Qianjun Zhou, Tianxiang Chen, Xin Xu, Jianfeng Zhang, Xuewen Yu, Han Wu, Xiao Zhang, Lifang Ma, Kun Qian, Daniel J Klionsky, Rui Kang, Guido Kroemer, Yongchun Yu, Daolin Tang, Jiayi Wang.
      Ferroptosis is a type of oxidative cell death, although its key metabolic processes remain incompletely understood. Here, we employ a comprehensive multiomics screening approach that identified cellular communication network factor 1 (CCN1) as a metabolic catalyst of ferroptosis. Upon ferroptosis induction, CCN1 relocates to mitochondrial complexes, facilitating electron transfer flavoprotein subunit alpha (ETFA)-dependent fatty acid β-oxidation. Compared with a traditional carnitine O-palmitoyltransferase 2 (CPT2)-ETFA pathway, the CCN1-ETFA pathway provides additional substrates for mitochondrial reactive oxygen species production, thereby stimulating ferroptosis through lipid peroxidation. A high-fat diet can enhance the anticancer efficacy of ferroptosis in lung cancer mouse models, depending on CCN1. Furthermore, primary lung cancer cells derived from patients with hypertriglyceridemia or high CCN1 expression demonstrate increased susceptibility to ferroptosis in vitro and in vivo. These findings do not only identify the metabolic role of mitochondrial CCN1 but also establish a strategy for enhancing ferroptosis-based anticancer therapies.
    Keywords:  CCN1; cell death; mitochondria
    DOI:  https://doi.org/10.1016/j.devcel.2025.04.004
  25. Phys Rev Lett. 2025 Apr 18. 134(15): 158401
    Local Clustering and Global Spreading of Receptors for Optimal Spatial Gradient Sensing.
    Albert Alonso, Robert G Endres, Julius B Kirkegaard.
      Spatial information from cell-surface receptors is crucial for processes that require signal processing and sensing of the environment. Here, we investigate the optimal placement of such receptors through a theoretical model that minimizes uncertainty in gradient estimation. Without requiring a priori knowledge of the physical limits of sensing or biochemical processes, we reproduce the emergence of clusters that closely resemble those observed in real cells. On perfect spherical surfaces, optimally placed receptors spread uniformly. When perturbations break their symmetry, receptors cluster in regions of high curvature, massively reducing estimation uncertainty. This agrees in many scenarios with mechanistic models that minimize elastic preference discrepancies between receptors and cell membranes. We further extend our model to motile receptors responding to cell-shape changes and external fluid flow, demonstrating the biological relevance of our model. Our findings provide a simple and utilitarian explanation for receptor clustering at high-curvature regions when high sensing accuracy is paramount.
    DOI:  https://doi.org/10.1103/PhysRevLett.134.158401
  26. Methods Mol Biol. 2025 ;2908 33-50
    Proximity Labeling of Cell Surface Proteins via Cell Surface Remodeling.
    Zak Vilen, Jia Meng Pang, Mia L Huang.
      Within the complex interplay of proteins, lipids and carbohydrates at the cell surface is the surfaceome, a dense layer of proteins and their posttranslationally modified counterparts that serves as a hub for cell signaling and signal transduction. The surfaceome plays crucial roles in mediating interactions between cells and the extracellular environment, which combined with their availability at the cell surface make it an attractive therapeutic target. Despite its importance, the development of technologies to selectively target cell surface proteins for empirical identification is challenged by their structural complexity. Here, we describe a proximity labeling-based technique to covalently label proteins at the cell surface with a biotin handle, enabling downstream streptavidin-based enrichment and manipulation in a variety of modalities, including fluorescence imaging, western blotting, and mass spectrometry-based proteomics.
    Keywords:  Cell surface; Lipid remodeling; Proteomics; Proximity labeling; Surfaceome
    DOI:  https://doi.org/10.1007/978-1-0716-4434-8_3
  27. Phys Rev Lett. 2025 Apr 18. 134(15): 158301
    Myosin-Independent Amoeboid Cell Motility.
    Winfried Schmidt, Walter Zimmermann, Chaouqi Misbah, Alexander Farutin.
      Mammalian cell polarization and motility are important processes involved in many physiological and pathological phenomena, such as embryonic development, wound healing, and cancer metastasis. The traditional view of mammalian cell motility suggests that molecular motors, adhesion, and cell deformation are all necessary components for mammalian cell movement. However, experiments on immune system cells have shown that the inhibition of molecular motors does not significantly affect cell motility. We present a new theory and simulations demonstrating that actin polymerization alone is sufficient to induce spontaneously cell polarity accompanied by the retrograde flow. These findings provide a new understanding of the fundamental mechanisms of cell movement and at the same time provide a simple mechanism for cell motility in diverse configurations, e.g., on an adherent substrate, in a nonadherent matrix, or in liquids.
    DOI:  https://doi.org/10.1103/PhysRevLett.134.158301
  28. J Cell Sci. 2025 May 01. pii: jcs263403. [Epub ahead of print]138(9):
    Mitochondria - the CEO of the cell.
    Laurie P Lee-Glover, Martin Picard, Timothy E Shutt.
      As we have learned more about mitochondria over the past decades, including about their essential cellular roles and how altered mitochondrial biology results in disease, it has become apparent that they are not just powerplants pumping out ATP at the whim of the cell. Rather, mitochondria are dynamic information and energy processors that play crucial roles in directing dozens of cellular processes and behaviors. They provide instructions to enact programs that regulate various cellular operations, such as complex metabolic networks, signaling and innate immunity, and even control cell fate, dictating when cells should divide, differentiate or die. To help current and future generations of cell biologists incorporate the dynamic, multifaceted nature of mitochondria and assimilate modern discoveries into their scientific framework, mitochondria need a 21st century 'rebranding'. In this Opinion article, we argue that mitochondria should be considered as the 'Chief Executive Organelle' - the CEO - of the cell.
    Keywords:  Mitochondria; Organelle; mtDNA
    DOI:  https://doi.org/10.1242/jcs.263403
  29. Nature. 2025 Apr 30.
    Cell cycle duration determines oncogenic transformation capacity.
    Danian Chen, Suying Lu, Katherine Huang, Joel D Pearson, Marek Pacal, Phillipos Peidis, Sean McCurdy, Tao Yu, Monika Sangwan, Angela Nguyen, Philippe P Monnier, Daniel Schramek, Liang Zhu, David Santamaria, Mariano Barbacid, Nagako Akeno, Kathryn A Wikenheiser-Brokamp, Rod Bremner.
      Oncogenic mutations are widespread in normal human tissues1. Similarly, in murine chimeras, cells carrying an oncogenic lesion contribute normal cells to adult tissues without causing cancer2-4. How lineages that escape cancer via normal development differ from the minority that succumb is unclear. Tumours exhibit characteristic cancer hallmarks; we therefore searched for hallmarks that differentiate cancer-prone lineages from resistant lineages. Here we show that total cell cycle duration (Tc) predicts transformation susceptibility across multiple tumour types. Cancer-prone Rb- and p107-deficient retina (Rb is also known as Rb1 and p107 is also known as Rbl1) exhibited defects in apoptosis, senescence, immune surveillance, angiogenesis, DNA repair, polarity and proliferation. Perturbing the SKP2-p27-CDK2/CDK1 axis could block cancer without affecting these hallmarks. Thus, cancer requires more than the presence of its hallmarks. Notably, every tumour-suppressive mutation that we tested increased Tc, and the Tc of the cell of origin of retinoblastoma cells was half that of resistant lineages. Tc also differentiated the cell of origin in Rb-/- pituitary cancer. In lung, loss of Rb and p53 (also known as Trp53) transforms neuroendocrine cells, whereas KrasG12D or BrafV600E mutations transform alveolar type 2 cells5-7. The shortest Tc consistently identified the cell of origin, regardless of mutation timing. Thus, relative Tc is a hallmark of initiation that distinguishes cancer-prone from cancer-resistant lineages in several settings, explaining how mutated cells escape transformation without inducing apoptosis, senescence or immune surveillance.
    DOI:  https://doi.org/10.1038/s41586-025-08935-x
  30. Nat Metab. 2025 May 02.
    NAD kinase essentiality in cancer: in real life, it is all about folates.
    Petra Marttila, Johannes Meiser.
      
    DOI:  https://doi.org/10.1038/s42255-025-01270-5
  31. Cancer Discov. 2025 May 02. 15(5): 872-874
    FABP4-tastic Pancreatic Stellate Cells Coddle KITL to Uphold Inherent Microenvironmental Tumor Suppression.
    Aleksandr Dolskii, Edna Cukierman.
      Oñate and colleagues demonstrate that KITL expression in pancreatic stellate cells is crucial for maintaining the inherent tumor-suppressive function of the pancreatic microenvironment, and its loss enables pancreatic cancer development. This pivotal discovery not only reinforces the century-old hypothesis of natural microenvironmental tumor suppression but also highlights a promising therapeutic avenue whereby restoring KITL expression could reestablish the tumor-suppressive functions of pancreas-resident fibroblastic cells. See related article by Oñate et al., p. 913.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-0212
  32. Endocrinology. 2025 Apr 29. pii: bqaf082. [Epub ahead of print]
    Hemoglobin S Promotes Glycemic Dysregulation in a Mouse Model of Human Sickle Cell Disease.
    Joseph L Zapater, Seth T Nicholoff, Nadia S Sweis, Santosh L Saraf, Brian T Layden.
      Hemoglobin S (HbS) presents a challenge to identifying glycemic dysregulation, as changes in red blood cell turnover produce inaccurate hemoglobin A1c (HbA1c) and incongruencies between HbA1c and other glycemic control measures. Concerningly, the prevalence of diabetes in those with HbS is rising, and studies demonstrate that HbS increases the risk of diabetes-related complications. Though a link between the sickle cell variant and HbA1c is reported, the precise mechanisms by which HbS affects glycemic control are unknown. Here, we utilized the Townes mouse model of sickle cell disease (SCD) to analyze the effect of sickle cell trait (SCT) and SCD on glucose homeostasis. We found that chow-fed SCD mice had greater ad libitum and fasting blood glucose than SCT or littermate controls from 8 to 20 weeks of age, along with declining fasting serum insulin with aging, regardless of sex. This was not a result of overt alterations in peripheral glucose or insulin tolerance, gross morphological changes in pancreatic structure, or deposition of iron in pancreatic islets. Furthermore, compared to age- and sex-matched SCT and littermate control mice, we found decreased pancreatic insulin content in 20-week-old SCD male mice and significantly reduced pancreatic islet area and β cell mass in SCD males and females. These findings suggest that having two copies of the HbS gene promotes early hyperglycemia and the development of pancreatic β cell dysfunction, which may enhance the risk for diabetes in this cohort.
    Keywords:  Type 2 diabetes; glucose metabolism; insulin dynamics; sickle cell anemia; sickle cell disease; sickle cell trait
    DOI:  https://doi.org/10.1210/endocr/bqaf082
  33. Nat Chem Biol. 2025 Apr 25.
    PSAT1 impairs ferroptosis and reduces immunotherapy efficacy via GPX4 hydroxylation.
    Peixiang Zheng, Zhiqiang Hu, Yuli Shen, Lina Gu, Yuan Ouyang, Yuran Duan, Guimei Ji, Bofei Dong, Yanni Lin, Ting Wen, Qi Tian, Yueru Hou, Qimin Zhou, Xue Sun, Xiaohan Chen, Katherine L Wang, Shudi Luo, Shiqi Wu, Yuening Sun, Min Li, Liwei Xiao, Qingang Wu, Ying Meng, Guijun Liu, Zheng Wang, Xueli Bai, Shengzhong Duan, Yuan Ding, Yanli Bi, Yuhao Wang, Gaopeng Li, Xiaoguang Liu, Zhimin Lu, Xiaohong Wu, Zhiyuan Tang, Daqian Xu.
      Tumor cells adapt to the inflammatory tumor microenvironment (TME) and develop resistance to immunotherapy, with ferroptosis being a major form of tumor cell death. However, the mechanisms by which tumor cells coordinate TME stimuli and their unique metabolic traits to evade ferroptosis and develop resistance to immunotherapy remain unclear. Here we showed that interferon-γ (IFNγ)-activated calcium/calmodulin-dependent protein kinase II phosphorylates phosphoserine aminotransferase 1 (PSAT1) at serine 337 (S337), allowing it to interact with glutathione peroxidase 4 (GPX4) and stabilize the protein, counteracting ferroptosis. PSAT1 elevates GPX4 stability by promoting α-ketoglutarate-dependent PHD3-mediated GPX4 proline 159 (P159) hydroxylation, disrupting its binding to HSC70 and inhibiting autophagy-mediated degradation. In mice, reconstitution of PSAT1 S337A or GPX4 P159A promotes ferroptosis and suppresses triple-negative breast cancer (TNBC) progression. Blocking PSAT1 pS337 with CPP elevates IFNγ-induced ferroptosis and enhances the efficacy of programmed cell death protein 1 (PD-1) antibodies in TNBC. Additionally, PSAT1-mediated GPX4 hydroxylation correlates with poor immunotherapy outcomes in patients with TNBC, highlighting PSAT1's noncanonical role in suppressing ferroptosis and immunotherapy sensitivity.
    DOI:  https://doi.org/10.1038/s41589-025-01887-3
  34. bioRxiv. 2025 Apr 08. pii: 2025.04.02.646782. [Epub ahead of print]
    SPAC: a scalable, integrated enterprise platform for end-to-end single cell spatial analysis of multiplexed tissue imaging.
    Fang Liu, Rui He, Thomas Sheeley, David Scheiblin, Stephen J Lockett, Lisa A Ridnour, David A Wink, Mark Jensen, Janelle Cortner, George Zaki.
       Background: Multiplexed tissue imaging enables the simultaneous detection of dozens of proteins at single-cell resolution, providing unprecedented insights into tissue organization and disease microenvironments. However, the resulting high-dimensional, gigabyte-scale datasets pose significant computational and methodological challenges. Existing analytical workflows, often fragmented between bespoke scripts and static visualizations, lack the scalability and user-friendly interfaces required for efficient, reproducible analysis. To overcome these limitations, we developed SPAC (analysis of SPAtial single-Cell datasets), a scalable, web-based ecosystem that integrates modular pipelines, high-performance computing (HPC) connectivity, and interactive visualization to democratize end-to-end single-cell spatial analysis applied to cellular positional data and protein expression levels.
    Results: SPAC is built on a modular, layered architecture that leverages community-based and newly developed tools for single-cell and spatial proteomics analysis. A specialized Python package extends these functionalities with custom analysis routines and established software engineering practices. An Interactive Analysis Layer provides web-hosted pipelines for configuring and executing complex workflows, and scalability enhancements that support distributed or parallel execution on GPU-enabled clusters. A Real-Time Visualization Layer delivers dynamic dashboards for immediate data exploration and sharing. As a showcase of its capabilities, SPAC was applied to a 4T1 breast cancer model, analyzing a multiplex imaging dataset comprising 2.6 million cells. GPU acceleration reduced unsupervised clustering runtimes from several hours to under ten minutes, and real-time visualization enabled detailed spatial characterization of tumor subregions.
    Conclusions: SPAC effectively overcomes key challenges in spatial single-cell analysis by streamlining high-throughput data processing and spatial profiling within an accessible and scalable framework. Its robust architecture, interactive interface and ease of access have the potential to accelerate biomedical research and clinical applications by converting complex imaging data into actionable biological and clinical insights.
    DOI:  https://doi.org/10.1101/2025.04.02.646782
  35. bioRxiv. 2025 Apr 10. pii: 2025.04.09.647627. [Epub ahead of print]
    Protein diffusion controls how single cells respond to electric fields.
    Ifunanya Nwogbaga, Nathan M Belliveau, Amit R Singh, Daiyue Sun, Natasha Mulenga, Julie A Theriot, Brian A Camley.
      Cells sense and respond to electric fields, using these fields as a guidance cue in wound healing and development. This sensing is done by redistribution of charged membrane proteins on the cell's surface ("sensors") via electrophoresis and electroosmotic flow. If membrane proteins have to physically rearrange on the cell's surface, how quickly can a cell respond to an applied signal? What limits the cell's ability to respond? Are galvanotaxing cells, like chemotaxing cells, limited by stochasticity from the finite number of molecules? Here, we develop a model for the response dynamics of galvanotaxing cells and show that, for weak enough field strengths, two relevant timescales emerge: the time for the cell's sensors to rearrange, which depends on their diffusion across the cell, and the time for the cell's orientation to respond to an applied field, which may be very different. We fit this model to experimental measurements on the recently-identified sensor galvanin (TMEM154) in neutrophil-like HL-60 cells, finding that given the dynamics of a cell responding to an applied field, we can predict the dynamics of the cell after the field is turned off. This fit constrains the noise of the galvanotaxis process, demonstrating that HL-60 is not limited by the stochasticity of finite sensor number. Our model also allows us to explain the effect of media viscosity on cell dynamics, and predict how cells respond to pulsed DC fields. These results place constraints on the ability to guide cells with pulsed fields, predicting that a field on half of the time is no better than a field that is always on with half the magnitude.
    DOI:  https://doi.org/10.1101/2025.04.09.647627
  36. bioRxiv. 2025 Apr 13. pii: 2025.02.07.632847. [Epub ahead of print]
    Post-transcriptional regulator HuR promotes immune evasion in pancreatic ductal adenocarcinoma.
    Yifei Guo, Jennifer M Finan, Alexandra Q Bartlett, Shamilene Sivagnanam, Katie E Blise, Nell Kirchberger, Konjit Betre, Grace A McCarthy, Kevin Hawthorne, Canping Chen, Aaron Grossberg, Zheng Xia, Lisa M Coussens, Rosalie C Sears, Jonathan R Brody, Robert Eil.
      The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is characterized by a limited infiltration of tumor-specific T cells and anti-tumor T cell activity. Extracellular factors in the PDAC TME have been widely reported to mediate immune suppression, but the contribution from tumor-intrinsic factors is not well understood. The RNA-binding protein, HuR (ELAVL1), is enriched in PDAC and negatively correlates with T cell infiltration. In an immunocompetent Kras-p53-Cre (KPC) orthotopic model of PDAC, we found that genetic disruption of HuR impaired tumor growth due to a novel role of HuR inducing T-cell suppression. Importantly, we found that HuR depletion in tumors enhanced both T cell number and activation states and diminished myeloid phenotypes by comprehensive spatial profiling of the PDAC TME. Mechanistically, HuR mediated the stabilization of mTOR pathway transcripts, and inhibition of mTOR activity rescued the impaired function of local T cells. Translating these findings, we demonstrated that HuR depletion sensitized PDAC tumors to immune checkpoint blockade, while isogenic, wildtype tumors are resistant. For the first time, we show that HuR facilitates tumor immune suppression in PDAC by inhibiting T cell infiltration and function and implicate targeting HuR as a potential therapeutic strategy in combination with immunotherapy.
    DOI:  https://doi.org/10.1101/2025.02.07.632847
  37. J Immunother Cancer. 2025 May 02. pii: e010908. [Epub ahead of print]13(5):
    B4GALT5 inhibits CD8+ T-cell response by downregulating MHC-I level through ERAD pathway in PDAC.
    Xin Xing, Shi-Qi Yin, Xia-Qing Li, Hui Li, Hong-Tai Ma, Aziguli Tulamaiti, Shu-Yu Xiao, Yu-Tong Liu, Hao Zhang, Zhigang Zhang, Yan-Miao Huo, Xiao-Mei Yang, Yan Yang, Xue-Li Zhang.
       BACKGROUND: Immune evasion is a crucial event in the progression of pancreatic ductal adenocarcinoma (PDAC). The identification of new immunotherapeutic targets may provide a promising platform for advancing PDAC treatment. This study aims to investigate the role of beta-1,4-galactosyltransferase-5 (B4GALT5) in immune evasion by pancreatic cancer cells and evaluate its potential as an immunotherapeutic target.
    METHODS: We conducted a comprehensive analysis using RNA sequencing data and tissue microarrays from patients with PDAC to investigate the association between B4GALT5 expression and patient prognosis. Using animal models, we further explored the impact of B4GALT5 on the quantity and activity of tumor-infiltrating CD8+ T cells. RNA sequencing and co-immunoprecipitation were used to explore the mechanism by which B4GALT5 regulates major histocompatibility complex (MHC-I) levels.
    RESULTS: Our study demonstrates that high expression of B4GALT5 in tumor cells is significantly associated with poor prognosis in patients with PDAC and reduced cytotoxic activity of tumor-infiltrating CD8+ T cells. Specifically, B4GALT5 suppresses MHC-I expression in tumor cells through the endoplasmic reticulum-associated degradation pathway, enabling them to evade immune surveillance by CD8+ T cells.
    CONCLUSIONS: B4GALT5 impairs CD8+ T-cell recognition of tumor cells by regulating MHC-I levels, thereby promoting immune evasion. This makes B4GALT5 a highly promising immunotherapeutic target for improving the poor prognosis of patients with PDAC.
    Keywords:  Immunotherapy; Major histocompatibility complex - MHC; T cell; Tumor microenvironment - TME
    DOI:  https://doi.org/10.1136/jitc-2024-010908
  38. BMC Genomics. 2025 Apr 25. 26(1): 407
    Identifying the specific lipid biomarkers and LYPLA1 as a novel candidate in intramuscular fat deposition of Erhualian pigs.
    Wenjing Meng, JiaYu Yan, Yuelei Zhao, Zijian Ye, Xiangfei Ma, Wei Wei, Jie Chen, Lifan Zhang.
       BACKGROUND: Intramuscular fat (IMF) is a key determinant of meat quality enhancement in pigs. However, its correlation with subcutaneous fat (SCF) deposition presents a challenge. The precise regulation of IMF lipogenesis, without impacting SCF deposition, is a critical issue in the pig industry. To investigate this, our study examined the lipid profiles of longissimus dorsi (LD) muscle and subcutaneous adipose tissue in high IMF (IMFH) and low IMF (IMFL) Chinese Erhualian pigs using lipidomics techniques.
    RESULTS: We identified 112 differentially abundant lipids (DALs) in the muscle and 101 DALs in the adipose tissue. Notably, 105 specific DALs associated with IMF, including various candidate markers like upregulated lipids of PS (19:2/18:1), TG (14:2/4:0/4:0), PS (17:1/18:2), FA(10:0) + COOH:(s), CL (20:4/18:2/18:2/18:2), and downregulated lipids of FA (20:4), SM (d43:5), TG (38:1/22:6), PC (22:3/20:3), and PC (18:2/24:8), were identified. These specific DALs were implicated in the regulation of linoleic, arachidonic, and alpha-linolenic acid metabolism, and choline metabolism in cancer. We further discovered that the lysophosphlipase 1 (LYPLA1) gene promotes differentiation and lipid deposition of intramuscular pre-adipocytes by affecting the phosphatidylcholine (PC) content.
    CONCLUSIONS: Our findings identify specific lipids associated with IMF accumulation in both skeletal muscle and subcutaneous adipose depots, thereby offering valuable insights into the lipid composition of porcine IMF and new avenues for targeted IMF deposition.
    Keywords:   LYPLA1 ; Intramuscular fat; Lipidomics; Meat quality; Pig
    DOI:  https://doi.org/10.1186/s12864-025-11611-z
  39. Cell. 2025 Apr 25. pii: S0092-8674(25)00405-2. [Epub ahead of print]
    Regional differences in progenitor metabolism shape brain growth during development.
    Natalia Baumann, Robin J Wagener, Awais Javed, Eleonora Conti, Philipp Abe, Andrea Lopes, Roberto Sansevrino, Adrien Lavalley, Elia Magrinelli, Timea Szalai, Daniel Fuciec, Clothilde Ferreira, Sabine Fièvre, Andreane Fouassier, Davide D'Amico, Oliver Harschnitz, Denis Jabaudon.
      Mammals have particularly large forebrains compared with other brain parts, yet the developmental mechanisms underlying this regional expansion remain poorly understood. Here, we provide a single-cell-resolution birthdate atlas of the mouse brain (www.neurobirth.org), which reveals that while hindbrain neurogenesis is transient and restricted to early development, forebrain neurogenesis is temporally sustained through reduced consumptive divisions of ventricular zone progenitors. This atlas additionally reveals region-specific patterns of direct and indirect neurogenesis. Using single-cell RNA sequencing, we identify evolutionarily conserved cell-cycle programs and metabolism-related molecular pathways that control regional temporal windows of proliferation. We identify the late neocortex-enriched mitochondrial protein FAM210B as a key regulator using in vivo gain- and loss-of-function experiments. FAM210B elongates mitochondria and increases lactate production, which promotes progenitor self-replicative divisions and, ultimately, the larger clonal size of their progeny. Together, these findings indicate that spatiotemporal heterogeneity in mitochondrial function regulates regional progenitor cycling behavior and associated clonal neuronal production during brain development.
    Keywords:  brain development; metabolism; mitochondria dynamics; progenitor diversity
    DOI:  https://doi.org/10.1016/j.cell.2025.04.003
  40. Nat Commun. 2025 Apr 29. 16(1): 4029
    Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling.
    Mateus Prates Mori, Oswaldo A Lozoya, Ashley M Brooks, Carl D Bortner, Cristina A Nadalutti, Birgitta Ryback, Brittany P Rickard, Marta Overchuk, Imran Rizvi, Tatiana Rogasevskaia, Kai Ting Huang, Prottoy Hasan, György Hajnóczky, Janine H Santos.
      Maintenance of the mitochondrial inner membrane potential (ΔΨm) is critical for many aspects of mitochondrial function. While ΔΨm loss and its consequences are well studied, little is known about the effects of mitochondrial hyperpolarization. In this study, we used cells deleted of ATP5IF1 (IF1), a natural inhibitor of the hydrolytic activity of the ATP synthase, as a genetic model of increased resting ΔΨm. We found that the nuclear DNA hypermethylates when the ΔΨm is chronically high, regulating the transcription of mitochondrial, carbohydrate and lipid genes. These effects can be reversed by decreasing the ΔΨm and recapitulated in wild-type (WT) cells exposed to environmental chemicals that cause hyperpolarization. Surprisingly, phospholipid changes, but not redox or metabolic alterations, linked the ΔΨm to the epigenome. Sorted hyperpolarized WT and ovarian cancer cells naturally depleted of IF1 also showed phospholipid remodeling, indicating this as an adaptation to mitochondrial hyperpolarization. These data provide a new framework for how mitochondria can impact epigenetics and cellular biology to influence health outcomes, including through chemical exposures and in disease states.
    DOI:  https://doi.org/10.1038/s41467-025-59427-5
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