bims-cagime 2026-05-24 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2026–05–24
34 papers selected by
Kıvanç Görgülü, Technical University of Munich

Ketogenic Diet Prevents Obesity-Associated Pancreatic Cancer Independent of Weight Loss and Induces Pancreatic Metabolic Reprogramming.
Quantifying interleaflet coupling of phase behavior and observing anti-registered phases in asymmetric lipid bilayers.
A deep-learning framework reveals whole-body perturbations at cell level.
Bleb expansion requires transient membrane invaginations that sequester curvature-preferring proteins.
Human pancreatic progenitor organoids define genetic and epigenetic barriers to early PDAC transformation.
Stress granules shape ferroptosis in cancer.
Fluorescence Correlation Spectroscopy to Examine Protein-Lipid Interactions in Membranes.
Biophysical principles of cell competition and elimination.
Anatomical dynamics define cancer cachexia subtypes and identify systemic inflammation as a marker of lethal wasting.
Metabolotheranostics of pancreatic cancer by targeting choline, glutamine, and glucose transporters with photoimmunotherapy.
Metabolic plasticity and optimal redox homeostasis are essential for efficient metastatic colonization.
Autophagy modulation in cancer.
Brain metastasis from KRAS wild-type pancreatic cancer and organoid correlates: a case report.
Asynchronous evolution of epithelium and stroma differentiates precursor lesions from pancreatic cancer.
NINJ1-Mediated Plasma Membrane Rupture in Lytic Cell Death: Mechanisms, Consequences, and Context.
GSTT1 mediates stemness and FGFR inhibitor sensitivity in pancreatic cancer through regulation of CD133 ( PROM1 ).
A Rosella-PLIN2 knock-in mouse reveals lipophagy and immunometabolic interplay in atherosclerosis.
Tie2 inhibition disrupts TMEM doorway function and reduces dissemination in pancreatic ductal adenocarcinoma.
LPLAT7 Reutilizes Unsaturated 1-Lysophospholipids Formed During Lysosomal Phospholipid Degradation.
Identification of a conserved receptor for degrading ribosomes through autophagy.
Blue period - features of senescence 30 years after beta-galactosidase.
CLOVER: An analysis protocol for visualization and identification of cell clusters through cluster overlaying for imaging mass cytometry.
Compression-induced metabolic adaptation drives confined tumor cell migration and distant metastasis via malate-dependent microtubule reinforcement.
Cholesteryl Esters Modulate Lipid Droplet Rigidity and Monolayer Organization during Liver Cancer Progression.
Emerging concepts, hot topics, and open questions in today's pancreatic cancer research.
Peroxisomes orchestrate metabolic flexibility and longevity via an interorganelle cascade.
GPX4 regulates lipid peroxidation and ferroptosis of stored red blood cells.
The Discovery of TNG456: A Highly Potent, Selective, Brain-Penetrant MTA-Cooperative PRMT5 Inhibitor for the Treatment of MTAP-Deleted Cancers.
A PUFA-rich diet increases endogenous genotoxic stress and mitochondrial DNA damage in mice.
Surface Plasmon Resonance for Measuring Interactions of Proteins with Lipids and Lipid Membranes.
CancerOmicsStudio (CoS): A web server for integrative and interpretable analysis of multi-omics cancer data.
Single-cell transcriptomic profiling of patient-derived pancreatic ductal adenocarcinoma primary cell cultures.
Loss of calcium-dependent phospholipase A2 contributes to multi-omic changes in mouse denervated skeletal muscle.
Chronic high-fat diet does not alter overall cancer incidence in Trp53R270H/+ mice.

Cancer Res. 2026 May 19.

Ketogenic Diet Prevents Obesity-Associated Pancreatic Cancer Independent of Weight Loss and Induces Pancreatic Metabolic Reprogramming.

Ericka Vélez-Bonet, Kristyn Gumpper-Fedus, Kaylin M Chasser, Zachary A Hurst, Adaliz Torres-Rosado, Hsiang-Yin Hsueh, Valentina Pita-Grisanti, Alexus Liette, Grace Vulic, Fouad Choueiry, Huan Zhang, Andrew Gold, Jiangjiang Zhu, Sue E Knoblaugh, Stacey Culp, Jeff S Volek, Zobeida Cruz-Monserrate.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor outcomes. Obesity increases the risk of PDAC through metabolic dysregulation and inflammation. The ketogenic diet (KD) can alter metabolism and has been evaluated for its effects on tumor progression in non-obese PDAC using genetically engineered mouse models (GEMMs). We hypothesized that KD may also prevent obesity-associated PDAC progression by altering body composition and cancer metabolism. Therefore, male PDAC GEMMs were subjected to diet-induced obesity (DIO) using high-fat diets or maintained on a low-fat diet (LFD) for 15 weeks. Mice were then randomized to continue the initial diets or switch to a KD or matched control diet for 6 weeks. Body weight and composition, glucose tolerance, ketone levels, pancreas histology, and tissue metabolomics were assessed. Furthermore, murine pancreas-derived organoids from DIO or LFD fed GEMMs were treated with a ketone body and analyzed using untargeted metabolomics. In obese PDAC GEMMs, KD delayed cancer progression independent of weight loss, an effect not observed in non-obese LFD-fed mice. KD-mediated PDAC suppression was associated with enrichment of pancreatic metabolic pathways that support non-glucose energy production. Ketone-treated organoids recapitulated a subset of the KD-associated metabolic differences observed in vivo, suggesting a direct metabolic effect on cancer cells. These findings suggest potential benefits of a KD in preventing obesity-associated PDAC. The diet-cancer metabolic interactions highlight potential opportunities for dietary or metabolic interventions to prevent PDAC in high-risk obese populations.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-2379
Biophys J. 2026 May 15. pii: S0006-3495(26)00362-0. [Epub ahead of print]

Quantifying interleaflet coupling of phase behavior and observing anti-registered phases in asymmetric lipid bilayers.

Kristen B Kennison-Cook, Averi M Cooper, Frederick A Heberle.

  Biological membranes are compositionally asymmetric, with distinct lipid mixtures in each leaflet, yet how this asymmetry influences lateral membrane organization remains poorly understood. Here, we use calcium-induced hemifusion to generate asymmetric giant unilamellar vesicles (aGUVs) and investigate how lipid composition modulates interleaflet coupling of liquid-liquid phase separation. Symmetric GUVs composed of cholesterol, the high-melting lipid DPPC, and a low-melting phosphatidylcholine (either 14:1-PC or 16:1-PC) were prepared at compositions exhibiting coexisting liquid-ordered (Lo) and liquid-disordered (Ld) phases. Hemifusion with a uniformly mixed supported lipid bilayer selectively altered the outer leaflet composition, producing aGUVs with controlled but variable asymmetry. Fluorescence measurements of outer leaflet exchange revealed substantial vesicle-to-vesicle variability, resulting in overlapping populations of phase-separated and uniformly mixed aGUVs. To account for this variability, we developed a statistical framework that jointly models the distribution of exchange fractions and the location of a phase boundary in asymmetric composition space, allowing all observed vesicles to contribute to the analysis. We find that aGUVs containing 14:1-PC require significantly greater outer leaflet exchange to abolish phase separation than those containing 16:1-PC. Only in the 14:1-PC system do we observe vesicles exhibiting coexistence of distinct anti-registered phases, a theoretically predicted but rarely observed regime consistent with large hydrophobic mismatch. By expressing symmetric and asymmetric miscibility boundaries in a common compositional framework, we introduce a phenomenological parameter, Δ∗, that quantifies the direction and strength of interleaflet coupling. These results demonstrate that modest changes in lipid chain length can markedly alter asymmetric phase boundaries, and provide a quantitative link between experimental observations, leaflet dominance concepts, and coupled-leaflet theories of membrane organization.

Keywords:  anti-registered bilayer phases; hemifusion; interleaflet coupling; liquid-liquid phase separation; membrane asymmetry

DOI:  https://doi.org/10.1016/j.bpj.2026.05.022
Nature. 2026 May 20.

A deep-learning framework reveals whole-body perturbations at cell level.

Doris Kaltenecker, Izabela Horvath, Rami Al-Maskari, Ying Chen, Zeynep Ilgin Kolabas, Luciano Hoeher, Mihail Todorov, David-Paul Minde, Saketh Kapoor, Sena Gül Turhan, Louis B Kuemmerle, Hanno Steinke, Tim Wohlgemuth, Mayar Ali, Florian Kofler, Pauline Morigny, Julia Geppert, Denise Jeridi, Bastian Wittmann, Jie Luo, Suprosanna Shit, Carolina Cigankova, Victor Miro Kolenic, Nilsu Gür, Eren Aydeniz, Alara Yücecan, Melissa Ertürk, Laurent H A Simons, Chenchen Pan, Marie Piraud, Daniel Rueckert, Maria Rohm, Farida Hellal, Markus Elsner, Harsharan Singh Bhatia, Ingo Bechmann, Bjoern H Menze, Stephan Herzig, Johannes Christian Paetzold, Mauricio Berriel Diaz, Ali Ertürk.

Many diseases, including obesity, have systemic effects that perturb multiple organ systems throughout the body1,2. However, tools for comprehensive, high-resolution analysis of disease-associated changes at the whole-body scale have been lacking. Here we developed MouseMapper, a suite of foundation-model-based deep-learning algorithms enabling multi-system analysis of disease across the entire mouse body. MouseMapper enables whole-body quantitative analysis of nerves and immune cells, resolving fine axonal branches and immune-cell clusters while automatically segmenting 31 organs and tissues. We used MouseMapper to study diet-induced obesity, and identified structural alterations of the infraorbital branch of the trigeminal ganglia. This structural impairment in infraorbital nerves was associated with functional sensory deficits in whisker sensing. Furthermore, we identified proteomic changes in the trigeminal ganglion affecting axon remodelling and complement pathways both in mice and humans. MouseMapper also generated detailed three-dimensional inflammation maps by characterizing immune cell cluster compositions across tissues. The MouseMapper framework demonstrates robust generalizability across different imaging resolutions and datasets. Our study provides a powerful, scalable approach for identifying and quantifying systemic pathologies, bridging molecular insights from animal models to human conditions.

DOI: https://doi.org/10.1038/s41586-026-10535-2
Proc Natl Acad Sci U S A. 2026 May 26. 123(21): e2534871123

Bleb expansion requires transient membrane invaginations that sequester curvature-preferring proteins.

Yuki Maekawa, Saori R Yoshii, Noboru Mizushima, Junichi Ikenouchi.

  Bleb-based cell migration involves rapid plasma membrane expansion driven by intracellular pressure. How the membrane reorganizes its curvature and protein composition during this process remains unclear. Here, we identify a distinct inward membrane structure, termed the sub-bleb invagination (SBI), that forms de novo at the bleb base during expansion. SBIs display strong positive curvature and transiently sequester curvature-preferring integral membrane proteins such as Caveolin-1 and Piezo1 without endocytosis. Live-cell imaging shows that these proteins transiently accumulate at the SBIs in concert with bleb growth, indicating that bleb expansion dynamically redistributes membrane curvature and protein localization. Overexpression of curvature-preferring proteins markedly inhibited bleb enlargement and induced the aberrant formation of SBI-like membrane invaginations, suggesting that their excessive accumulation limits the membrane from unfurling. Our findings reveal a curvature-based mechanism for membrane protein sorting during bleb expansion and highlight how the interplay between membrane curvature and integral membrane protein organization shapes PM dynamics.

Keywords:  Caveolin-1; bleb; curvature-preferring proteins; membrane curvature; plasma membrane invagination

DOI:  https://doi.org/10.1073/pnas.2534871123
Dev Cell. 2026 May 19. pii: S1534-5807(26)00159-0. [Epub ahead of print]

Human pancreatic progenitor organoids define genetic and epigenetic barriers to early PDAC transformation.

Xian Zhang, Wilfred Wong, Hyein S Cho, Dapeng Yang, Gary Dixon, Renhe Luo, Dingyu Liu, Denis Torre, Shigeaki Umeda, Federico González, Gokce Askan, Aslihan Yavas, Jeyaram Ravichandran Damodaran, Robert W Rickert, Rajya Kappagantula, Fong Cheng Pan, Victoria G Aveson, Adrien Grimont, William B Fall, Xianming Wang, Julian Pulecio, Samuel J Kaplan, Heng Pan, Xianlu Laura Peng, Jen Jen Yeh, Steven D Leach, Christine A Iacobuzio-Donahue, Rohit Chandwani, Christina S Leslie, Danwei Huangfu.

  The lack of accurate human models that recapitulate pancreatic ductal adenocarcinoma (PDAC) initiation has hindered therapeutic development. Using pluripotent stem cell-derived pancreatic progenitor organoids, we established a human PDAC model that faithfully reproduces the genetic, epigenetic, and transcriptomic trajectories of tumor initiation and progression, validated against clinical datasets and tumor histopathology. We demonstrate that CDKN2A loss, which is nearly universal in patients but dispensable in mouse models, is essential for neoplastic transformation when combined with KRAS and TP53 mutations, whereas SMAD4 loss promotes tumor progression. Multi-omics profiling reveals epigenetic repression of the pancreatic lineage program during PDAC initiation, alongside AP-1-driven chromatin remodeling. We identify TET1 suppression as a mechanistic link between oncogenic ERK signaling and hypermethylation of essential pancreatic transcription factors. This model captures genetic and epigenetic determinants of human PDAC, reveals antagonism between oncogenic and lineage restriction programs, and supports TET-based lineage restoration as a potential early intervention strategy.

Keywords:  DNA methylation; TET1 suppression; activator protein-1; chromatin remodeling; gene editing; lineage plasticity; oncogenic KRAS; pancreatic ductal adenocarcinoma; pancreatic progenitor organoid; tumor suppressor gene

DOI:  https://doi.org/10.1016/j.devcel.2026.04.012
Nat Cell Biol. 2026 May 22.

Stress granules shape ferroptosis in cancer.

Maria Livia Sassano, Patrizia Agostinis.

DOI: https://doi.org/10.1038/s41556-026-01950-8
Methods Mol Biol. 2026 ;3001 429-466

Fluorescence Correlation Spectroscopy to Examine Protein-Lipid Interactions in Membranes.

Viktoria Betaneli, Jan-Hagen Krohn, Jonas Mücksch, Petra Schwille.

  Fluorescence correlation spectroscopy (FCS) is a versatile technique to study membrane dynamics and protein-lipid interactions. It can provide information about diffusion coefficients, concentrations, and molecular interactions of proteins and lipids in the membrane. These parameters allow the determination of protein partitioning into different lipid environments, the identification of lipid domains, and the detection of lipid-protein complexes on the membrane. During the last decades, FCS studies were successfully performed on model membrane systems as also on living cells, to characterize protein-lipid interactions. Recent developments of the method described here improved quantitative measurements on membranes and decreased the number of potential artifacts. The aim of this chapter is to provide the reader with the necessary information and some practical guidelines to perform FCS studies on artificial and cellular membranes.

Keywords:  Cross-correlation; Diffusion; FCCS; FCS; Fluorescence correlation spectroscopy; Giant unilamellar vesicles; Lipid rafts; Model membranes; Protein–lipid interactions

DOI:  https://doi.org/10.1007/978-1-0716-5054-7_18
Trends Cell Biol. 2026 May 18. pii: S0962-8924(26)00067-X. [Epub ahead of print]

Biophysical principles of cell competition and elimination.

Andreas Schoenit, René-Marc Mège, Benoît Ladoux.

  Cell competition is a highly conserved mechanism through which cells with lower fitness levels than surrounding cells are actively removed from tissues. Differences in fitness may result from intrinsic tissue heterogeneity or be caused by differentiation, infections, or mutations. The resulting competition dynamics act as a key regulator of various biological processes during development and homeostasis. The underlying mechanical factors often remain unclear. Here, we discuss the biophysical principles of cell competition and elimination via extrusion or delamination. Recent advances have uncovered how fitness is determined by cellular mechanical properties, which can regulate winning or losing, and how cells use forces to outcompete each other. Furthermore, forces can influence the fate and direction of eliminated loser cells, which govern functional tissue development and disease progression.

Keywords:  cell competition; cell extrusion; epithelia; force transmission; tissue mechanics

DOI:  https://doi.org/10.1016/j.tcb.2026.04.009
medRxiv. 2026 May 05. pii: 2026.05.04.26352250. [Epub ahead of print]

Anatomical dynamics define cancer cachexia subtypes and identify systemic inflammation as a marker of lethal wasting.

Sonia Boscenco, Venise Jan Castillon, Jamie Wang, Ethan Tse, Samuel S Freeman, Ziad Bakouny, Saksham Mohan, X Alex Guo, River Walser, Junmin Song, Constantinos P Zambirinis, Linda Bojmar, Ritesh R Kotecha, Marc Hilmi, Michael S May, Gerardo A Vitiello, Tobias Janowitz, Marcus D Goncalves, Natalie Gangai, David Lyden, Adrianna Z Herskovits, Puneeth Iyengar, William R Jarnigan, Robert E Schwartz, Ramon Sosa, Justin Jee, Eileen M O'Reilly, Nikolaus Schultz, Sohrab P Shah, Wungki Park, John W Garrett, Perry J Pickhardt, Nathaniel C Swinburne, Ed Reznik.

Cancer cachexia is a wasting syndrome that remodels the anatomy of the patient. How this remodeling unfolds across tissues, whether it defines distinct disease states, and how these states relate to underlying biology remain unknown. We used longitudinal computed tomography imaging from 4,516 patients to quantify evolution of muscle, adipose, and organs during cachexia. Across two independent institutional cohorts, unsupervised analysis identified three reproducible anatomical subtypes of cachexia, including an inflammatory Type A marked by progressive hepatosplenic enlargement and inferior survival, a Type B dominated by visceral organ atrophy, and a mild Type C. These anatomical subtypes were associated with distinct serological signatures and reflected in molecular phenotypes in tumors and non-cancerous liver tissue, establishing cachexia as discrete anatomical disease states that link whole-body remodeling to systemic and tissue-level biology. This anatomy-first framework for cachexia classification provides a foundation for future patient stratification and development of subtype-specific anti-cachexia therapies.

DOI: https://doi.org/10.64898/2026.05.04.26352250
Npj Imaging. 2026 May 21.

Metabolotheranostics of pancreatic cancer by targeting choline, glutamine, and glucose transporters with photoimmunotherapy.

Puneet Khandelwal, Jiefu Jin, James D Barnett, Yelena Mironchik, Balaji Krishnamachary, Saleem Yousf, Raj Kumar Sharma, Hisataka Kobayashi, Zaver M Bhujwalla.

Altered choline, glutamine, and glucose metabolism form a triumvirate of metabolic reprogramming in most cancers that significantly influences growth, progression, and response to treatment. Photoimmunotherapy (PIT) is a highly target-specific treatment where a targeting antibody (Ab) is conjugated to a photosensitizing dye, IR700, that damages the target only when exposed to near-infrared (NIR) light irradiation. The requirement of an extracellular target has restricted PIT targeting to cell surface receptors and antigens. Here, for the first time, we exploited the extracellular domain of three metabolic transporters, CTL1 for choline, ASCT2 for glutamine, and GLUT1 for glucose for PIT, to demonstrate metabolotheranostics of cancer cells. We analyzed the TCGA database to establish increased expression of the three transporters in human pancreatic ductal adenocarcinoma (PDAC). For the PIT studies, we used two patient-derived PDAC cell lines selected for differences in transporter expression and demonstrated an expression-dependent reduction of cell viability following PIT. A single CTL1-PIT treatment of Pa04C tumors resulted in the eradication of four out of five established tumors. In PDAC, the PIT of metabolic transporters would be most effective in the intraoperative setting, where it could significantly impact cancer cells that may have invaded critical structures.

DOI: https://doi.org/10.1038/s44303-026-00175-6
Mol Metab. 2026 May 20. pii: S2212-8778(26)00066-9. [Epub ahead of print] 102382

Metabolic plasticity and optimal redox homeostasis are essential for efficient metastatic colonization.

Ece Grace, Deyu Zou, Romy Böttcher-Loschinski, Martin Böttcher, Harald Schuhwerk, Yussuf Hajjaj, Annemarie Schwab, Simon Brandt, Ana Clavel Ezquerra, Witold Szymanski, Johannes Graumann, Philipp Arnold, Renato Liguori, Fulvia Ferrazzi, Constantin P Krempe, Luiza Martins Nascentes Melo, Gabriele Allies, Sven W Meckelmann, Dirk Mielenz, Simone Brabletz, Dimitrios Mougiakakos, Alpaslan Tasdogan, Thomas Brabletz, Marc P Stemmler.

  Cancer cells dynamically reprogram their metabolism to adapt to changing microenvironmental conditions during tumor growth and metastatic dissemination. Metastasis of solid tumors-the principal cause of cancer-related mortality-is often driven through activation of epithelial-mesenchymal transition (EMT), regulated by the transcription factor ZEB1, which is frequently upregulated during tumor progression. To investigate the role of metabolic plasticity in metastasis, we employed murine pancreatic ductal adenocarcinoma (PDAC) cell lines with distinct EMT states, ZEB1 expression and lung colonization capacities. Highly plastic epithelial-type cancer cells (KPCepi) efficiently colonize the lung, whereas Zeb1-deficient cancer cells (KPCZ) with compromised metabolic plasticity show markedly reduced colonization, correlated with absent glycolytic reserve, mitochondrial dysfunction, and reduced anti-oxidant metabolite levels. Interestingly, mesenchymal-type cancer cells (KPCmes) also exhibit poor lung colonization despite retaining normal glycolytic capacity and a high proportion of functional mitochondria; however, similar to KPCZ cells, they display diminished levels of detoxifying metabolites. Low metastatic capacity correlates with increased susceptibility to ferroptosis even in epithelial-type KPCZ cells, indicating a limited ability to counteract reactive oxygen species under stress. Together, these findings demonstrate that metabolic plasticity and redox homeostasis are essential prerequisites for efficient lung colonization. Thus, concurrent targeting of metabolic adaptability and redox buffering may represent a promising strategy to prevent metastasis in aggressive PDAC tumors.

Keywords:  Cancer; Cellular plasticity; Epithelial-to-mesenchymal transition; Ferroptosis; Glycolysis; Metabolism; Metastasis; Mitochondria; Pancreatic ductal adenocarcinoma (PDAC); Redox balance

DOI:  https://doi.org/10.1016/j.molmet.2026.102382
Nat Rev Drug Discov. 2026 May 18.

Autophagy modulation in cancer.

Emma Guilbaud, Kevin M Ryan, Douglas R Green, Lorenzo Galluzzi.

Autophagy is a highly conserved, finely regulated and lysosome-dependent biological process through which eukaryotic cells mobilize metabolites in response to nutrient deprivation and dispose of supernumerary or toxic cytoplasmic entities to ensure cellular quality control. In line with the notion that autophagy globally preserves cellular homeostasis, defects in the molecular machinery for autophagy generally favour malignant transformation. Conversely, proficient autophagic responses are often beneficial to developing tumours as they support the survival of malignant cells facing harsh microenvironmental conditions. Finally, the ability of neoplastic cells to undergo autophagy influences their susceptibility to anticancer immune responses in a context-dependent manner. Thus, although autophagy stands out as a major target to intercept cancer at multiple inflection points of the disease, one-size-fits-all approaches are inherently incapable of capturing the complex influence of autophagy on the cancer cell (immuno)biology as a whole. Further complicating this scenario, healthy cells, including tumour-targeting immune effectors, rely on autophagy for their maturation, survival and functions, and pharmacological autophagy inhibitors currently available for use in humans are intrinsically nonspecific. Here, we discuss the promise and limitations of targeting autophagy to limit malignant transformation, exacerbate cancer cell death as driven by conventional therapeutics and restore immunosurveillance in support of superior disease responses to immunotherapy.

DOI: https://doi.org/10.1038/s41573-026-01449-9
J Gastrointest Oncol. 2026 Apr 30. 17(2): 101

Brain metastasis from KRAS wild-type pancreatic cancer and organoid correlates: a case report.

Fatim M Kouassi, Hardik Patel, Elias-Ramzey Karnoub, Caitlin F Tsang, Julien Hohenleitner, Olca Basturk, Deepthi Budagavi, Madonna Moza, Fiyinfolu Balogun, Amber N Habowski, David A Tuveson, Kenneth H Yu.

   Background: Although pancreatic cancer is an aggressive malignancy with a propensity for metastatic spread, brain metastases (BrMs) remain exceptionally rare (<1% incidence).
Case Description: We present a case of BrMs in a 69-year-old pancreatic cancer patient. This patient initially presented with a history of chronic pancreatitis, abdominal and back pain, and significant weight loss. After the diagnostic biopsy confirmed pancreatic cancer, the patient was enrolled onto the PASS-01 clinical trial and was treated with standard of care chemotherapy before progressing and developing BrMs 10 months after cancer diagnosis. The BrMs were removed via craniotomy, and the patient also underwent radiation and chemotherapy before enrolling onto the MYTHIC clinical trial for PKMYT1 inhibitor, RP-6306. Successful generation of a BrM-derived organoid line enabled high-throughput drug screening, which recapitulated the patient's clinical resistance to standard therapies [gemcitabine/nab-paclitaxel, 5-fluorouracil (5-FU)], and showed sensitivity to afatinib, everolimus and RMC-6236.
Conclusions: This case report demonstrates the importance of precision medicine to characterize patient tumor and identify actionable targets and potential therapies. Physicians should also be aware that KRAS wild-type pancreatic cancer with atypical amplifications is likely to exhibit unique metastatic tropisms. Finally, we suggest that patient-derived organoids pharmacotyping can mirror clinical drug responses and help evaluate therapeutic avenues for patient treatment.

Keywords:  Case report; brain metastasis (BrM); organoids; pancreatic cancer; precision medicine

DOI:  https://doi.org/10.21037/jgo-2025-aw-818
Cancer Discov. 2026 May 21.

Asynchronous evolution of epithelium and stroma differentiates precursor lesions from pancreatic cancer.

Ahmed M Elhossiny, Padma Kadiyala, Jude Ogechukwu Okoye, Harrison L Hiraki, Megan C Procario, Thejaswini Giridharan, Hannah R Watkoske, Mariana Tannus Ruckert, Jiayue Wang, Brian D Griffith, Alexander W Bray, Jamie N Mills, Carlos E Espinoza, Jörg Zeller, Nicole Peterson, Filip Bednar, Yaqing Zhang, Arvind Rao, Costas A Lyssiotis, Julianne M Szczepanski, Jiaqi Shi, Atul Deshpande, Anirban Maitra, Elana J Fertig, Eileen S Carpenter, Timothy L Frankel, Marina Pasca di Magliano.

Pancreatic intraepithelial neoplasia (PanIN) precedes pancreatic cancer, a deadly disease characterized by an extensive tumor microenvironment. How the microenvironment evolves during cancer progression is largely unknown, as PanINs are microscopic and non-diseased pancreas samples are exceedingly rare, while adjacent normal samples are disrupted by the presence of malignancy. Leveraging donor organs and spatial technologies we mapped the evolution of PanIN to cancer. The PanIN epithelial component falls on a continuum with cancer while the PanIN microenvironment is drastically distinct. Progression to cancer is accompanied by profound geographical reorganization of myeloid cells and lymphocytes and the formation of a cancer-specific fibroblast population characterized by high levels of Smooth Muscle Actin, LRRC15 and the WNT signaling component LEF1. Together, our data show asynchronous evolution of epithelial and stromal components during pancreatic carcinogenesis. Lack of stromal reprogramming might explain why most PanINs do not progress to cancer. Compiled data available at https://pascadimagliano-lab.github.io/PancAtlas.

DOI: https://doi.org/10.1158/2159-8290.CD-25-2001
FASEB J. 2026 May 31. 40(10): e71919

NINJ1-Mediated Plasma Membrane Rupture in Lytic Cell Death: Mechanisms, Consequences, and Context.

Zeinab A El-Moaty, Rabab S Hamad, Mohamed A M Ali, Elsayed A Elmorsy, Ahmed Shata, Ghada M Nassar, Nesreen Elsayed Morsy, Samar Ibrahim, Manal A Hamouda, Ramy M El Sabaa, Anis Ahmad Chaudhary, Sameh Saber.

  Lytic cell death has long been interpreted as a terminal consequence of inflammasome activation, gasdermin cleavage, and osmotic membrane failure. Recent evidence supports a more differentiated cellular model in which early membrane permeabilization and terminal plasma membrane rupture are distinct events. However, these processes are still frequently treated as a single continuum, and a unifying framework that separates and integrates them across lytic death pathways is lacking. Within this revised framework, ninjurin 1 (NINJ1) has emerged as the best-supported mediator of plasma membrane rupture during terminal lytic cell death. Studies in pyroptosis, post-apoptotic lysis, ferroptosis, and related necrotic settings indicate that NINJ1 is not required for inflammasome assembly, gasdermin processing, or early cytokine release, but is crucial for terminal membrane disruption and release of large intracellular contents. Structural, biochemical, and imaging data further show that NINJ1 transitions from an autoinhibited membrane-associated state to higher order assemblies that destabilize or excise plasma membrane regions. These findings support a staged model of lytic death in which gasdermin pores establish a permeabilized state, whereas NINJ1 drives the final disintegration of the cell surface. Across these contexts, NINJ1 is best viewed as a convergent membrane-rupture effector that defines a distinct downstream layer of lytic cell death rather than a pathway-restricted component. This distinction has important implications for understanding how membrane rupture shapes cell morphology, extracellular release patterns, and tissue injury. By integrating evidence across lytic death programs, this review advances a unified framework in which permeabilization and terminal rupture are mechanistically separable, differentially regulated processes.

Keywords:  NINJ1; lytic cell death; membrane permeabilization; plasma membrane rupture; pyroptosis; tissue injury

DOI:  https://doi.org/10.1096/fj.202601655R
bioRxiv. 2026 May 05. pii: 2025.08.06.668944. [Epub ahead of print]

GSTT1 mediates stemness and FGFR inhibitor sensitivity in pancreatic cancer through regulation of CD133 ( PROM1 ).

Deborah de la Caridad Delgado Herrera, Alejandro Arroyo Roman, Riyan N Campbell, Emily Lasse-Opsahl, Carrie McCracken, Lisa Sadzewicz, Luke Tallon, Elana J Fertig, Christina M Ferrer.

Pancreatic ductal adenocarcinoma (PDA) is among the deadliest malignancies, driven by metastatic progression and profound cellular heterogeneity. We previously identified glutathione S-transferase theta 1 (GSTT1) as a regulator of a slow-cycling, highly metastatic tumor cell population, suggesting that GSTT1 High cells may possess stem-like properties. Here, we define the functional and molecular features of this subpopulation in metastatic PDA. Using a mCherry-tagged Gstt1 reporter system in metastatic murine PDAC cells, we enriched for Gstt1 High cells and observed increased tumor sphere formation, accompanied by upregulation of stemness-associated genes including PROM1 (CD133) and activation of Wnt and FGF signaling pathways. In human PDA models, CD133 High GSTT1 High cells exhibited enhanced tumor sphere initiation and expansion compared to other populations, defining a maximal stem-like state. Notably, sensitivity to FGFR inhibitors was observed only under tumor sphere conditions, highlighting a context-dependent therapeutic vulnerability. Mechanistically, FGFR3 expression correlated with GSTT1 and CD133 levels, and FGF signaling was required to sustain this state. GSTT1 knockdown reduced CD133 protein levels, impaired tumor sphere formation, and altered sensitivity to FGFR inhibition. These findings were largely recapitulated in patient-derived PDA organoids, where GSTT1 and PROM1 co-expression predicted increased tumor sphere formation and enhanced response to the multi-kinase inhibitor Nintedanib. Together, these results identify a GSTT1 High CD133 High stem-like subpopulation in metastatic PDA and identify an FGFR-dependent signaling axis that sustains this state, representing a potential therapeutic vulnerability.

DOI: https://doi.org/10.1101/2025.08.06.668944
Autophagy. 2026 May 20.

A Rosella-PLIN2 knock-in mouse reveals lipophagy and immunometabolic interplay in atherosclerosis.

Thomas Laval, Nathan Joyce, Dominique M Boucher, Honora Labrana, Valérie Rochon, Christina Emerton, Mishita Dharia, Sabrina Robichaud, Victoria Lorant, My-Anh Nguyen, Michèle Geoffrion, Katey J Rayner, Derrick Gibbings, Lauryl M J Nutter, Ryan C Russell, Mireille Ouimet.

  Cytosolic lipid droplets (LDs) regulate lipid homeostasis, with abnormal LD dynamics linked to metabolic diseases like atherosclerosis. In macrophage foam cells, LDs undergo autophagic degradation via lipophagy, but the extent of this process in vascular smooth muscle cell (VSMC) foam cells remains unclear. To track lipophagy in real time, we developed a Rosella-PLIN2 (perilipin 2) biosensor by tagging PLIN2 with the fluorescent pH-biosensor Rosella. We show that proatherogenic lipoproteins and autophagy activators stimulate lipophagy in human macrophages. Targeting LDs with an LC3 fusion protein or LD-autophagy tethering compounds (LD-ATTECs) selectively enhanced lipophagy, promoting foam cell LD clearance. In an atherosclerosis model, Rosella-PLIN2 accurately tracked lipophagy in arterial foam cells, revealing distinct PLIN2 expression patterns in macrophage and non-leukocyte foam cells. We identified a lipophagy deficiency in VSMC foam cells and demonstrate that enhancing lipophagy promotes LD catabolism in primary VSMC foam cells. TREM2+ macrophages exhibited high lipid content and low lipophagy flux, whereas TREM2- macrophages had low lipid content and high lipophagy flux. Our findings highlight a cell-specific interplay between lipophagy and immunometabolism in arterial foam cells, unveiling novel therapeutic avenues for atherosclerosis. Additionally, the Rosella-PLIN2 model provides a powerful tool for studying LD metabolism, offering new insights into lipid homeostasis and disease mechanisms.

Keywords:  Atherosclerosis; autophagy; foam cells; lipid droplet; lipophagy; macrophages; reporter mouse; vascular smooth muscle cells

DOI:  https://doi.org/10.1080/15548627.2026.2674711
J Exp Clin Cancer Res. 2026 May 16. pii: 126. [Epub ahead of print]45(1):

Tie2 inhibition disrupts TMEM doorway function and reduces dissemination in pancreatic ductal adenocarcinoma.

Erika Pereira Zambalde, Lina A Ariyan, Francisco Puerta-Martinez, Yu Qin Zhu, Priyanka Patil, Nicole C Panarelli, Jiufeng Li, Yookyung Jung, Christian Adkisson, Jakeb Petersen, Dianne Cox, Hava Gil-Henn, Robert Eddy, Ben Z Stanger, David Entenberg, Maja H Oktay, John S Condeelis, John C McAuliffe.

   BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic malignancy with limited treatment options. Metastatic dissemination is the principal cause of mortality in PDAC, yet the cellular mechanism by which PDAC tumor cells enter the bloodstream remains unknown. A portal of intravasation is the Tumor Microenvironment of Metastasis (TMEM) doorways. The TMEM doorway is composed of a tumor cell, a Tie2 + macrophage, and endothelial cell, in direct contact triggering a brief, localized vascular opening that permits intravasation.
METHODS: We performed time-lapse intravital microscopy in PDAC mouse models to visualize serum extravasation and tumor cell intravasation. TMEM doorway density was quantified using immunohistochemistry of resected human PDAC specimes. TMEM doorway activity was quantified by aligned immunohistochemistry/immunofluorescence of tumor specimens. Mechanistic underpinnings of intravasation were tested using an in vitro intravasation transendothelial migration (iTEM) assay. Tie2 signaling was inhibited in vivo with the Tie2 inhibitor rebastinib (~ 0.44 mg/day in chow for 3 weeks). A macrophage-specific Tie2 conditional knockout mouse was generated to evaluate macrophage Tie2-mediated PDAC dissemination. The therapeutic impact of Tie2 blockade was evaluated in an orthotopic perioperative PDAC model incorporating distal pancreatectomy and perioperative FOLFIRINOX plus rebastinib. Statistical analyses used included Mann-Whitney and Kruskal-Wallis tests for clinicopathologic comparisons, one-way ANOVA with Tukey's post hoc test for iTEM, Student's t-test for two-group comparisons, and Kaplan-Meier survival analysis with log-rank testing.
RESULTS: In vivo imaging revealed transient, localized vascular openings spatially linked to TMEM doorways. PDAC tumor cell intravasation was observed at TMEM doorways. TMEM doorways were detectable in human PDAC tissues; higher TMEM density was associated with aggressive pathologic factors and was reduced after neoadjuvant therapy. Tie2 inhibition selectively impaired macrophage-driven vascular opening and reduced TMEM doorway activity, diminished tumor cell transendothelial migration, and lowered disseminated tumor cell burden in vivo. In therapeutic studies, Tie2 inhibition combined with FOLFIRINOX improved survival compared with FOLFIRINOX alone.
CONCLUSIONS: Intravasation and dissemination is TMEM doorway mediated in PDAC. TMEM doorway function is mediated by Tie2 signaling. Inhibition of Tie2 pharmacologically and genetically decreases TMEM doorway function and PDAC dissemination. Tie2 inhibition may have therapeutic potential combined with chemotherapy or emerging therapies for PDAC.

Keywords:  Intravasation; Intravital microscopy; Metastasis; Pancreatic ductal adenocarcinoma; Rebastinib; TMEM doorway; Tie2; Tumor microenvironment of metastasis; Tumor-associated macrophages

DOI:  https://doi.org/10.1186/s13046-026-03730-6
J Lipid Res. 2026 May 21. pii: S0022-2275(26)00090-8. [Epub ahead of print] 101064

LPLAT7 Reutilizes Unsaturated 1-Lysophospholipids Formed During Lysosomal Phospholipid Degradation.

Yang Xu, Sujith Rajan, Colin K L Phoon, Mindong Ren, M Mahmood Hussain, Michael Schlame.

  Lysosomal phospholipid degradation produces two types of metabolites, either 2-lysophospholipids with saturated fatty acids in sn-1 position or 1-lysophospholipids with unsaturated fatty acids in sn-2 position. They may either be degraded further or re-used for phospholipid synthesis. We found that LPLAT7 (LPGAT1), an acyltransferase of the endoplasmic reticulum, re-acylates specifically lysosome-derived 1-lysophospholipids that carry an unsaturated chain. The enzymatic activity of LPLAT7 was specific for stearoyl-CoA and 1-lyso-2-acyl positional isomers of unsaturated lysophospholipids. In Huh7 cells, Lplat7 knockout prevented the reacylation of 1-lysophospholipids generated by the lysosomal degradation of exogenous 2H-phosphatidylcholine. Inhibition of lysosomal phospholipid degradation reduced the abundance of 1-stearoyl-2-unsaturated PC in Huh7 cells. Lplat7 knockout blunted the loss of unsaturated lysophosphatidylcholine (LPC) in response to lysosomal inhibition, suggesting that LPLAT7 consumes unsaturated LPC formed by lysosomes. In mice, Lplat7 knockout increased the concentration of unsaturated lysophospholipids, reduced the abundance of 1-stearoyl-2-unsaturated species of phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine, and inhibited the regeneration of cellular membranes. It also triggered the accumulation of triglycerides, confirming earlier reports that unsaturated lysophospholipids induce lipid droplet formation. Thus, by re-acylating unsaturated 1-lysophospholipids, LPLAT7 shifts lipid metabolism from the biogenesis of lipid droplets to the biogenesis of membranes.

Keywords:  Lipidomics; lysophospholipid; phospholipase A; phospholipid/biosynthesis; phospholipid/metabolism

DOI:  https://doi.org/10.1016/j.jlr.2026.101064
Autophagy. 2026 Jun;22(6): 1149-1150

Identification of a conserved receptor for degrading ribosomes through autophagy.

Chhabi K Govind, Daniel J Klionsky.

  Ribosomes consist of approximately 80 distinct ribosomal proteins and rRNA. The genes encoding these ribosomal components are among the most highly expressed in growing cells. Changes in ribosome composition, such as those induced by oxidative stress, may compromise ribosome function. Such ribosomes are subsequently targeted for degradation. Additionally, under stress, both protein synthesis and ribosome biogenesis are downregulated. Under starvation stress, excess ribosomes are degraded through a process called ribophagy, a selective form of macroautophagy/autophagy that utilizes the autophagy pathway. While receptors for several selective autophagy pathways are known, the evolutionarily conserved ribophagy receptor was not identified until recently. In a recent publication, the authors identify Rpl12 and its homologs as receptors that promotes ribophagy from yeast to humans. They also demonstrate that ribophagy enhances lifespan and facilitates the clearance of pathogenic bacteria.Abbreviations: AIM: Atg8-family interacting motif; ATG: autophagy related; LIR: LC3-interacting region; NUFIP1: nuclear FMR1 interacting protein 1.

Keywords:  Autophagy; Rpl12A; ribophagy; ribosomes; starvation

DOI:  https://doi.org/10.1080/15548627.2026.2624242
Aging (Albany NY). 2026 May 15. 18(1): 554-571

Blue period - features of senescence 30 years after beta-galactosidase.

Chisaka Kuehnemann, Christopher D Wiley.

  Cellular senescence is a multi-phenotypic stress or damage response characterized by a stable cell cycle arrest and the secretion of a myriad of biologically active molecules, commonly known as the senescence-associated secretory phenotype (SASP). Thirty years ago, the identification of activated beta-galactosidase during senescence led to one of the first characterizations of senescent cell accumulation during biological aging. Since then, interventions that either selectively eliminate senescent cells or suppress the SASP have demonstrated that they are a major etiological agent for several degenerative pathologies associated with aging. As interest in the development of targeted therapeutics for senescence has grown, so too has the interest in the study of these cells. This has resulted in discovery of new features and phenotypes that often associate with senescence. Here, we review several of these key features of senescence, highlighting the strengths and caveats associated with each.

Keywords:  SASP; aging; biomarkers; cell death; senescence

DOI:  https://doi.org/10.18632/aging.206380
STAR Protoc. 2026 May 20. pii: S2666-1667(26)00210-8. [Epub ahead of print]7(2): 104557

CLOVER: An analysis protocol for visualization and identification of cell clusters through cluster overlaying for imaging mass cytometry.

Suthicha Kanacharoen, Sarah M Shin, Yanyi Sun, Courtney D Cannon, Laura D Wood, Won Jin Ho.

  Imaging mass cytometry (IMC) enables spatial single-cell analysis on formalin-fixed paraffin-embedded (FFPE) sections. Here, we present a protocol for visualizing and identifying cell clusters through cluster overlaying of IMC data. We outline steps to source and preprocess images, compile and format data frames, and generate cluster-specific overlays in a high-throughput manner. We then describe procedures to composite these overlays onto corresponding reference images and export finalized visualizations. This workflow integrates high-dimensional data with ground-truth tissue images to support more accurate cell-type classification within tissue microenvironments. For complete details on the sample data used for the execution of this protocol, please refer to Bever et al.1.

Keywords:  Cancer; Immunology; Mass Cytometry; Microscopy; Single Cell

DOI:  https://doi.org/10.1016/j.xpro.2026.104557
Cell Res. 2026 May 18.

Compression-induced metabolic adaptation drives confined tumor cell migration and distant metastasis via malate-dependent microtubule reinforcement.

Min Liu, Bing Liu, Chen Chen, Yi-Ran Wang, Xiaoyan Li, Yajuan Zhang, Xinyang Liu, Dingpei Zhou, Hong Gao, Yijun Qi, Chen Su, Dong Gao, Yun Zhao, Yan-Jun Liu, Quanlin Li, Weiwei Yang.

ABSTACT: Metastasis, responsible for > 90% of cancer-related mortality, represents the most lethal yet least mechanistically understood phase of cancer progression. A critical bottleneck is tumor cell migration through physically confined environments, including dense extracellular matrix, narrow capillaries and endothelial gaps. Although tumor cells reprogram their metabolism to facilitate cancer progression, it remains unclear how specific metabolic adaptations enable them to overcome the unique physical challenges posed by these confined spaces, thereby promoting distant metastasis. We conducted a CRISPR screen targeting 1685 metabolic enzymes and identified dihydrolipoamide dehydrogenase (DLD), a mitochondrial enzyme involved in energy metabolism, as essential for confined migration of tumor cells. Depletion or pharmacological inhibition of DLD suppressed CRC metastasis by impairing tumor cell migration through capillaries and endothelial gaps. Upon mechanical compression, heterogeneous nuclear ribonucleoprotein A0 (hnRNPA0) binds to the adenylate uridylate-rich element (ARE) in the 3'UTR of DLD, enhancing its mRNA stability and upregulating DLD expression in tumor cells during confined migration. Elevated DLD expression enhances tricarboxylic acid (TCA) cycle metabolism, increasing malate levels. Malate interacts with tubulin alpha-1B chain (TUBA1B) to promote microtubule assembly, facilitating confined migration and metastasis. Knock-in of an ARE-deleted DLD mutant (DLD ΔARE) or disruption of the malate-TUBA1B interaction significantly suppressed tumor metastasis. In CRC patients, DLD expression was upregulated in tumor cells within capillaries of primary tumors and correlated with metastatic recurrence. Our findings reveal that compressive forces drive metastatic dissemination by epigenetically reprogramming mitochondrial metabolism, which in turn fuels cytoskeletal remodeling.

DOI: https://doi.org/10.1038/s41422-026-01254-4
bioRxiv. 2026 May 05. pii: 2026.05.01.722229. [Epub ahead of print]

Cholesteryl Esters Modulate Lipid Droplet Rigidity and Monolayer Organization during Liver Cancer Progression.

Oluwatoyin Campbell, Cecilia Leal, Viviana Monje.

In mammalian cells, lipid monolayers support the integrity of lipid droplets (LDs), organelles that function as storage for neutral lipids. Liver-targeting illnesses such as liver cancer interrupt normal LD metabolism and prompt changes in the chemical content of these organelles, which can have effects on structural and organizational behavior of the lipids. In LDs, liver cancer induces concentric crystalline phases of cholesteryl esters (CEs) and triglycerides near the NL-monolayer interface, which become more pronounced as CE concentration increases. Yet, there is little known about how this phenomenon may link to persistence of undigested LDs in liver cancer patients. To shed light on this, all-atom molecular dynamics simulations were used to model LD micropipette aspiration experiments and gain insight into the effect of CE concentration on partitioning, structural, and mechanical properties of LDs. We successfully model micropipette aspiration by application of constant surface tension laterally, which stretches lipid bilayers and monolayers as the magnitude increased. The results show increased phospholipid packing due to insertion of CE fatty tails into the monolayer. Increasing CE concentration induces a non-linear change in surface packing defects on the LDs, notable rigidification, and stiffness. Taken together, these insights improve our understanding of the physical properties at the LD monolayer-core interface during liver cancer progression.

DOI: https://doi.org/10.64898/2026.05.01.722229
Biochim Biophys Acta Rev Cancer. 2026 May 15. pii: S0304-419X(26)00086-7. [Epub ahead of print]1881(4): 189614

Emerging concepts, hot topics, and open questions in today's pancreatic cancer research.

Corinna Keber, Mark Schmitt, Alexander Visekruna, Anna Brichkina, Elke Pogge von Strandmann, Jörg W Bartsch, Magdalena Huber, Uta-Maria Bauer, Thomas M Gress, Matthias Lauth.

  Despite intense research, pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies to date. The low 5-year survival rate of currently 8-10% has only marginally improved over the last years, necessitating novel approaches and a thinking "outside the box". We as translational basic and medical scientists working in a clinical research unit on tumor-stroma interactions in PDAC (the DFG-funded CRU325) have sought to identify emerging concepts in current pancreatic cancer research. We have addressed recent developments and open questions, covering a wide spectrum of topics, including clinical treatment, lifestyle, the tumor microenvironment, drug targeting, vaccination, and the microbiome. This selection of topics is highly personal and does not claim to be complete, yet it represents those areas that we believe may contribute to relevant developments in the near future. In our review, we not only briefly describe the state of the art but also pinpoint the potential of recent advances, while not ignoring current contradictions or uncertainties. Taken together, we provide our subjective view on upcoming topics in today's PDAC research landscape.

Keywords:  CAF; Exposome; Extracellular vesicles; KRAS; Microbiome; PDAC; Pancreatic cancer; TAM; TAN; TLS; Tumor stroma; Tumor vaccination

DOI:  https://doi.org/10.1016/j.bbcan.2026.189614
Nat Aging. 2026 May;6(5): 987-1006

Peroxisomes orchestrate metabolic flexibility and longevity via an interorganelle cascade.

Arpit Sharma, Aditi Prabhakar, Miriam Valera-Alberni, Jamie D Kraft, Abigail E Ellis, Ryan D Sheldon, Meeta Mistry, Pallas Yao, Yanshan Liang, Sheng Hui, William B Mair.

Aging impairs coordinated organelle dynamics essential for lipid metabolism, causing a decline in intracellular metabolic flexibility. However, the drivers of organelle collapse and their temporal order remain unclear. Here we identify peroxisomal function as a critical regulator of metabolic flexibility during youth and low-energy states. Using Caenorhabditis elegans, we show that fasting robustly induces peroxisomal function in youth, whereas this response is blunted during aging. Loss of peroxisomal import via PRX-5 declines over age, causing pathological lipid droplet expansion, dysfunctional mitochondrial bioenergetics and metabolic inflexibility. Although targeted PRX-5 degradation recapitulates metabolic aging, its overexpression preserves lipid dynamics and mitochondrial integrity. Notably, dietary restriction maintains peroxisomal pathways and organelle coordination into late life and peroxisomal function causally underpins dietary restriction-mediated longevity. Our findings highlight peroxisomes as central upstream regulators of a dynamic interorganelle cascade driving metabolic plasticity and highlight peroxisomal maintenance as a key determinant of metabolic flexibility during aging.

DOI: https://doi.org/10.1038/s43587-026-01122-1
Blood Red Cells Iron. 2025 Dec;pii: 100020. [Epub ahead of print]1(3):

GPX4 regulates lipid peroxidation and ferroptosis of stored red blood cells.

Daniel Stephenson, Gregory R Keele, Ariel Hay, Monika Dzieciatkowska, Julie A Reisz, Zachary B Haiman, Amy L Moore, Travis Nemkov, Xutao Deng, Mars Stone, Kirk C Hansen, Steven Kleinman, Philip J Norris, Michael P Busch, Gary A Churchill, Brent R Stockwell, Nareg Roubinian, James C Zimring, Grier P Page, Angelo D'Alessandro.

  Red blood cell (RBC) membrane lipid peroxidation during blood bank storage profoundly impacts transfusion efficacy; however, the genetic determinants underlying RBC resilience remain incompletely defined. Here, we identify a critical role for glutathione peroxidase 4 (GPX4) - a pivotal enzyme protecting against iron-dependent lipid peroxidation (ferroptosis) - in regulating RBC storage quality and post-transfusion survival. Conditional erythroid-specific deletion of Gpx4 in mice exacerbated lipid hydroperoxide accumulation, oxidation and ubiquitination of membrane proteins, and reduced RBC recovery after transfusion. Multi-omics analyses in 13,091 human blood donors from the REDS RBC Omics cohort identified regulatory intergenic (rs8178962), intronic and missense genetic variants in GPX4 (rs73507255, rs8178967), particularly prevalent among donors of African descent, that were linked to increased lipid peroxidation and compromised post-transfusion hemoglobin increments. Single protein- and metabolome-wide association studies (pQTL/mQTL) highlighted genetic variants associated with enhanced (rs8178962) or impaired GPX4 expression, disrupted glutathione homeostasis, lipid hydroperoxide accumulation, accelerated membrane damage, and activation of ferroptotic signatures during RBC storage. These effects were exacerbated by genetic traits impairing redox homeostasis, including glucose 6-phosphate dehydrogenase (G6PD) deficiency (African variant rs1050828 V68M/N126D). Storage of murine RBCs in presence of the ferroptosis inhibitor ferrostatin-1 prevented storage-induced lipid peroxidation and boosted post-transfusion recovery, a beneficial effect in part phenocopied by supplementation of lipophilic antioxidants vitamin E and Lands cycle fueling via L-carnitine, and in part ablated by GPX4 inhibition via the covalent inhibitor ML210. This study offers mechanistic insights into RBC ferroptosis and positions GPX4 genetic status as a promising biomarker for precision transfusion medicine.

Keywords:  Glutathione; hemolysis; precision transfusion medicine; transfusion

DOI:  https://doi.org/10.1016/j.brci.2025.100020
J Med Chem. 2026 May 18.

The Discovery of TNG456: A Highly Potent, Selective, Brain-Penetrant MTA-Cooperative PRMT5 Inhibitor for the Treatment of MTAP-Deleted Cancers.

Kevin M Cottrell, Kimberly J Briggs, Alice Tsai, Colin Liang, Patrick McCarren, Douglas A Whittington, Minjie Zhang, Wenhai Zhang, Alan Huang, Jannik Andersen, John P Maxwell.

Homozygous deletion of the methylthioadenosine phosphorylase (MTAP) gene occurs in 10-15% of all human cancers and up to 50% of high-grade malignant gliomas, representing one of the largest opportunities for precision oncology. Loss of MTAP leads to the accumulation of 5'-methylthioadenosine (MTA), which sensitizes tumor cells to inhibition of protein arginine methyltransferase 5 (PRMT5). Herein we describe the discovery of TNG456, a potent and highly selective MTA-cooperative PRMT5 inhibitor that is brain penetrant in preclinical species and currently in Phase I/II clinical studies for the treatment of advanced or metastatic solid tumors with MTAP loss, with a focus on glioblastoma.

DOI: https://doi.org/10.1021/acs.jmedchem.6c00035
Genes Environ. 2026 May 21.

A PUFA-rich diet increases endogenous genotoxic stress and mitochondrial DNA damage in mice.

Masatomi Shimizu, Ayako Daizo, Kenichi Kawada, Masayo Ikeda, Petr Grúz.

   BACKGROUND: Substitution of dietary saturated fat with seed oils highly enriched in n-6 polyunsaturated fatty acids (PUFAs) has been advocated as healthy strategy to offset elevated cholesterol levels. However, both n-6 as well as n-3 PUFAs, considered essential because vertebrates lack the enzymatic apparatus for their de novo synthesis, are the main source of endogenous DNA damage during the aging process due to their high oxidizability. The membrane pacemaker theory of aging is an extension to the oxidative theory of aging and postulates that higher PUFA content in membrane lipids determines the lifespan of different species.
OBJECTIVE: We have examined whether a saturated fat-rich diet lacking the essential fatty acids versus a PUFA-rich diet differentially affects lipid profiles and membrane fatty-acid composition, as well as markers of oxidative protein and DNA damage and mitochondrial DNA (mtDNA) integrity in vivo.
METHODS: Three-week-old male C57BL/6J mice were fed isocaloric, high-fat diets containing either coconut oil (SFA-rich) or soybean oil (PUFA-rich) for 12 weeks. Plasma and liver lipids were measured, and the fatty acid composition was analyzed in liver and erythrocyte membranes. Endogenous DNA damage was assessed using 1,N⁶-etheno-2'-deoxyadenosine (εdA) detection in blood and liver. mtDNA damage and lipid peroxidation derived protein adducts from liver were also examined.
RESULTS: Mice were maintained on a SFA-rich diet for 12 weeks without exhibiting any symptoms of essential fatty acid deficiency (EFAD) as described in historical literature despite the massive synthesis of compensatory n-9 PUFAs. Furthermore, EFAD mice showed reduced levels of endogenous εdA and mtDNA damage as well as protein adducts originating from the primary n-6 PUFA lipid peroxidation product, 4-hydroxy-2-nonenal. However, some other lipid peroxidation-derived protein adducts, such as malondialdehyde and, surprisingly, 4-hydroxy-2-hexenal, were elevated on a SFA-rich diet.
CONCLUSIONS: A PUFA-rich diet, relative to the SFA-rich diet, is associated with increased lipid-peroxidation linked adducts and a greater degree of mtDNA damage in vivo, in parallel with membrane enrichment in n-6 PUFA. These findings provide clear evidence of the biological effects of a PUFA-rich diet on endogenous genotoxic stress.

Keywords:  1,N⁶-etheno-2'-deoxyadenosine; 4-HNE; Essential fatty acid deficiency; Lipid peroxidation; Mitochondrial DNA damage; Mouse dietary model; Polyunsaturated fatty acids; Reactive aldehydes; Saturated fatty acids; n-6 fatty acids

DOI:  https://doi.org/10.1186/s41021-026-00360-4
Methods Mol Biol. 2026 ;3001 57-74

Surface Plasmon Resonance for Measuring Interactions of Proteins with Lipids and Lipid Membranes.

Aleksandra Šakanović, Vesna Hodnik, Apolonija Bedina Zavec, Kristina Eleršič Filipič, Gregor Anderluh.

  Surface plasmon resonance (SPR) is an established method for studying molecular interactions in real time. It allows obtaining qualitative and quantitative data on interactions of proteins with lipids or lipid membranes. In most of the approaches, a lipid membrane or a membrane-mimetic surface is prepared on the surface of Biacore (Cytiva) sensor chips, HPA or L1, and the studied protein is then injected across the surface. Here, we provide an overview of SPR in protein-lipid and protein-membrane interactions, different approaches described in the literature and a general protocol for conducting an SPR experiment, including lipid membranes, together with some experimental considerations.

Keywords:  Biacore; Custom made chip; Lipid membrane; Protein–membrane interactions; Sensor chip HPA; Sensor chip L1

DOI:  https://doi.org/10.1007/978-1-0716-5054-7_3
Bioinformatics. 2026 May 20. pii: btag240. [Epub ahead of print]

CancerOmicsStudio (CoS): A web server for integrative and interpretable analysis of multi-omics cancer data.

Chenqi Liao, Rui Dou, Danyang Sun, Chengxiu Hu, Hui Hu, Long Cheng, Yuzhong Xu, Xiong Wang.

MOTIVATION: Large-scale omics resources, including The Cancer Genome Atlas, Genomics of Drug Sensitivity in Cancer, and the Cancer Dependency Map, have become essential for cancer research. However, these datasets are distributed across different platforms, formats and analysis frameworks, which limits their practical use by researchers without extensive computational expertise.
RESULTS: We developed CancerOmicsStudio (CoS), a web server for integrative and interpretable analysis of multi-omics cancer data across 33 cancer types. CoS provides five major modules: CosAI, Traditional Analysis, Drug Sensitivity, CRISPR Dependency and Single-Cell Tumor Microenvironment. The Traditional Analysis module supports expression comparison, diagnostic evaluation, survival analysis, enrichment analysis and gene correlation. The Drug Sensitivity and CRISPR Dependency modules enable systematic evaluation of gene-drug response associations and gene essentiality in cancer cell lines. The Single-Cell Tumor Microenvironment module supports tumor microenvironment analysis at single-cell resolution. In total, approximately 1.23 million results have been precomputed to enable rapid retrieval. CosAI further allows users to submit natural-language queries and obtain results through a Real-time Analysis as Retrieval framework, with responses summarized by a lightweight language model.
AVAILABILITY AND IMPLEMENTATION: CancerOmicsStudio is freely available at Zenodo (doi: 10.5281/zenodo.18744990) and https://cos.wanglab.bio.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

DOI: https://doi.org/10.1093/bioinformatics/btag240
Sci Data. 2026 May 18.

Single-cell transcriptomic profiling of patient-derived pancreatic ductal adenocarcinoma primary cell cultures.

Vladimir Chocoloff, Alex Chauvin, Brice Chanez, Loïc Moubri, Julie Roques, Philippe Soubeyran, Juan Iovanna, Nelson Dusetti, Nicolas Fraunhoffer.

Single-cell RNA sequencing is a powerful approach for characterising cellular heterogeneity and elucidating transcriptional programs that drive tumour plasticity, therapeutic resistance, and disease progression. In this study, we present a single-cell transcriptomic dataset comprising 41 patient-derived cell cultures (PDCs) established from pancreatic ductal adenocarcinoma (PDAC). The dataset was generated using Evercode™ technology, which is based on Split Pool Ligation-based Transcriptome sequencing (SPLiT-seq). This scalable method enables high-throughput profiling across multiple samples without droplet-based microfluidics, allowing efficient capture of inter-sample heterogeneity. This functionally annotated collection of experimentally derived models reveals transcriptional heterogeneity both within and across PDCs, enabling in-depth exploration of PDAC cell diversity, to support the development of computational tools for single-cell analysis, and to guide functional studies on tumour cell subpopulations. This resource constitutes a valuable reference for computational and experimental studies aiming to decipher PDAC heterogeneity and identify therapeutic vulnerabilities.

DOI: https://doi.org/10.1038/s41597-026-07380-3
Physiol Rep. 2026 May;14(10): e70906

Loss of calcium-dependent phospholipase A2 contributes to multi-omic changes in mouse denervated skeletal muscle.

Agnieszka Czyżowska-Froemling, Hongyang Xu, Kylene Harold, Jessica Thomason, Kara Kneuper, Elizabeth Duggan, Atul Pranay, Jie Zhu, Martin-Paul Agbaga, Constantin Georgescu, Victoria Tyrrell, Valerie O'Donnell, Ken Humphries, Holly Van Remmen, Jacob L Brown.

  Age-related loss of innervation in skeletal muscle is a key driver of sarcopenia. We investigated the role of calcium-dependent phospholipase A2 (cPLA2) in denervation-atrophy. cPLA2 mediates the release of polyunsaturated fatty acid substrates, and the oxidation of the free fatty acids generates oxylipins, which are bioactive signaling facilitators. We hypothesized that loss of cPLA2 would protect against muscle atrophy by altering hydroperoxide and oxylipin generation, thereby modifying the transcriptome and lipidome of denervated muscle to mitigate atrophy. We used a sciatic nerve transection model in wildtype and cPLA2 knockout (KO) mice to test this hypothesis. Surprisingly, oxylipin content was significantly higher in 4,10,11,13,14-HDoHE, 12-HEPE, 9,10-EpOME, and 12,13-EpOME in gastrocnemius muscle from mice with genetic deletion of cPLA2 compared to wildtype controls. We observed reductions in several glycolytic intermediates after denervation such as fructose-6-phosphate, glucose-6-phosphate, fructose-1,6-bisphosphate, and phosphoenol pyruvate. Both alpha-hydroxy-glutarate and glucose-6-phosphate were lower in muscle from mice lacking cPLA2. Transcriptomic analysis showed that G-protein coupled receptor signaling was differentially expressed when comparing wildtype and cPLA2 KO mice. In contrast to the protective effects previously reported with inhibition of cPLA2, we found that genetic deletion of cPLA2 did not mitigate denervation-induced muscle atrophy despite having lower hydroperoxide generation in gastrocnemius muscle.

Keywords:  atrophy; denervation; lipids; oxylipins; transcriptomics

DOI:  https://doi.org/10.14814/phy2.70906
Cancer Res Commun. 2026 May 20.

Chronic high-fat diet does not alter overall cancer incidence in Trp53R270H/+ mice.

Ilaria Panzeri, Zachary B Madaj, Luca Fagnocchi, Stefanos Apostle, Megan Tompkins, Kristin Gallik, Eric H Ma, Galen Hostetter, Russell G Jones, John Andrew Pospisilik.

Obesity is a complex chronic disease characterized by excessive adiposity and multiple co-morbidities, including an elevated risk of several cancers. Despite long-standing epidemiological links, the causal relationship between body mass index (BMI) and reduced cancer survival remains controversial, underscoring the need to define how obesity-related factors - such as chronic high-fat diet (HFD) exposure - influence tumor development in the context of defined oncogenic lesions. Here, we report the effects of a chronic HFD-induced obesity on cancer progression in Trp53R270H/+ mice, a model of human Li-Fraumeni syndrome characterized by spontaneous multi-cancer susceptibility. Surprisingly, despite rapid, sustained, and highly penetrant obesity, more than one year of HFD had no significant effect on overall survival, tumor burden, or tumor spectrum across more than 20 anatomical sites in Trp53 mutant mice. Crucially, we did identify a single, tissue-specific exception in the lung, with HFD-fed animals showing increased prevalence of lung tumors that correlated with unique, diet-specific changes in Trp53 allelic and protein profiles. Notably, chronic HFD in this model triggered adipose-specific, not systemic, inflammation. These robust findings, replicated independently in two cohorts totaling 359 mice, suggest that Trp53R270H-driven multi-cancer syndrome is largely refractory to HFD-driven acceleration. Our results provide evidence that chronic diet-induced obesity does not universally enhance tumorigenesis, highlighting the complexity, tissue-specificity, and context-dependent nature of obesity-cancer interactions.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0280