bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2025–06–22
27 papers selected by
Kıvanç Görgülü, Technical University of Munich



  1. J Mol Biol. 2025 Jun 11. pii: S0022-2836(25)00354-7. [Epub ahead of print] 169288
      Autophagy proteins coordinate the biogenesis of a phagophore, the formation and maturation of an autophagosome. Genetic mutations of these proteins can result in dysregulated autophagy, stalled autophagosome biogenesis, and lead to cell death. ATG9, the sole transmembrane ATG (autophagy related) protein governs the nucleation of the phagophore. At a molecular level ATG9 has been shown to be a lipid scramblase capable of redistributing lipids across the lipid bilayer. ATG9-positive vesicles can also deliver lipid-modifying enzymes to alter the lipid composition of membranes. Both functions are required for autophagy. However, ATG proteins, including ATG9, play key molecular roles in pathways unrelated to autophagy. ATG9 has been shown to function in multiple pathways at the Golgi, plasma membrane, and lysosomes. ATG9 can also play an important role in immune signalling. The trafficking of ATG9 in ATG9-positive vesicles is essential to many of these pathways. In this review we highlight the functions of ATG9 in autophagy and autophagy-unrelated pathways, here referred to as "non-canonical functions", and summarise the broader role of ATG9A in cell homeostasis.
    Keywords:  ATG9A; Atg9; autophagy; membrane trafficking
    DOI:  https://doi.org/10.1016/j.jmb.2025.169288
  2. Trends Cell Biol. 2025 Jun 16. pii: S0962-8924(25)00115-1. [Epub ahead of print]
      The plasma membrane (PM) of eukaryotic cells is constantly exposed to many challenges that can cause wounds that necessitate rapid and efficient repair mechanisms to ensure cell survival. PM wound repair not only encompasses the immediate resealing of the membrane barrier, which involves exocytosis of internal vesicles to deliver membrane, but also subsequent processes that are essential to restore cellular homeostasis. These include restoration of membrane and cortical cytoskeleton structures, as well as replenishment of intracellular organelles consumed during resealing. Recent evidence suggests that the different steps in PM repair, resealing, restructuring, and restoration, are spatiotemporally correlated and regulated by membrane tension. Recent advances in understanding the different phases of PM repair are reviewed and a time-dependent classification of repair mechanisms is proposed.
    Keywords:  calcium; endocytosis; exocytosis; membrane wound
    DOI:  https://doi.org/10.1016/j.tcb.2025.05.005
  3. J Cell Biol. 2025 Jul 07. pii: e202505027. [Epub ahead of print]224(7):
      In this issue, Williams et al. (https://doi.org/10.1083/jcb.202408159) reveal a two-step plasma membrane repair process upon injury: annexins first stabilize damage sites, then calcium-activated calpains cleave these patches, triggering microvesicle shedding-mirroring the clot-and-scab resolution seen in tissue-level wound healing.
    DOI:  https://doi.org/10.1083/jcb.202505027
  4. Mol Cell Oncol. 2025 ;12(1): 2518773
      Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited treatment options, underscoring the need for novel therapeutic targets. Metabolic reprogramming is a hallmark of PDAC, enabling tumor cells to sustain rapid proliferation and survive under nutrient-deprived conditions. While glutathione S-transferase pi 1 (GSTP1) is a known regulator of redox homeostasis in PDAC, its role in metabolic adaptation remains unclear. Here, we show that GSTP1 knockdown disrupts PDAC metabolism, leading to downregulation of key metabolic enzymes (ALDH7A1, CPT1A, SLC2A3, PGM1), ATP depletion, mitochondrial dysfunction, and phospholipid remodeling. Phospholipid remodeling, including an increase in phosphatidylcholine (PC) levels, further suggests a compensatory response to metabolic stress. Importantly, GSTP1 knockdown led to elevated lipid peroxidation, increasing 4-hydroxynonenal (4-HNE) accumulation. Treatment with the antioxidant N-acetyl cysteine (NAC) partially restored metabolic gene expression, reinforcing GSTP1's role in the interplay between redox regulation and metabolism in PDAC. By disrupting multiple metabolic pathways, GSTP1 depletion creates potential therapeutic vulnerabilities that could be targeted through metabolic and oxidative stress-inducing therapies to enhance treatment efficacy.
    Keywords:  Pancreatic ductal adenocarcinoma; glutathione S-transferase pi 1 (GSTP1); metabolic reprogramming; metabolomics; therapeutic targeting
    DOI:  https://doi.org/10.1080/23723556.2025.2518773
  5. STAR Protoc. 2025 Jun 12. pii: S2666-1667(25)00293-X. [Epub ahead of print]6(2): 103887
      Orthotopic mouse models of colorectal cancer (CRC) better recapitulate the physiological processes of tumor development and metastatic dissemination. Here, we provide a protocol for colonoscopy-guided transplantation of organoids into the murine colon. We describe the steps for preparing mouse organoids, equipment, and mice for injections, as well as performing colonoscopy-guided mucosal injections and providing subsequent care. This model can be used to investigate various experimental setups, including survival, metastatic potential, and the effects of treatments. For complete details on the use and execution of this protocol, please refer to Felchle et al.1.
    Keywords:  Cancer; Health Sciences; Model Organisms; Organoids
    DOI:  https://doi.org/10.1016/j.xpro.2025.103887
  6. Cancer Res. 2025 Jun 20.
      Immune checkpoint blockade (ICB) has transformed cancer treatment, but success rates remain limited. Recent research suggests that dietary fiber enhances ICB efficacy through microbiome-dependent mechanisms. However, prior studies in mice compared grain-based chow (high-fiber) to low-fiber purified diet, but these diets also differed in other dimensions, including phytochemicals. Therefore, further work is needed to establish the robustness of the effect of fiber on ICB across cancer types and dietary contexts. Here, we investigated gut microbiome composition, metabolite levels, and ICB activity in mice fed grain-based chow or purified diets with differing quantities of isolated fibers (cellulose and inulin). Compared to dietary fiber content, consumption of chow versus purified diet had a greater effect on the gut microbiome and a much stronger impact on the metabolome. Studies in multiple tumor models revealed that fiber has a weaker impact on ICB (anti-PD-1) efficacy than previously reported. While diet impacted ICB in some models, the effect was not directionally consistent. None of the models tested displayed the pattern expected if fiber controlled ICB efficacy: strong efficacy in both chow and high-fiber purified diet but low efficacy in low-fiber purified diet. Thus, dietary fiber appears to have limited or inconsistent effects on ICB efficacy in mouse models, and other dietary factors that correlate with fiber intake may underlie clinical correlations between fiber consumption and immunotherapy efficacy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-4378
  7. Cell. 2025 Jun 11. pii: S0092-8674(25)00572-0. [Epub ahead of print]
      Metazoan life requires the coordinated activities of thousands of genes in spatially organized cell types. Understanding the basis of tissue function requires approaches to dissect the genetic control of diverse cellular and tissue phenotypes in vivo. Here, we present Perturb-Multimodal (Perturb-Multi), a paired imaging and sequencing method to construct large-scale, multimodal genotype-phenotype maps in tissues with pooled genetic perturbations. Using imaging, we identify perturbations in individual cells while simultaneously measuring their gene expression profiles and subcellular morphology. Using single-cell sequencing, we measure full transcriptomic responses to the same perturbations. We apply Perturb-Multi to study hundreds of genetic perturbations in the mouse liver. Our data suggest the genetic regulators and mechanisms underlying the dynamic control of hepatocyte zonation, the unfolded protein response, and steatosis. Perturb-Multi accelerates discoveries of the genetic basis of complex cell and tissue physiology and provides critical training data for emerging machine learning models of cellular function.
    Keywords:  RCA-MERFISH; hepatocyte stress response; in vivo pooled screening; lipid droplet accumulation; liver zonation; machine learning morphology; multimodal phenotyping; multiplexed RNA imaging; multiplexed protein imaging; scRNA-seq
    DOI:  https://doi.org/10.1016/j.cell.2025.05.022
  8. J Am Chem Soc. 2025 Jun 17.
      The structural diversity of the fatty acids esterified in organellar membrane lipids is thought to confer the characteristic physiological properties of the membranes. However, the abundance profiles of fatty acid derivatives are still poorly characterized at organelle-level spatial resolution. Here, we have developed a technology for organelle-specific labeling and quantitative analysis of fatty acid derivatives involving the metabolic incorporation of azide fatty acids and organelle-localizing clickable dyes. This approach was used to investigate palmitate- and oleate-derived lipids in different organelle membranes. The relative abundances of fatty acid-containing lipids were found to differ depending on the organelle and the structure of the fatty acid. In addition, organelle-specific temporal variations in fatty acid derivatives were revealed that are difficult to detect using conventional lipid analysis.
    DOI:  https://doi.org/10.1021/jacs.5c02871
  9. Autophagy. 2025 Jun 18. 1-20
      Lysosomes contribute to the development of drug resistance through various mechanisms that include drug sequestration and the activation of adaptive stress pathways. While inhibitors of DNA-to-RNA transcription exhibit potent anticancer effects, the role of lysosomes in modulating responses to such transcription inhibitors remains largely unexplored. This study investigates this aspect in the context of two potent POLR1 (RNA polymerase I) transcription inhibitors, CX-3543 (quarfloxin) and CX-5461 (pidnarulex). Unexpectedly, CX-3543 was found to accumulate within lysosomes, leading to lysosomal membrane permeabilization (LMP) and the subsequent activation of cellular stress adaptation pathways, including those regulated by the transcription factor TFEB and autophagy. Disrupting TFEB or autophagy increased cell sensitivity to CX-3543, highlighting the cytoprotective role of these processes in counteracting CX-3543-induced cell death. Moreover, targeting lysosomal membranes with chloroquine derivatives or blue light exposure induced substantial LMP, releasing compound CX-3543 from lysosomes. This effect enhanced both the inhibition of DNA-to-RNA transcription and CX-3543-induced cell death. Similar effects were observed when chloroquine derivatives were combined with CX-5461. Additionally, combining CX-3543 with the chloroquine derivative DC661 more effectively reduced the fibrosarcoma growth in immunocompetent mice than either agent alone. Altogether, our results reveal an unanticipated lysosome-related mechanism that contributes to cancer cell resistance to POLR1 inhibitors and propose a strategy to overcome this resistance.Abbreviations: ATG7: autophagy related 7; ATG13: autophagy related 13; Baf A1: bafilomycin A1; CTSB: cathepsin B; DKO: double knockout; G4: Guanine quadruplex; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; LGALS3: galectin 3; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTORC1: mechanistic target of rapamycin kinase complex 1; NCL: nucleolin; POLR1: RNA polymerase I; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TFE3: transcription factor E3; ULK1: unc-51 like autophagy activating kinase 1.
    Keywords:  Autophagy; TFEB; cancer; cell death; guanine quadruplex ligands; resistance to therapy
    DOI:  https://doi.org/10.1080/15548627.2025.2497614
  10. STAR Protoc. 2025 Jun 18. pii: S2666-1667(25)00313-2. [Epub ahead of print]6(3): 103907
      Introducing additional genetic modifications or environmental stimuli accelerates early pancreatic carcinogenesis in the p48Cre/+; LSL-KrasG12D/+ (KC) mouse model. Here, we present a protocol employing adeno-associated virus (AAV)-mediated gene delivery specifically in the pancreas to facilitate the progression from acinar cells through acinar-to-ductal metaplasia (ADM) to pancreatic intraepithelial neoplasia (PanIN). We describe steps for AAV production, preparing KC mice, intra-pancreatic AAV injection, and analysis. This protocol allows the investigation of early events of pancreatic carcinogenesis in a spatially and temporally controlled manner. For complete details on the use and execution of this protocol, please refer to Li et al.1.
    Keywords:  cancer; cell culture; health sciences
    DOI:  https://doi.org/10.1016/j.xpro.2025.103907
  11. Lab Chip. 2025 Jun 19.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive and heterogeneous malignancy, posing challenges for reproducible modeling and functional phenotypic analysis. To address these limitations, we developed a standardized 3D patternoid platform using collagen-based microcavity arrays to enhance organoid formation consistency and quantify subtype-specific invasion mechanisms. We utilized murine primary PDAC cells stratified by epithelial-mesenchymal transition (EMT) into three subtypes: epithelial (E-9591), hybrid EMT (Mlow-8028), and mesenchymal (M-16992). The platform's sensitivity was verified by a strong correlation between EMT scores and invasive phenotypes, as well as responses to physiological concentrations of the protease inhibitor batimastat. Key invasion parameters-including invasive area, maximum invasion distance, and branching complexity-were measured under both genomic and drug-induced conditions. The platform demonstrated high inter-organoid reproducibility, with precise control over initial cell numbers ensuring batch-to-batch comparability. Invasion dynamics analysis revealed that epithelial cells (E-9591) primarily relied on spatial constraints within the microcavity to invade. Batimastat drug sensitivity assays further distinguished invasion dependencies of the mesenchymal subtypes, confirming that M-16992 patternoids exhibit a stronger sensitivity towards MMP inhibition compared to Mlow-8028 patternoids. Concurrentlty, both subtypes experienced a shift towards epithelial-like spatial constraint triggered invasion morphology, reflecting the plasticity of PDAC invasiveness. This scalable and adaptable 3D patternoid platform enables high-throughput analysis of invasive behaviors and therapeutic responses, offering significant potential for preclinical cancer research and personalized medicine.
    DOI:  https://doi.org/10.1039/d5lc00203f
  12. Expert Rev Gastroenterol Hepatol. 2025 Jun 17. 1-4
      
    Keywords:  Intra-pancreatic fat deposition; acute pancreatitis; chronic pancreatitis; expert consensus; fatty pancreas; pancreatic cancer
    DOI:  https://doi.org/10.1080/17474124.2025.2521343
  13. STAR Protoc. 2025 Jun 18. pii: S2666-1667(25)00307-7. [Epub ahead of print]6(3): 103901
      Here, we present a protocol for spatial proteomic profiling of the tumor microenvironment in tonsil cancer using multiplexed imaging-powered deep visual proteomics (mipDVP). We describe steps for automated 22-plex immunofluorescence staining and imaging on formalin-fixed paraffin-embedded (FFPE) tissue sections, automated single-cell laser microdissection, and single-cell-type mass spectrometry. This workflow enables the spatially resolved isolation of distinct cell populations for proteomic analysis. We optimized this protocol for studying tumor-immune interactions, where it facilitates the systematic identification of biomarkers and functional cellular networks. For complete details on the use and execution of this protocol, please refer to Zheng et al.1.
    Keywords:  Biotechnology and bioengineering; Cancer; Microscopy
    DOI:  https://doi.org/10.1016/j.xpro.2025.103901
  14. Biochim Biophys Acta Rev Cancer. 2025 Jun 11. pii: S0304-419X(25)00115-5. [Epub ahead of print]1880(4): 189373
      Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. During tumor progression, metabolic reprogramming plays a crucial role in both tumor proliferation and immune evasion. In PDAC, genetic mutations and environment limitations lead to resulting in increased lactate production through enhanced glycolysis. Elevated glycolysis is a significant metabolic feature in pancreatic cancer, leading to lactate accumulation within both the tumor cells and tumor immune microenvironment. Lactate not only promotes tumor growth and sustains its survival but also has a profound impact on the immune-suppressive phenotype switch of immune cells. Lactate promotes tumor progression through various biological processes. Pharmacological agents targeting lactate generation, accumulation and lactate-related molecular pathways show potential clinical translation value in cancer treatment.
    Keywords:  GPR81; Lactate metabolism; Lactylation; Metabolic reprogramming; PDAC; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189373
  15. Cancer Cell. 2025 Jun 10. pii: S1535-6108(25)00224-7. [Epub ahead of print]
      Cellular senescence is a state of stable cell-cycle arrest induced by various intrinsic and extrinsic stressors, serving as a protective mechanism to prevent the proliferation of damaged cells. While this process is crucial for tissue homeostasis and tumor suppression, the progressive accumulation of senescent cells (SnCs) over time is implicated in age-related pathologies, including immune dysfunction and cancer. In oncology, senescence plays a paradoxical role: it can inhibit tumor development by halting the growth of potentially malignant cells, yet it may also facilitate tumor progression through the senescence-associated secretory phenotype (SASP). This review explores the defining features of senescence in cancer, its complex interactions with tumor cells, the stroma, and the immune system, and its context-dependent outcomes. We also discuss current and emerging therapeutic strategies that target SnCs-either by inducing or eliminating them-as well as AI-driven approaches for their detection and characterization in cancer.
    Keywords:  AI-approaches for senescence; PICS; SASP modulators; cancer; hallmarks of senescence; oncogene-induced senescence; prosenescence; senescence; senescence immune system; senescence in tumor microenvironment; senolytics; senomorphic; therapy-induced senescence
    DOI:  https://doi.org/10.1016/j.ccell.2025.05.015
  16. Nat Rev Cancer. 2025 Jun 16.
      The nervous and immune systems have co-evolved to detect and respond to internal and external threats, working together to restore homeostasis after tissue injury or infection. Sharing several receptors and ligands, they engage in direct cross-talk that substantially influences disease development. The emerging field of cancer neuro-immunity focuses on the intricate interactions between the nervous system, immune responses and tumour growth. Additional findings have revealed that nerve fibres infiltrating peripheral tumours can release neuromodulatory factors that shape both immune cell behaviour and tumour progression. Conversely, tumour-infiltrating immune cells can modify the activity of local neurons, including pain-transmitting nociceptive sensory neurons. Beyond sensory fibres, sympathetic signalling can foster immunosuppression by recruiting myeloid-derived suppressor cells and promoting T cell exhaustion. This Review summarizes current evidence on how neuronal signalling regulates peripheral antitumour immune responses within the tumour microenvironment. We describe the complex, reciprocal interactions among neurons, immune cells and malignant cells, highlighting the key parts played by the peripheral nervous system in modulating immunity against cancer. By understanding this neuro-immune axis, novel therapeutic approaches may be uncovered to strengthen antitumour immunity and enhance responses to existing cancer treatments.
    DOI:  https://doi.org/10.1038/s41568-025-00831-w
  17. Commun Biol. 2025 Jun 17. 8(1): 936
      VDACs, the most abundant proteins in the outer mitochondrial membrane (MOM), are crucial for mitochondrial physiology. VDAC regulate metabolite and ion exchange, modulate calcium homeostasis, and play roles in numerous cellular events such as apoptosis, mitochondrial DNA (mtDNA) release, and different diseases. Mitochondrial function is closely tied to VDAC oligomerization, influencing key processes like mtDNA release and apoptosis, but the molecular drivers of this oligomerization remain unclear. In this study, we investigate the effects of three major MOM lipids on VDAC assemblies using atomic force microscopy and molecular dynamics simulations. Our results show that phosphatidylethanolamine and cholesterol regulate VDAC assembly, with the formation of stable lipid-protein organization of various size and compaction. Deviations from physiological lipid content disrupted native-like VDAC assemblies, highlighting the importance of lipid environment in VDAC organization. These findings underscore how lipid heterogeneity and changes in membranes influence VDAC function.
    DOI:  https://doi.org/10.1038/s42003-025-08311-5
  18. Nat Cell Biol. 2025 Jun;27(6): 890-901
      Mitochondria are critical double-membraned organelles that act as biosynthetic and bioenergetic cellular factories, with the outer membrane providing an interface with the rest of the cell. Mitochondrial outer membrane proteins regulate a variety of processes, including metabolism, innate immunity and apoptosis. Although the biophysical and functional diversity of these proteins is highly documented, the mechanisms of their biogenesis and the integration of that into cellular homeostasis are just starting to take shape. Here, focusing on α-helical outer membrane proteins, we review recent insights into the mechanisms of synthesis and cytosolic chaperoning, insertion and assembly in the lipid bilayer, and quality control of unassembled or mislocalized transmembrane domains. We further discuss the role convergent evolution played in this process, comparing key biogenesis players from lower eukaryotes, including yeast and trypanosomes, with multicellular metazoan systems, and draw comparisons with the endoplasmic reticulum biogenesis system, in which membrane proteins face similar challenges.
    DOI:  https://doi.org/10.1038/s41556-025-01683-0
  19. Trends Pharmacol Sci. 2025 Jun 19. pii: S0165-6147(25)00119-1. [Epub ahead of print]
      An effective therapeutic strategy to treat oncogenic Wnt signaling in the context of colorectal cancer (CRC) remains elusive. A new study from Cho and colleagues describes a novel mechanistic link between the loss of canonical adenomatous polyposis coli (APC) function, membrane cholesterol, and an innovative drug target to specifically suppress the cholesterol-Dvl-β-catenin signaling axis.
    Keywords:  Dvl; Wnt; cholesterol; colon cancer; plasma membrane; therapeutics
    DOI:  https://doi.org/10.1016/j.tips.2025.06.001
  20. STAR Protoc. 2025 Jun 14. pii: S2666-1667(25)00301-6. [Epub ahead of print]6(3): 103895
      We present a protocol to generate immunocompetent 3D tumor-on-chip models from human solid tumors, enabling more accurate therapy response assessment than traditional 2D assays. We outline the isolation and culture of autologous tumor cells, CD8+ tumor-infiltrating lymphocytes, and cancer-associated fibroblasts, followed by their encapsulation in a 3D biomimetic matrix within microfluidic devices and subsequent video microscopy. The protocol is adaptable to other tumor types, including breast and colon cancer. For complete details on the use and execution of this protocol, please refer to Veith et al.1.
    Keywords:  Cancer; Cell culture; Cell isolation; Immunology; Tissue Engineering
    DOI:  https://doi.org/10.1016/j.xpro.2025.103895
  21. Nat Photonics. 2025 Mar;19(3): 238-247
      Optical super-resolution microscopy is a key technology for structural biology that offers high imaging contrast and live-cell compatibility. Minimal (fluorescence) photon flux microscopy, or MINFLUX, is an emerging super-resolution technique that localizes single fluorophores with high spatiotemporal precision by targeted scanning of a patterned excitation beam featuring a minimum. MINFLUX offers super-resolution imaging with nanometre resolution. When tracking single fluorophores, MINFLUX can achieve nanometre spatial and submillisecond temporal resolution over long tracks, greatly outperforming camera-based techniques. In this Review, we present the basic working principle of MINFLUX and explain how it can reach high photon efficiencies. We then outline the advantages and limitations of MINFLUX, describe recent extensions and variations of MINFLUX and, finally, provide an outlook for future developments.
    DOI:  https://doi.org/10.1038/s41566-025-01625-0
  22. Gut. 2025 Jun 19. pii: gutjnl-2024-334237. [Epub ahead of print]
    PanGenEU Centres and Investigators
       BACKGROUND: Diagnosing the presence of metastasis of pancreatic cancer is pivotal for patient management and treatment, with contrast-enhanced CT scans (CECT) as the cornerstone of diagnostic evaluation. However, this diagnostic modality requires a multifaceted approach.
    OBJECTIVE: To develop a convolutional neural network (CNN)-based model (PMPD, Pancreatic cancer Metastasis Prediction Deep-learning algorithm) to predict the presence of metastases based on CECT images of the primary tumour.
    DESIGN: CECT images in the portal venous phase of 335 patients with pancreatic ductal adenocarcinoma (PDAC) from the PanGenEU study and The First Affiliated Hospital of Zhengzhou University (ZZU) were randomly divided into training and internal validation sets by applying fivefold cross-validation. Two independent external validation datasets of 143 patients from the Radboud University Medical Center (RUMC), included in the PANCAIM study (RUMC-PANCAIM) and 183 patients from the PREOPANC trial of the Dutch Pancreatic Cancer Group (PREOPANC-DPCG) were used to evaluate the results.
    RESULTS: The area under the receiver operating characteristic curve (AUROC) for the internally tested model was 0.895 (0.853-0.937) and 0.779 (0.741-0.817) in the PanGenEU and ZZU sets, respectively. In the external validation sets, the mean AUROC was 0.806 (0.787-0.826) for the RUMC-PANCAIM and 0.761 (0.717-0.804) for the PREOPANC-DPCG. When stratified by the different metastasis sites, the PMPD model achieved the average AUROC between 0.901-0.927 in PanGenEU, 0.782-0.807 in ZZU and 0.761-0.820 in PREOPANC-DPCG sets. A PMPD-derived Metastasis Risk Score (MRS) (HR: 2.77, 95% CI 1.99 to 3.86, p=1.59e-09) outperformed the Resectability status from the National Comprehensive Cancer Network guideline and the CA19-9 biomarker in predicting overall survival. Meanwhile, the MRS could potentially predict developed metastasis (AUROC: 0.716 for within 3 months, 0.645 for within 6 months).
    CONCLUSION: This study represents a pioneering utilisation of a high-performance deep-learning model to predict extrapancreatic organ metastasis in patients with PDAC.
    Keywords:  AI (Artificial Intelligence); LIVER METASTASES; PANCREATIC CANCER; PANCREATIC SURGERY; RADIOLOGY
    DOI:  https://doi.org/10.1136/gutjnl-2024-334237
  23. Oncologist. 2025 Jun 04. pii: oyaf154. [Epub ahead of print]30(6):
      Oligometastatic pancreatic cancer is a distinct clinical entity with limited metastatic burden. This unique subset of patients harbor a favorable tumor biology and potentially better prognosis compared to widespread metastatic disease. This review explores definitions of oligometastatic pancreatic cancer and the current state of management, including systemic therapy, surgery, and locoregional techniques. While there are few randomized clinical trials directing the management of oligometastatic pancreatic cancer, we provide insights into the treatment challenges, evolving therapeutic approaches, and future directions for this unique subset of patients.
    Keywords:  locoregional therapy; metastasis-directed therapy; oligometastatic disease; pancreatic ductal adenocarcinoma; surgical metastasectomy; systemic therapy
    DOI:  https://doi.org/10.1093/oncolo/oyaf154
  24. Curr Opin Cell Biol. 2025 Jun 17. pii: S0955-0674(25)00101-2. [Epub ahead of print]95 102563
      Macropinocytosis is a conserved pathway for non-selective bulk uptake of extracellular fluid. It plays important roles in various cellular processes, including nutrient acquisition in Dictyostelium and cancer cells and antigen sampling by immune cells. This process is initiated by localized actin polymerization, which drives the formation of membrane protrusions that close to generate macropinosomes. Once formed, macropinosomes undergo maturation and traffic through the endolysosomal system for cargo degradation, whereas non-degradable material is exocytosed. Recent studies have uncovered conserved regulatory networks controlling macropinosome formation and maturation. This review provides an overview of these pathways, highlighting key molecular regulators and their coordinated responses to environmental signals. We also examine the interplay between macropinocytosis and cell migration, discussing potential mechanisms that balance these processes to optimize cellular function.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102563
  25. Aging Cell. 2025 Jun 18. e70127
      The relationship between in vitro senescence cell induction and intracellular biomolecular dysregulation is still poorly understood. In this study, we have found that a range of metabolic subphenotypes exists and is dependent on the induction method that is used. To develop understanding of these subphenotypes, we developed and employed a novel bioanalytical pipeline integrating untargeted metabolomics, label-free proteomics, and stable isotope tracing alongside cellular deformability measurements and established senescence biomarkers. Initially, standard senescent markers indicated all induction methods were consistent by showing elevated SA-β-Gal expression, p21 levels, and γH2AX DNA damage markers alongside a decrease in Ki67 and an increase in shape, volume, and deformability. However, when probed at the metabolic and protein levels, all senescence models indicated both shared and unique biomolecular responses. A metabolic shift toward reductive pathways (driven by serine and taurine rewiring) and impaired proteostasis was an observed shared response. These findings suggest that targeting metabolic redox circuits, alongside serine and taurine metabolic processes, presents novel therapeutic strategies for addressing senescence and aging. But importantly, alongside this general shift, we found that significant metabolic and proteomic heterogeneity also exists across different senescence induction methods. This demonstrates that the method of senescence induction significantly influences cell metabolic and proteomic profiles. Critically, methods of senescence induction are not interchangeable, and careful consideration is needed when choosing between different induction methods and when comparing cellular phenotypes across different in vitro senescence experiments.
    Keywords:  aging; isotope labeling; metabolomics; proteomics; rheo‐morphology; senescence
    DOI:  https://doi.org/10.1111/acel.70127
  26. J Mol Med (Berl). 2025 Jun 17.
      The interplay between selenium (Se) metabolism and ferroptosis presents a compelling area of study in cancer biology. This review synthesizes the current understanding of key pathways implicated in ferroptosis susceptibility, with a focus on the role of selenoproteins, particularly glutathione peroxidase 4 (GPX4), which mitigates lipid peroxidation and prevents ferroptotic cell death through the system Xc-/GSH axis. Additionally, selenoprotein P contributes to Se transport, playing a crucial role in ferroptosis resistance observed in certain cancers. Targeting Se pathways, especially disrupting GPX4 and selenoprotein P functions, offers promising avenues for cancer therapy. The differential dependence of cancer cells on Se and selenoproteins highlights the potential for selective induction of ferroptosis in malignant cells. Future research should focus on unraveling the mechanistic underpinnings of Se-mediated ferroptosis and exploring combinatorial therapeutic strategies. This review sets the stage for innovative approaches that leverage Se metabolism to enhance cancer treatment efficacy through ferroptosis modulation. KEY MESSAGES: Selenium (Se) and selenoproteins regulate ferroptosis, a lipid peroxidation-driven form of cell death. GPX4, a Se-dependent enzyme, defends cells by neutralizing lipid hydroperoxides. Xc-/GSH/GPX4 and FSP1-CoQ10 pathways are critical in modulating ferroptosis susceptibility. Selenoprotein P, SEPHS2, and SQOR highlight vulnerabilities in Se-dependent cancer cell survival. Se's role in balancing antioxidant defense and ferroptosis offers therapeutic insights.
    Keywords:  Biosynthesis; Cancer; Ferroptosis; Selenium; Selenoprotein
    DOI:  https://doi.org/10.1007/s00109-025-02563-8
  27. Ann Surg. 2025 Jun 18.
       OBJECTIVE: To evaluate whether mutations in pancreatic ductal adenocarcinoma (PDAC) driver genes (KRAS, TP53, SMAD4, and CDKN2A) are associated with pathological characteristics and prognosis.
    SUMMARY BACKGROUND DATA: The prognostic significance of specific mutations in PDAC driver genes is incompletely understood.
    METHODS: We analyzed patients who underwent pancreatectomy between 2018 and 2022 for localized PDAC and whose cancer was profiled using targeted next-generation DNA sequencing. We investigated associations between mutational status, clinical-pathological characteristics, and overall survival (OS).
    RESULTS: Analysis of 508 patients defined KRAS mutations as the most common genetic mutation (456, 89.8%), followed by TP53 (292, 57.5%), SMAD4 (104, 20.3%), and CDKN2A (88, 17.3%). The presence of wild-type KRAS (KRAS-wt) was associated with lower T- (P<0.001) and N-stage (P=0.04) and lower rates of perineural invasion (P=0.03), when adjusting for receipt of neoadjuvant therapy. TP53 mutations compared with TP53-wt were associated with higher T-stage (P=0.02), perineural invasion (P=0.01), and advanced tumor grade (P=0.03). Mutations in KRAS and TP53 were associated with shorter mOS compared to wild-type (HR 2.29, P=0.002 and HR 1.62, P<0.001, respectively). On multivariable analysis, N0 stage, anatomically resectable cancer, and absent lympho-vascular invasion were associated with improved mOS (all P<0.02). The presence of two (HR 1.71) or three-plus (HR 1.63) driver mutation genes was associated with shorter mOS compared to one mutation (P<0.01).
    CONCLUSIONS: In patients with resected PDAC, KRAS-wt and TP53-wt were associated with improved pathological characteristics and mOS, regardless of neoadjuvant therapy. The co-occurrence of two or more driver gene mutations was associated with worse mOS.
    Keywords:  NGS; PDAC; histopathologic characteristics; molecular profiling; pancreatic cancer; pancreatic neoplasm; surgical resection
    DOI:  https://doi.org/10.1097/SLA.0000000000006794