bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2025–11–09
37 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Lipid packing and local geometry influence septin curvature sensing.
  2. Lymph node environment drives FSP1 targetability in metastasizing melanoma.
  3. The Aging Microenvironment is a Determinant of Immune Exclusion and Metastatic Fate in Pancreatic Cancer.
  4. Targeting FSP1 triggers ferroptosis in lung cancer.
  5. Contrastive virtual staining enhances deep learning-based PDAC subtyping from H&E-stained tissue cores.
  6. Aging represses oncogenic KRAS-driven lung tumorigenesis and alters tumor suppression.
  7. Senolytic-sensitive p16Ink4a+ fibroblasts in the tumor stroma rewire lung cancer metabolism and plasticity.
  8. Lung endothelial PEAR1 induces tumor cell dormancy.
  9. Breaking the Mechanical Compass: Disrupting Durotaxis to Halt Fibrosis and Metastasis.
  10. USP20-Driven Cholesterol Metabolism Links Inflammatory Signaling to Malignancy and Stromal Co-evolution in Pancreatic Cancer.
  11. Golgiphagy mediated by TM9SF3 acts as quality control for stressed Golgi.
  12. Systematic membrane thickness variation across cellular organelles revealed by cryo-ET.
  13. Benchmarking porcine pancreatic ductal organoids for drug screening applications.
  14. Chemical compensation to mechanical loss in cell mechanosensation.
  15. Cellular senescence in precancer lesions and early-stage cancers.
  16. Toward a new standard: Sequential multi-agent neoadjuvant chemotherapy in resectable pancreatic cancer.
  17. Decoding the spatial dynamics of tumor and immune cell interactions in solid cancers.
  18. Transcriptional landscape of skeletal muscle in cancer patients.
  19. ESPRESSO: spatiotemporal omics based on organelle phenotyping.
  20. DeepTarget predicts anti-cancer mechanisms of action of small molecules by integrating drug and genetic screens.
  21. TGF-β builds a dual immune barrier in colorectal cancer by impairing T cell recruitment and instructing immunosuppressive SPP1+ macrophages.
  22. Cell aging - a relevant factor in live cell microscopy (mini-review).
  23. Leveraging genetic and phenotypic variation to discover metabolite-protein interactions.
  24. Protocol to study metastatic dormancy using 4T07-mCherry breast cancer cells and an algorithm-based quantification of disseminated cancer cells.
  25. A multimodal whole-slide foundation model for pathology.
  26. Phase IB trial of high dose ascorbic acid + nab-paclitaxel + cisplatin + gemcitabine in patients with untreated metastatic pancreatic cancer.
  27. Magnetoelectric Nanotherapy Achieves Complete Tumor Ablation and Prolonged Survival in Pancreatic Cancer Murine Models.
  28. Ferroptosis Pathway Discrimination and Anticancer Therapeutic Screening Enabled by Cascade-Activated Fluorescence Reporting of Cysteine-Viscosity Dynamics.
  29. Aspirin use and acute pancreatitis mortality.
  30. Electromechanically induced membrane restructuring enables learning and memory.
  31. Epistemology of the Origin of Cancer III: Fundamentals of How Metastasis Arises.
  32. The Japan autophagy consortium.
  33. The CILLO-E Hypothesis: Erythrocyte-Driven Acidosis and Early Eryptosis as Drivers of Cancer-Associated Anemia.
  34. Acinar-specific loss of activating transcription factor 3 restricts KRASG12D mediated transcriptional changes and PanIN progression.
  35. Beyond the Secretory Pathway: New Insights Into Protein Release.
  36. Hypoxia-induced alterations in lipid polyunsaturation and associated proteins drive aggressive metastasis in pancreatic cancer via the PPAR/hypoxia pathway.
  37. Buried Nanopore Membranes with Enhanced Mechanical Robustness for High-Resolution Single-Molecule Sensing.
  1. J Cell Biol. 2026 Jan 05. pii: e202502062. [Epub ahead of print]225(1):
    Lipid packing and local geometry influence septin curvature sensing.
    Brandy N Curtis, Ellysa J D Vogt, Joanne L Ekena, Christopher Edelmaier, Amy S Gladfelter.
      Septins can assemble into scaffolds at the plasma membrane to regulate cell morphology. While septins preferentially bind convex membranes via amphipathic helices, their assembly on varied geometries in cells suggests additional localization cues. We tested the hypothesis that lipid composition directs septin assembly through the property of lipid packing. We used pharmacological perturbations that alter fatty acid chain saturation to manipulate lipid packing and found septin structures were selectively disrupted at flat regions of the plasma membrane. To determine whether lipid packing is sufficient to impact septin assembly, molecular dynamics simulations were used to design lipid mixtures with varied packing to monitor septin adsorption in vitro. Septins strongly favored loosely packed lipid bilayers, but additional geometrical cues act in conjunction with this membrane property. This work demonstrates that packing defects and geometry jointly regulate septin localization, highlighting how distinct membrane properties are integrated to organize the septin cytoskeleton.
    DOI:  https://doi.org/10.1083/jcb.202502062
  2. Nature. 2025 Nov 05.
    Lymph node environment drives FSP1 targetability in metastasizing melanoma.
    Mario Palma, Milena Chaufan, Cort B Breuer, Sebastian Müller, Marie Sabatier, Cameron S Fraser, Krystina J Szylo, Mahsa Yavari, Alanis Carmona, Mayher Kaur, Luiza Martins Nascentes Melo, Feyza Cansiz, June Monge-Lorenzo, Midori Flores, Eikan Mishima, Toshitaka Nakamura, Bettina Proneth, Marcos Labrado, Yanshan Liang, Nicole Cayting, Lan Zheng, Tatiana Cañeque, Ludovic Colombeau, Adam Wahida, José Pedro Friedmann Angeli, Alpaslan Tasdogan, Sheng Hui, Raphaël Rodriguez, Marcus Conrad, Nathan E Reticker-Flynn, Jessalyn M Ubellacker.
      Ferroptosis has emerged as an actionable target to eliminate therapy-resistant and metastatic cancers1. However, which ferroptosis surveillance systems may offer a therapeutic window to leverage redox maladaptation in cancer remains unclear. In melanoma, glutathione peroxidase 4 (GPX4) impedes ferroptosis during haematogenous metastasis, but is dispensable during lymphatic metastasis2. Here, using a metastatic mouse melanoma model selected for lymph node metastasis, we show that lymph-node-derived metastatic cells exhibit markedly diminished expression of glutamate-cysteine ligase (GCLC) and reduced glutathione (GSH) levels relative to their parental counterparts. This metabolic shift occurs within the hypoxic lymphatic niche. Under comparable low-oxygen conditions, GPX4 undergoes ubiquitination and proteasomal degradation. In response, lymph node metastatic cells acquire increased reliance on ferroptosis suppressor protein 1 (FSP1), which is localized with perinuclear lysosomes. These findings reveal that the reduced reliance on the GPX4 axis enables melanoma cells to shift toward FSP1 dependency. Notably, intratumoural monotherapy with selective FSP1 inhibitors (viFSP1 and FSEN1) effectively suppresses melanoma growth in lymph nodes, but not in subcutaneous tumours, emphasizing a microenvironment-specific dependency on FSP1. Thus, targeting FSP1 in the lymph nodes holds strong potential for blocking melanoma progression.
    DOI:  https://doi.org/10.1038/s41586-025-09709-1
  3. Cancer Res. 2025 Nov 07.
    The Aging Microenvironment is a Determinant of Immune Exclusion and Metastatic Fate in Pancreatic Cancer.
    Priyanka Gupta, Rabi Murad, Li Ling, Yijuan Zhang, Karen Duong-Polk, Weiliang Huang, Marzia Scortegagna, Swetha Maganti, Cheska Marie Galapate, Cosimo Commisso.
      Aging is a critical yet understudied determinant in pancreatic ductal adenocarcinoma (PDAC) risk and outcomes. Despite a strong epidemiological association with age, conventional PDAC preclinical models fail to capture the histopathological and stromal complexities that emerge in older organisms. Using an age-relevant syngeneic orthotopic model, we demonstrated that organismal aging accelerates PDAC progression and metastasis. Transcriptomic and secretome profiling identified a conserved extracellular matrix gene signature enriched in cancer-associated fibroblasts (CAFs) from aged tumors, consistent with an augmented fibrotic landscape that supports immunosuppression, metastatic tropism, and poor prognosis. Direct testing of the functional impact of stromal aging in heterochronic co-implantation models revealed that revitalizing the aged tumor stroma with young CAFs restores immune infiltration and attenuates metastasis in older hosts. Conversely, aged CAFs, while immunosuppressive, failed to enhance metastasis in young hosts, suggesting that a youthful microenvironment exerts dominant regulatory control over disease progression. These findings demonstrate that stromal age is a critical modulator of both immune exclusion and metastatic behavior in PDAC. Importantly, this work establishes a conceptual framework for understanding how aging shapes the tumor microenvironment in PDAC and opens a fertile avenue of investigation into age-specific stromal regulation. Moreover, these findings raise compelling questions about the underlying molecular mechanisms and lay the foundation for future efforts to therapeutically target stromal aging in PDAC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-1904
  4. Nature. 2025 Nov 05.
    Targeting FSP1 triggers ferroptosis in lung cancer.
    Katherine Wu, Alec J Vaughan, Jozef P Bossowski, Yuan Hao, Aikaterini Ziogou, Seon Min Kim, Tae Ha Kim, Mari N Nakamura, Ray Pillai, Mariana Mancini, Sahith Rajalingam, Mingqi Han, Toshitaka Nakamura, Lidong Wang, Suckwoo Chung, Diane Simeone, David Shackelford, Yun Pyo Kang, Marcus Conrad, Thales Papagiannakopoulos.
      Emerging evidence indicates that cancer cells are susceptible to ferroptosis, a form of cell death that is triggered by uncontrolled lipid peroxidation1-3. Despite broad enthusiasm about harnessing ferroptosis as a novel anti-cancer strategy, whether ferroptosis is a barrier to tumorigenesis and can be leveraged therapeutically remains unknown4,5. Here, using genetically engineered mouse models of lung adenocarcinoma, we performed tumour-specific loss-of-function studies of two key ferroptosis suppressors, GPX46,7 and ferroptosis suppressor protein 1 (FSP1)8,9, and observed increased lipid peroxidation and robust suppression of tumorigenesis, suggesting that lung tumours are highly sensitive to ferroptosis. Furthermore, across multiple pre-clinical models, we found that FSP1 was required for ferroptosis protection in vivo, but not in vitro, underscoring a heightened need to buffer lipid peroxidation under physiological conditions. Lipidomic analyses revealed that Fsp1-knockout tumours had an accumulation of lipid peroxides, and inhibition of ferroptosis with genetic, dietary or pharmacological approaches effectively restored the growth of Fsp1-knockout tumours in vivo. Unlike GPX4, expression of FSP1 (also known as AIFM2) was prognostic for disease progression and poorer survival in patients with lung adenocarcinoma, highlighting its potential as a viable therapeutic target. To this end, we demonstrated that pharmacologic inhibition of FSP1 had significant therapeutic benefit in pre-clinical lung cancer models. Our studies highlight the importance of ferroptosis suppression in vivo and pave the way for FSP1 inhibition as a therapeutic strategy for patients with lung cancer.
    DOI:  https://doi.org/10.1038/s41586-025-09710-8
  5. J Pathol. 2025 Nov 04.
    Contrastive virtual staining enhances deep learning-based PDAC subtyping from H&E-stained tissue cores.
    Maximilian Fischer, Alexander Muckenhuber, Robin Peretzke, Luay Farah, Constantin Ulrich, Sebastian Ziegler, Philipp Schader, Lorenz Feineis, Hanno Gao, Shuhan Xiao, Michael Götz, Marco Nolden, Katja Steiger, Jens T Sieveke, Lukas Endrös, Rickmer Braren, Jens Kleesiek, Peter Schüffler, Peter Neher, Klaus Maier-Hein.
      Pancreatic ductal adenocarcinoma (PDAC) subtyping typically relies on immunohistochemistry (IHC) staining for critical markers like HNF1A and KRT81, a labor-intensive manual staining process that introduces variability. Virtual staining methods offer promising alternatives by generating synthetic IHC images from routine hematoxylin and eosin (H&E) slides. However, most current approaches evaluate success by image quality measures rather than assessing diagnostically relevant features. Here, we introduce a novel cycleGAN framework utilizing a contrastive-inspired approach trained on semipaired datasets derived from consecutive tissue sections. Our method significantly enhances PDAC subtyping accuracy based on synthetic IHC images generated from standard H&E inputs, improving the classification F1-score from 0.66 to 0.77 for KRT81 and from 0.61 to 0.73 for HNF1A, compared with classification directly on H&E images. This approach also substantially outperforms baseline CycleGAN models. These results underscore the clinical potential of contrastive virtual staining to streamline PDAC diagnostics and improve their robustness. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
    Keywords:  CycleGAN; H&E; IHC; PDAC subtyping; contrastive learning; digital pathology; virtual staining
    DOI:  https://doi.org/10.1002/path.6491
  6. Nat Aging. 2025 Nov 04.
    Aging represses oncogenic KRAS-driven lung tumorigenesis and alters tumor suppression.
    Emily G Shuldiner, Saswati Karmakar, Min K Tsai, Jess D Hebert, Yuning J Tang, Laura Andrejka, Maggie R Robertson, Minwei Wang, Colin R Detrick, Hongchen Cai, Rui Tang, Christian A Kunder, David M Feldser, Dmitri A Petrov, Monte M Winslow.
      Most cancers are diagnosed in people over 60 years of age, but little is known about how age impacts tumorigenesis. While aging is accompanied by mutation accumulation (widely understood to contribute to cancer risk) it is associated with numerous other cellular and molecular changes likely to impact tumorigenesis. Moreover, cancer incidence decreases in the oldest part of the population, suggesting that very old age may reduce carcinogenesis. Here we show that aging represses oncogenic KRAS-driven tumor initiation and growth in genetically engineered mouse models of human lung cancer. Moreover, aging dampens the impact of inactivating many tumor suppressor genes with the impact of inactivating PTEN, a negative regulator of the PI3K-AKT pathway, weakened disproportionately. Single-cell transcriptomic analysis revealed that neoplastic cells in aged mice retain age-related transcriptomic changes, showing that the impact of age persists through oncogenic transformation. Furthermore, the consequences of PTEN inactivation were strikingly age-dependent, with PTEN deficiency reducing signatures of aging in cancer cells and the tumor microenvironment. Our findings underscore the interconnectedness of the pathways involved in aging and tumorigenesis and document tumor-suppressive effects of aging that may contribute to the deceleration in cancer incidence with age.
    DOI:  https://doi.org/10.1038/s43587-025-00986-z
  7. Cell Stem Cell. 2025 Nov 03. pii: S1934-5909(25)00373-X. [Epub ahead of print]
    Senolytic-sensitive p16Ink4a+ fibroblasts in the tumor stroma rewire lung cancer metabolism and plasticity.
    Jin Young Lee, Nabora Reyes, Sang-Ho Woo, Nancy C Allen, Tsukasa Kadota, Andrew Lechner, Ritusree Biswas, Sakshi Goel, Fia Stratton, Chaoyuan Kuang, Tatsuya Tsukui, Vincent Auyeung, Aaron S Mansfield, Lindsay M LaFave, Tien Peng.
      Senescence has been demonstrated to either inhibit or promote tumorigenesis. Resolving this paradox requires spatial mapping and functional characterization of senescent cells in the native tumor niche. Here, we identify p16Ink4a+ cancer-associated fibroblasts enriched with senescent phenotypes that promote fatty acid uptake and utilization by aggressive lung adenocarcinoma (LUAD) driven by Kras and p53 mutations. Furthermore, rewiring of lung cancer metabolism by p16Ink4a+ cancer-associated fibroblasts also alters tumor cell identity to a highly plastic/dedifferentiated state associated with progression in murine and human LUAD. Our ex vivo senolytic screening platform identifies XL888, an HSP90 inhibitor, that clears p16Ink4a+ cancer-associated fibroblasts in vivo. XL888 administration after establishment of advanced LUAD significantly reduces tumor burden concurrent with the loss of plastic tumor cells. Our study identifies a druggable component of the tumor stroma that fulfills the metabolic requirement of tumor cells to acquire a more aggressive phenotype.
    Keywords:  cancer-associated fibroblasts; lung adenocarcinoma; p16(INK4a); senescence; senolytics; spatial transcriptomics; tumor cell plasticity; tumor metabolism; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.stem.2025.10.005
  8. Mol Cancer. 2025 Nov 03. 24(1): 278
    Lung endothelial PEAR1 induces tumor cell dormancy.
    Kenneth Anthony Roquid, Adriana Vucetic, Elena Dyukova, Mika J Hanssen, Haaglim Cho, Rémy Bonnavion, Kenny Mattonet, Mario Looso, Miloslav Sanda, Boris Strilic, Stefan Offermanns.
      In many cancer patients, distant metastases develop after years of dormancy. Understanding how disseminated tumor cells (DTCs), which are often found in proximity to the microvasculature, remain dormant and what regulates their reactivation is one of the major challenges in tumor biology. In a screen for endothelial secreted and plasma membrane proteins able to regulate tumor cell dormancy, we identified the transmembrane protein platelet and endothelial aggregation receptor 1 (PEAR1). Human and murine endothelial cells lacking PEAR1 lost the ability to promote dormancy of different tumor cells, and the extracellular part of PEAR1 was able to rescue this effect. Similarly, in mice lacking PEAR1 in endothelial cells, tumor cell dormancy in the lung was reduced and tumor metastasis was increased. We found that PEAR1 induces tumor cell dormancy by binding lysyl oxidase like 2 (LOXL2) and cathepsin D (CTSD), which both inhibit tumor cell dormancy and promote tumor growth and metastasis. Tumor cells with suppressed CTSD expression showed increased dormancy and decreased metastatic potential in vivo. Our data identify a mechanism underlying tumor cell dormancy and suggest CTSD and LOXL2 as targets for approaches to promote dormancy.
    Keywords:  CTSD; Dormancy; Endothelial; LOXL2; Metastasis; PEAR1; p27
    DOI:  https://doi.org/10.1186/s12943-025-02488-3
  9. Cancer Res. 2025 Nov 06.
    Breaking the Mechanical Compass: Disrupting Durotaxis to Halt Fibrosis and Metastasis.
    Jessica L Chitty, Amelia L Parker, Thomas R Cox.
      Durotaxis is the directed migration of cells along tissue stiffness gradients, and is emerging as a fundamental mechanobiological process orchestrating progression in diseases such as fibrosis and cancer. Despite compelling in vitro evidence demonstrating durotactic behaviour across multiple cell types, translating these findings to in vivo contexts has remained challenging due to the inherent complexity of isolating biomechanical cues from the myriad biochemical and architectural features that collectively define tissue properties. In their recent Nature Cell Biology study, Al-Hilal and colleagues address this translational gap through innovative bioengineering approaches combined with genetic models. Using high-resolution atomic force microscopy and intravital two-photon imaging, the authors demonstrate that pathological stiffness gradients drive fibroblast recruitment and activation in bleomycin-induced lung fibrosis, whilst simultaneously promoting quasi-mesenchymal pancreatic cancer cell dissemination. Critically, they identify the FAK-paxillin signalling axis as the mechanosensory machinery underpinning durotactic behaviour in both contexts. Pharmacological inhibition of this pathway using JP-153, or genetic disruption of tumour cell durotaxis, significantly attenuates fibrosis and metastatic burden without affecting primary tumour growth. These findings establish durotaxis as a therapeutically tractable mechanism in fibrotic and neoplastic disease, introducing a paradigm shift whereby targeting biomechanical sensing pathways may offer precise therapeutic intervention whilst preserving developmental and homeostatic processes dependent on functional mechanosensing.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-4947
  10. Cancer Res. 2025 Nov 06.
    USP20-Driven Cholesterol Metabolism Links Inflammatory Signaling to Malignancy and Stromal Co-evolution in Pancreatic Cancer.
    Xiangyan Jiang, Bin Zhao, Tao Wang, Yong Ma, Wenbo Liu, Haonan Sun, Zhigang Li, Keshen Wang, Qichen He, Xiaoying Guan, Long Qin, Wengui Shi, Yuman Dong, Zhenzhen Ye, Chengliang Zhou, Xiaoe He, Huiguo Qing, Bo Long, Huinian Zhou, Zeyuan Yu, Zuoyi Jiao.
      Inflammatory signaling, metabolic reprogramming, and stromal complexity have emerged as core hallmarks of pancreatic ductal adenocarcinoma (PDAC). Crosstalk between these programs could represent potential targets to concurrently perturb multiple tumor-promoting processes. By integrating multi-omics data from clinical cohorts, patient-derived organoids, and autochthonous models, we uncovered tumor-intrinsic inflammatory cascades in PDAC as master regulators of mevalonate pathway hijacking, which drove both malignant progression and stromal co-evolution. TNFSF13B+ tumor-associated macrophages activated STAT3 signaling in neoplastic epithelia, leading to the transcriptional upregulation of USP20. This deubiquitinase stabilized HMGCR to potentiate mevalonate flux, resulting in cholesterol and geranylgeranyl pyrophosphate overproduction. Stimulation of YAP/TAZ signaling induced by the USP20-mediated metabolic alterations promoted tumor cell proliferation and triggered the activation of cancer-associated fibroblasts (CAFs). Genetic ablation or pharmacological inhibition of USP20 using a selective inhibitor reversed tumor metabolic dysregulation, suppressing both tumor growth and stromal desmoplasia. Furthermore, the combination of USP20 inhibition and anti-PD-1/anti-CTLA-4 immunotherapy resulted in enhanced anti-tumor efficacy. These findings reveal the STAT3-USP20-HMGCR axis as a central coordinator of PDAC malignancy and position USP20 inhibition as a strategy to suppress oncogenic signaling, perturb metabolic reprogramming, and reverse microenvironmental remodeling.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-1228
  11. Dev Cell. 2025 Nov 03. pii: S1534-5807(25)00604-5. [Epub ahead of print]60(21): 2841-2843
    Golgiphagy mediated by TM9SF3 acts as quality control for stressed Golgi.
    Hallvard L Olsvik, Terje Johansen.
      Selective autophagy is important for organelle quality control. In this issue of Developmental Cell, Yang et al. identify the Golgi resident transmembrane protein TM9SF3 as a selective autophagy receptor required for lysosomal degradation of Golgi fragments (Golgiphagy) following nutrient stress, pH disruption, blockade of ER-to-Golgi trafficking, and defects in Golgi-mediated glycosylation functions.
    DOI:  https://doi.org/10.1016/j.devcel.2025.09.019
  12. J Cell Biol. 2026 Jan 05. pii: e202504053. [Epub ahead of print]225(1):
    Systematic membrane thickness variation across cellular organelles revealed by cryo-ET.
    Desislava Glushkova, Stefanie Böhm, Martin Beck.
      In eukaryotes, membrane-bound organelles create distinct molecular environments. The compartmentalizing lipid bilayer is a dynamic composite material whose thickness and curvature modulate the structure and function of membrane proteins. In vitro, bilayer thickness correlates with lipid composition. Cellular membranes in situ, however, are continuously remodeled, and the spatial variation of their biophysical properties remains understudied. Here, we present a computational approach to measure local membrane thickness in cryo-electron tomograms. Our analysis of Chlamydomonas reinhardtii and human cells reveals systematic thickness variations within and across organelles. Notably, we observe thickness gradients across the Golgi apparatus that orthogonally support long-standing models of differential sorting of transmembrane proteins based on hydrophobic matching. Our publicly available workflow readily integrates within existing tomogram analysis pipelines and, when applied across experimental systems, provides a quantitative foundation for exploring relationships between membrane thickness and function in native cellular environments.
    DOI:  https://doi.org/10.1083/jcb.202504053
  13. EMBO Mol Med. 2025 Nov 04.
    Benchmarking porcine pancreatic ductal organoids for drug screening applications.
    Christos Karampelias, Kaiyuan Yang, Falk J Farkas, Michael Sterr, Mireia Molina van Den Bosch, Simone Renner, Janina Fuß, Christine von Toerne, Sören Franzenburg, Tatsuya Kin, Eckhard Wolf, Elisabeth Kemter, Heiko Lickert.
      Primary human pancreatic ductal organoids (HPDO) have emerged as a model to study pancreas biology and model disease like pancreatitis and pancreatic cancer. Yet, donor material availability, genetic variability and a lack of extensive benchmarking to healthy and disease pancreas limits the range of applications. To address this gap, we established porcine pancreatic ductal organoids (PPDO) as a system from a reliable, genetically defined and easily obtainable source to model pancreatic ductal/progenitor biology. We benchmarked PPDO to HPDO and primary porcine pancreas using single-cell RNA sequencing (scRNA-Seq). We observed no overt phenotypic differences in PPDO derived from distinct developmental stages using extensive proteomics profiling, with a WNT/basal cell signaling enriched population characterizing PPDO. PPDO exhibited differentiation potential towards mature ductal cells and limited potential towards endocrine lineages. We used PPDO as a chemical screening platform to assess the safety of FDA-approved drugs and showed conserved toxicity of statins and α-adrenergic receptor inhibitors between PPDO and HPDO cultures. Overall, our results highlight the PPDO as a model for mammalian duct/progenitor applications.
    Keywords:  Chemical Screen; Cross-species Comparison; Omics Profile; Pancreatic Ductal Organoids; Porcine Pancreas; Proteome Profile; scRNA-Seq Profile
    DOI:  https://doi.org/10.1038/s44321-025-00330-3
  14. Proc Natl Acad Sci U S A. 2025 Nov 11. 122(45): e2507935122
    Chemical compensation to mechanical loss in cell mechanosensation.
    Qin Ni, Zhuoxu Ge, Anindya Sen, Yufei Wu, Jinyu Fu, Alice Amitrano, Nitish Srivastava, Konstantinos Konstantopoulos, Sean X Sun.
      Mammalian cells sense and respond to environmental changes using a complex and intelligent system that integrates chemical and mechanical signals. The transduction of mechanical cues into chemical changes modulates cell physiology, allowing a cell to adapt to its microenvironment. Understanding how the chemical and mechanical regulatory modules interact is crucial for elucidating mechanisms of mechanosensation and cellular homeostasis. In this study, we find that cells exhibit nonmonotonic changes in cell volume and intracellular pH when subjected to physical stimuli and varying degrees of actomyosin cytoskeleton disruption. We find that these nonmonotonic responses are mediated by a chemical compensation mechanism, where the attenuation of actomyosin activity stimulates the activity of PI3K/Akt pathway. This, in turn, activates sodium-hydrogen exchanger 1 (NHE1), resulting in elevated intracellular pH and increased cell volume. Furthermore, we identify a competitive interaction between the PI3K/Akt and MAPK/ERK pathways-two major regulators of cell proliferation and motility. This competition modulates the chemical compensation based on the relative activities of these pathways. Our mathematical modeling reveals the network structure that is essential for establishing the nonmonotonic response. Interestingly, this regulatory system is altered in HT1080 fibrosarcoma, highlighting a potential mechanistic divergence in cancer cells in contrast to their normal-like counterpart, such as NIH 3T3 and HFF-1 fibroblasts. Overall, our work reveals a compensatory mechanism between chemical and mechanical signals, providing an infrastructure to elucidate the integrated mechanochemical response to environmental stimuli.
    Keywords:  PI3K signaling; biophysical modeling; cell volume; cytoskeleton; mechanosensation
    DOI:  https://doi.org/10.1073/pnas.2507935122
  15. Cancer Cell. 2025 Nov 06. pii: S1535-6108(25)00447-7. [Epub ahead of print]
    Cellular senescence in precancer lesions and early-stage cancers.
    TBEL Consortium
      Cellular senescence plays dual roles in precancer lesions: initially serving as a tumor-suppressive barrier within the epithelial compartment and later contributing to a pro-tumoral precancer tissue microenvironment (PreTME) via a sustained, paracrine secretome known as senescent-associated secretory phenotype (SASP). This commentary highlights the role of senescence across various PreTME cell types, explores emerging pharmacologic and lifestyle interception strategies, and outlines current challenges for advancing biomarkers and clinical translation.
    DOI:  https://doi.org/10.1016/j.ccell.2025.10.006
  16. Cancer Cell. 2025 Nov 06. pii: S1535-6108(25)00444-1. [Epub ahead of print]
    Toward a new standard: Sequential multi-agent neoadjuvant chemotherapy in resectable pancreatic cancer.
    Artur Rebelo, Thomas Seufferlein, Jorg Kleeff.
      For resectable pancreatic cancer, upfront surgery followed by adjuvant therapy has long been the standard of care. A randomized trial by Bai et al. in Cancer Cell demonstrates that sequential neoadjuvant gemcitabine/nab-paclitaxel followed by mFOLFIRINOX significantly improved event-free survival compared with upfront surgery, supporting a shift toward a sequential neoadjuvant approach in this setting.
    DOI:  https://doi.org/10.1016/j.ccell.2025.10.003
  17. Cancer Cell. 2025 Nov 06. pii: S1535-6108(25)00448-9. [Epub ahead of print]
    Decoding the spatial dynamics of tumor and immune cell interactions in solid cancers.
    Eleanor Minogue, Pilar Baldominos, Lauren Hsu, Marcia C Haigis, Judith Agudo.
      The spatial landscape of the tumor immune microenvironment (TIME) is under significant investigation as a driver of immunotherapy resistance in solid tumors. Most work centers on constituent immune cells within intra-tumoral niches, overlooking tumor cell phenotypes. Yet cancer cells shape their milieu by multiple modalities, including secreting and depleting metabolites. Here, we argue that integrating cancer cell phenotypic heterogeneity into spatial analyses is essential to reveal the mechanisms that generate TIME diversity and to better address resistance to immunotherapy.
    DOI:  https://doi.org/10.1016/j.ccell.2025.10.007
  18. Trends Mol Med. 2025 Oct 31. pii: S1471-4914(25)00255-2. [Epub ahead of print]
    Transcriptional landscape of skeletal muscle in cancer patients.
    Samet Agca, Serkan Kir.
      Bhatt et al. have identified two RNAome-based skeletal muscle subtypes in cancer cachexia. The first subtype is cachexia associated with weight and muscle loss, fiber atrophy, and shortened survival. Furthermore, this subtype has dysregulated post-transcriptional networks involving hub long noncoding (lnc)RNAs, neuronal, immune, and metabolic pathways. The study highlights new biomarkers and network-targeted interventions.
    Keywords:  RNAome; cancer cachexia; skeletal muscle
    DOI:  https://doi.org/10.1016/j.molmed.2025.10.004
  19. Nat Methods. 2025 Nov 03.
    ESPRESSO: spatiotemporal omics based on organelle phenotyping.
    Lorenzo Scipioni, Giulia Tedeschi, Mariana X Navarro, Yunlong Y Jia, Songning Zhu, Lila P Halbers, Melody Di Bona, Scott X Atwood, Jennifer A Prescher, Enrico Gratton, Michelle A Digman.
      Omics technologies such as genomics, transcriptomics, proteomics and metabolomics methods, have been instrumental in improving our understanding of complex biological systems by providing high-dimensional phenotypes of cell populations and single cells. Despite fast-paced advancements, these methods are limited in their ability to include a temporal dimension. Here, we introduce ESPRESSO (Environmental Sensor Phenotyping RElayed by Subcellular Structures and Organelles), a technique that provides single-cell, high-dimensional phenotyping resolved in space and time. ESPRESSO combines fluorescent labeling, advanced microscopy and image and data analysis methods to extract morphological and functional information from organelles at the single-cell level. We validate ESPRESSO's methodology and its application across numerous cellular systems for the analysis of cell type, stress response, differentiation and immune cell polarization. We show that ESPRESSO can correlate phenotype changes with gene expression, and demonstrate its applicability to 3D cultures, offering a path to improved spatially and temporally resolved biological exploration of cellular states.
    DOI:  https://doi.org/10.1038/s41592-025-02863-4
  20. NPJ Precis Oncol. 2025 Nov 05. 9(1): 340
    DeepTarget predicts anti-cancer mechanisms of action of small molecules by integrating drug and genetic screens.
    Sanju Sinha, Neelam Sinha, Marlenne Perales, Adi Tarrab, Trinh Nguyen, Lihe Liu, Thomas Cantore, Kyle Alvarez, Sumeet Patiyal, Sumit Mukherjee, Sanna Madan, Kevin Tharp, Jianhua Zhao, Ranjit Kumar, Greg Flanigan, John A Beutler, Barry R O'Keefe, Daoud Meerzaman, Uri Ben-David, Aniruddha J Deshpande, Eytan Ruppin.
      Identifying the mechanisms of action (MOA) driving a drug's anti-cancer efficacy is critical for its clinical success, guiding the search for its best biomarkers, indications and combinations. Yet, systematically identifying MOAs remains challenging due to drugs often engaging multiple targets with varying affinities across different cellular contexts. Addressing this challenge, we present DeepTarget, a computational tool that integrates large-scale drug and genetic knockdown viability screens with omics data to predict a drug's MOAs driving its cancer cell killing. To test its performance, we curated eight datasets of high-confidence drug-target pairs focused on cancer drugs and benchmarked DeepTarget. We show that DeepTarget outperforms recent tools in predicting drug targets and their mutation-specificity, achieving strong predictive performance across diverse validation datasets. We experimentally validate DeepTarget's predictions in two case studies: (a) Demonstrating that pyrimethamine, an anti-parasitic drug, affects cellular viability through modulation of mitochondrial function, specifically the oxidative phosphorylation pathway, and (b) Confirming that T790-mutated EGFR mediates ibrutinib response in BTK-negative solid tumors. Additionally, we demonstrate that kinase inhibitors predicted by DeepTarget to have higher target specificity show increased progression in clinical trials. We provide DeepTarget as an open-source tool ( https://github.com/CBIIT-CGBB/DeepTarget ) along with predicted target profiles for 1,500 cancer-related drugs and 33,000 unpublished natural product extracts. DeepTarget represents a significant computational advancement among target discovery methods that complements the leading structure-based methods by considering cellular context and can potentially accelerate drug development and repurposing efforts in oncology.
    DOI:  https://doi.org/10.1038/s41698-025-01111-4
  21. Nat Genet. 2025 Nov 07.
    TGF-β builds a dual immune barrier in colorectal cancer by impairing T cell recruitment and instructing immunosuppressive SPP1+ macrophages.
    Ana Henriques, Maria Salvany-Celades, Paula Nieto, Sergio Palomo-Ponce, Marta Sevillano, Xavier Hernando-Momblona, Emily Middendorp-Guerra, Montserrat Llanses Martinez, Elisabeth Marjolein Haak, Juan Nieto, Ginevra Caratú, Domenica Marchese, Max Ruiz Gil, Sebastien Tosi, Theresa Suckert, Jordi Badia-Ramentol, Adrià Caballé-Mestres, Carolina Sanchez-Zarzalejo, Lidia Mateo, Daniele V F Tauriello, Antoni Riera, Elena Sancho, Camille Stephan-Otto Attolini, Alejandro Prados, Holger Heyn, Eduard Batlle.
      Transforming growth factor β (TGF-β) signaling in the tumor microenvironment predicts resistance to immune checkpoint blockade (ICB). While TGF-β inhibition enhances ICB efficacy in murine cancer models, clinical trials have yet to demonstrate benefit, underscoring the need to better understand its immunoregulatory roles across disease contexts. Using mouse models of advanced colorectal cancer and patient-derived data, we demonstrate that TGF-β impairs antitumor immunity at multiple levels in liver metastases. It acts directly on T cells to block recruitment of peripheral memory CD8+ T cells, thereby limiting the effectiveness of ICB. Concurrently, TGF-β instructs tumor-associated macrophages to suppress clonal expansion of newly arrived T cells by inducing SPP1 expression. This extracellular matrix protein promotes collagen deposition and accumulation of tumor-associated macrophages and fibroblasts, ultimately driving ICB resistance. Our findings reveal how TGF-β coordinates immunosuppressive mechanisms across innate and adaptive immune compartments to promote metastasis, offering new avenues to improve immunotherapy in colorectal cancer.
    DOI:  https://doi.org/10.1038/s41588-025-02380-2
  22. Prog Biophys Mol Biol. 2025 Oct 31. pii: S0079-6107(25)00055-0. [Epub ahead of print]198 61-70
    Cell aging - a relevant factor in live cell microscopy (mini-review).
    Tina Karimian, Christoph Cremer, Julian Weghuber, Herbert Schneckenburger.
      Live-cell microscopy is gaining importance for studying cellular behavior in response to environmental cues. However, cell aging can result in modifications of various cellular structures and functions, affecting or distorting microscopy-based readouts. These changes include gene expression, nuclear architecture, energy metabolism, or changes in the mechanical properties of cell membranes and microtubules. In this mini-review, we briefly discuss how cell aging affects critical subcellular compartments and alters live-cell imaging outcomes. In contrast to many papers available on cell aging, here we are focusing on the influence of cell aging on the performance and outcome of advanced microscopy techniques such as super-resolution imaging, fluorescence lifetime imaging (FLIM), variable-angle total internal reflection fluorescence microscopy (VA-TIRFM), as well as micromanipulation techniques such as laser-assisted optoporation. Our findings highlight the importance of considering cell passage number and senescence markers in experimental design and data interpretation.
    Keywords:  Fluorescence microscopy; Light microscopy; Living cells; Senescence; cell passage number
    DOI:  https://doi.org/10.1016/j.pbiomolbio.2025.10.003
  23. Cell Metab. 2025 Nov 04. pii: S1550-4131(25)00442-5. [Epub ahead of print]37(11): 2105-2106
    Leveraging genetic and phenotypic variation to discover metabolite-protein interactions.
    Gregory S Ducker, Jared Rutter.
      How metabolites regulate protein function is still poorly understood. Leveraging the power of genetic variation, Xiao et al. built a global protein-metabolite covariation dataset to reveal novel protein-metabolite regulations in mouse that led to the discovery of cysteine catabolism as an unexpected regulator of cholesterol.
    DOI:  https://doi.org/10.1016/j.cmet.2025.10.008
  24. STAR Protoc. 2025 Nov 03. pii: S2666-1667(25)00588-X. [Epub ahead of print]6(4): 104182
    Protocol to study metastatic dormancy using 4T07-mCherry breast cancer cells and an algorithm-based quantification of disseminated cancer cells.
    Paulo Pereira, Virginia Cecconi, Maries van den Broek.
      Dormant disseminated cancer cells are responsible for late relapses of breast cancer. Here, we present a protocol to orthotopically inject 4T07-mCherry breast cancer cells into mice and describe how to resect the primary tumor. We detail steps for collecting and processing the lungs to detect and quantify cancer cells using an algorithm-based approach. This protocol allows studying the induction, maintenance, and awakening from metastatic dormancy. For complete details on the use and execution of this protocol, please refer to Pereira et al.1.
    Keywords:  Cancer; Immunology; Microscopy
    DOI:  https://doi.org/10.1016/j.xpro.2025.104182
  25. Nat Med. 2025 Nov 05.
    A multimodal whole-slide foundation model for pathology.
    Tong Ding, Sophia J Wagner, Andrew H Song, Richard J Chen, Ming Y Lu, Andrew Zhang, Anurag J Vaidya, Guillaume Jaume, Muhammad Shaban, Ahrong Kim, Drew F K Williamson, Harry Robertson, Bowen Chen, Cristina Almagro-Pérez, Paul Doucet, Sharifa Sahai, Chengkuan Chen, Christina S Chen, Daisuke Komura, Akihiro Kawabe, Mieko Ochi, Shinya Sato, Tomoyuki Yokose, Yohei Miyagi, Shumpei Ishikawa, Georg Gerber, Tingying Peng, Long Phi Le, Faisal Mahmood.
      The field of computational pathology has been transformed with recent advances in foundation models that encode histopathology region-of-interests (ROIs) into versatile and transferable feature representations via self-supervised learning. However, translating these advancements to address complex clinical challenges at the patient and slide level remains constrained by limited clinical data in disease-specific cohorts, especially for rare clinical conditions. We propose Transformer-based pathology Image and Text Alignment Network (TITAN), a multimodal whole-slide foundation model pretrained using 335,645 whole-slide images via visual self-supervised learning and vision-language alignment with corresponding pathology reports and 423,122 synthetic captions generated from a multimodal generative AI copilot for pathology. Without any fine-tuning or requiring clinical labels, TITAN can extract general-purpose slide representations and generate pathology reports that generalize to resource-limited clinical scenarios such as rare disease retrieval and cancer prognosis. We evaluate TITAN on diverse clinical tasks and find that it outperforms both ROI and slide foundation models across machine learning settings, including linear probing, few-shot and zero-shot classification, rare cancer retrieval, cross-modal retrieval and pathology report generation.
    DOI:  https://doi.org/10.1038/s41591-025-03982-3
  26. Redox Biol. 2025 Oct 25. pii: S2213-2317(25)00408-2. [Epub ahead of print]88 103895
    Phase IB trial of high dose ascorbic acid + nab-paclitaxel + cisplatin + gemcitabine in patients with untreated metastatic pancreatic cancer.
    Gayle S Jameson, S Danielle LeGrand, Michael S Gordon, Denise J Roe, Betsy C Wertheim, Kellen Olszewski, Josh Rabinowitz, Ron Evans, Michael Downes, Morgan Truitt, Ron Korn, Haiyong Han, Richard M Miller, Michael T Barrett, David Propper, Daniel D Von Hoff, Erkut Borazanci.
       BACKGROUND: Preclinical studies suggest that cancer cells take up oxidized vitamin C (dehydroascorbate, DHA) via the GLUT1 transporter, leading to oxidative stress and glutathione depletion. This mechanism may offer a therapeutic strategy for KRAS-mutated cancers. This Phase IB trial evaluated high-dose intravenous ascorbic acid (AA) combined with nab-paclitaxel, cisplatin, and gemcitabine (NABPLAGEM) in patients with untreated metastatic pancreatic ductal adenocarcinoma (PDAC).
    METHODS: Eligible patients (≥18 years, ECOG 0-1, measurable PDAC, adequate organ function) received AA (25, 37.5, or 56.25 g/m2 twice weekly) plus NABPLAGEM on Days 1 and 8 of 21-day cycles. The primary endpoint was determining the maximum tolerated dose (MTD) of AA.
    RESULTS: Seventeen patients were enrolled (median age 63.9; 70.6 % female; 82.4 % white). No MTD was reached; AA up to 56.25 g/m2 twice weekly was feasible. Patients on the lowest AA dose remained on treatment longer. Grade ≥3 treatment-related adverse events (TRAEs) included thrombocytopenia (82.4 %), anemia (35.3 %), neutropenia (29.4 %), hypokalemia (29.4 %), diarrhea (11.8 %), and colitis (11.8 %), with no significant differences between dose groups. Peak AA levels >20 mM were achieved in 57 % of patients at the highest dose. Median progression-free survival (PFS) and overall survival (OS) were 7.1 and 14.2 months, respectively, with no significant differences by AA dose. Textural imaging showed decreased liver fat in 3 of 4 patients with baseline steatosis.
    CONCLUSION: High-dose AA with NABPLAGEM was tolerable in patients with advanced PDAC but did not improve disease response compared to historical data for chemotherapy alone. A separate study suggests AA may enhance gemcitabine and nab-paclitaxel efficacy without cisplatin. AA and cisplatin may have overlapping DNA-damaging effects, or differences in AA dosing frequency and exposure may influence outcomes - variables to consider in future trials.
    TRIAL REGISTRATION: NCT03410030.
    Keywords:  Ascorbic acid + nab-paclitaxel + cisplatin + gemcitabine; Clinical trial; Pancreatic ductal adenocarcinoma; Untreated metastatic pancreatic adenocarcinoma
    DOI:  https://doi.org/10.1016/j.redox.2025.103895
  27. Adv Sci (Weinh). 2025 Nov 03. e17228
    Magnetoelectric Nanotherapy Achieves Complete Tumor Ablation and Prolonged Survival in Pancreatic Cancer Murine Models.
    John Michael Bryant, Max Shotbolt, Emmanuel Stimphil, Victoria Andre, Elric Zhang, Veronica Estrella, Kazim Husain, Joseph Weygand, Doug Marchion, Alex Sebastian Lopez, Dominique Abrahams, Shawnus Chen, Mostafa Abdel-Mottaleb, Skye Conlan, Ibrahim Oraiqat, Vaseem Khatri, Jose Alejandro Guevara, Shari Pilon-Thomas, Gage Redler, Kujtim Latifi, Natarajan Raghunand, Kosj Yamoah, Sarah Hoffe, James Costello, Jessica M Frakes, Ping Liang, Robert A Gatenby, Mokenge Malafa, Sakhrat Khizroev.
      Magnetoelectric nanoparticles (MENPs), when activated by a magnetic field, are shown to provide a minimally invasive, drug-free, theranostic approach to pancreatic ductal adenocarcinoma (PDAC) treatment. The magnetoelectric effect allows intravenously administered MENPs to be magnetically guided to PDAC xenograft tumors and remotely activated with a 7T-MRI field to induce targeted, electrode-free tumor ablation with real-time imaging feedback. A single MENP treatment achieved a threefold median reduction in tumor volume and complete tumor responses in 33.3% of mice at 300 and 600 µg doses (N = 17) and significantly longer mean overall survival as compared to the control cohorts (54.1 vs 28.8 days, χ2 = 40.14, p = 0.045), without evident toxicity in any imaged organ. In contrast, mice receiving subtherapeutic doses, non-activated MENPs, or saline controls showed no significant response. MRI T2* relaxation time decreases closely correlated with tumor reduction (ρ = -0.73, p < 0.001), supporting MENPs as both a therapeutic and imaging biomarker. Mechanistically, MENPs preferentially target cancer cells via magnetic-field-driven electrostatic interactions specific to tumor cell membranes, in agreement with multiphysics numerical simulations. Flow cytometry confirmed that MENP activation primarily induces apoptosis, with minimal necrosis, and time-course studies showed a progressive apoptotic response over 3-hour post-treatment. The findings establish MENPs as a versatile, image-guided, theranostic platform with translational promise for minimally invasive oncology.
    Keywords:  magnetoelectric nanoparticles; pancreatic cancer; theranostics
    DOI:  https://doi.org/10.1002/advs.202517228
  28. Anal Chem. 2025 Nov 05.
    Ferroptosis Pathway Discrimination and Anticancer Therapeutic Screening Enabled by Cascade-Activated Fluorescence Reporting of Cysteine-Viscosity Dynamics.
    Lu Li, Qinglin Fei, Xuwen Sun, Qiaochun Wang, Jianhua Su, Longyun Ye, Weiding Wu, Lifang Guo.
      Elucidating pathway-specific ferroptosis mechanisms is crucial for advancing our understanding of cell death regulation; however, this goal has been hindered by the persistent absence of reliable detection techniques and standardized analytical approaches. Mechanistically, ferroptosis is governed by the nexus between Glutathione Peroxidase 4 (GPX4) inactivation and lipid-peroxide-driven membrane destabilization, with cysteine (Cys) as a key regulator for GPX4 synthesis and ferroptosis trigger differentiation. Lipid peroxide accumulation elevates cytoplasmic viscosity, enabling the decryption of ferroptosis-trigger mechanisms by elucidating Cys-viscosity dynamics. For this, we engineer an innovative dual-parameter sensing platform: a conformationally flexible molecular scaffold with triple-emission viscosity sensitivity was functionalized with a Cys-reactive aldehyde group. This probe system features a fluorescence quenching mechanism and then sequentially restores red and blue fluorescence in the presence of Cys and high viscosity. Notably, while distinct ferroptosis pathways induce an observable viscosity increase, the Cys flux profiles exhibit pathway-specific signatures. Direct synthesis blockade displays a remarkable Cys fluctuation (Δ[Cys] = 20%, 4 h) compared to GPX4 inhibition (Δ[Cys] = 21%, 12 h), whereas overload iron demonstrates imperceptible variation (Δ[Cys] = 28%, 36 h latency). Furthermore, the evaluation of Cys-dependent ferroptosis in pancreatic cancer models uncovers therapy response mechanisms. This work highlights the key role of Cys and viscosity kinetics in ferroptosis initiation and execution phases, advancing the fundamental research and precise regulation of ferroptosis.
    DOI:  https://doi.org/10.1021/acs.analchem.5c03834
  29. Pancreatology. 2025 Oct 29. pii: S1424-3903(25)00668-4. [Epub ahead of print]
    Aspirin use and acute pancreatitis mortality.
    Kuan-Fu Liao, Shih-Wei Lai.
      
    DOI:  https://doi.org/10.1016/j.pan.2025.10.008
  30. Proc Natl Acad Sci U S A. 2025 Nov 11. 122(45): e2510664122
    Electromechanically induced membrane restructuring enables learning and memory.
    Peter T Podar, Dima Bolmatov, Teshani Kumarage, Rana Ashkar, Ariana Adkisson, Olivia Ziemer, Victoria Sullivan, Ahmed S Mohamed, Joseph S Najem, C Patrick Collier, John Katsaras.
      Human neural networks of interconnected neurons have evolved to be remarkably efficient and are capable of learning and memory through the brain's synaptic plasticity, including short-term plasticity (STP), and long-term potentiation (LTP) and depression (LTD). These activity-dependent mechanisms induce changes in synaptic efficiency over both transient and extended timescales. Understanding the molecular basis of learning and memory is central to deciphering brain function and advancing therapeutics for neurodegenerative diseases. Here, we report that lipid bilayers with embedded gramicidin A ion channels can structurally reorganize when interrogated using a neurologically inspired electrical stimulation protocol, adopting metastable structures with enhanced STP response and emergent LTP or LTD. Specifically, voltage-induced electrocompression is found to restructure membranes, driving them into nonequilibrium steady states with enhanced stability and increased ionic conductivity, leading to stronger and persistent membrane ion conductance. These results show how membrane restructuring and emergent complexity may regulate synaptic plasticity at the molecular level.
    Keywords:  droplet interface bilayers; long-term potentiation; membranes; neuromorphic materials; short-term synaptic plasticity
    DOI:  https://doi.org/10.1073/pnas.2510664122
  31. Cell Physiol Biochem. 2025 Nov 02. 59(6): 753-799
    Epistemology of the Origin of Cancer III: Fundamentals of How Metastasis Arises.
    Björn L D M Brücher, Ijaz S Jamall.
      Metastasis, like carcinogenesis, involves the disruption of homeostasis such that cancer cells travel from the primary tumor to distant parts of the body. Almost all cancer deaths are due to metastatic spread. The prevailing theory of metastasis is an incomplete doctrine and far from sufficient as only 0.2% of free cancer cells result in the spread of cancer. To develop reasonable and effective cancer therapies and to prevent (or reverse) carcinogenesis and metastasis, a comprehensive understanding of how both carcinogenesis and metastasis arise is necessary. Fundamental questions in cancer biology have been asked and answered over decades of research: How do most cancers develop (Epistemology of the Origin of Cancer I, 2014-2022)? Which is the first cancer cell (II, 2023)? The third basic question in cancer biology remaining to be addressed is: What are the fundamentals of how metastasis develops? The pre-cancerous niche (PCN) that forms during carcinogenesis is altered by ongoing complex signaling into a premetastatic niche 1 (PMN-1): p130(cas)/crk/DOCK180 formation is necessary for lamellipodia formation, thereby enabling cell mobility. Cancer-associated fibroblasts (CAFs) begin to release fibronectin CXCL12 and Keratin 19. PMN-1 is transformed into PMN-2 during ongoing crosstalk and transformation of anti- into pro-tumorigenic platelets, macrophages, and neutrophils. Finally, persistent signaling and immune evasion result in the conversion of PMN-2 to PMN-3 with heterogeneous cancer satellites - the term "satellite" is used herein in accordance with its original meaning (a cell or particle escorting another). PMN-3 serves as a prerequisite for intravasation, traveling, and dissemination of cancer cells away from the primary tumor. Eight heterogeneous cancer satellites, including Trojan horses (immune evasion), travel alone or in combination: (1) cancer cells and (2) CAFs migrate along the CXCL12 and fibronectin gradient; (3) cancer cells surrounded by CAFs are shielded from the immune system and travel away from the primary cancer; (4) CXCL12 and Keratin 19 coat cancer cells; (5) platelets surround cancer cells and (6) CAFs, thereby facilitating cancer spread; and (7) neutrophil extracellular traps shield cancer cells and (8) CAFs. Metastasis in epithelial cancer occurs in parallel with carcinogenesis after the pre-cancerous niche is transformed into pre-metastatic niches (PMNs), which are indispensable to the origin of metastasis. Eight heterogeneous cancer satellites, including Trojan horses responsible for immune evasion, alongside reciprocally affecting sequences, wander alone or in conjunction with other cancer cells. This elucidates why the current practice of multimodal anti-cancer cell therapy should now be seen in a new light in which the benefits depend not on direct cancer cell effects, but on indirect cytopenic effects, which have previously been regarded merely as adverse effects.
    Keywords:  Biochemistry ; Biology ; Carcinogenesis ; Metastasis ; Physiology
    DOI:  https://doi.org/10.33594/000000826
  32. Nat Struct Mol Biol. 2025 Nov 03.
    The Japan autophagy consortium.
    Miwako Ishido, Yoshiari Shimmyo, Etsuko Tsutsumi, Masaaki Komatsu.
      
    DOI:  https://doi.org/10.1038/s41594-025-01683-6
  33. Front Oncol. 2025 ;15 1697588
    The CILLO-E Hypothesis: Erythrocyte-Driven Acidosis and Early Eryptosis as Drivers of Cancer-Associated Anemia.
    Hüseyin Aydın.
       Background: The tumor microenvironment (TME) is characterized by high lactate and proton accumulation resulting from glycolytic metabolism. While acidosis is known to influence immune and stromal cells, its direct effects on erythrocytes-the most abundant circulating cells-remain underexplored.
    Methods: An integrative review of cancer metabolism, erythrocyte physiology, and lactate transport systems was conducted using PubMed and Web of Science. From this synthesis, the CILLO-E hypothesis (Cancer-Induced Lactate Load on Erythrocytes) was formulated.
    Results: The hypothesis proposes that lactate and protons enter erythrocytes via MCT1, leading to intracellular acidification. This process disrupts glycolytic enzymes, reduces ATP production, and impairs Na+/K+-ATPase and Ca²+-ATPase activity. Energy depletion causes Ca²+ overload, which activates scramblase and inhibits flippase, resulting in PS exposure and premature eryptosis. In parallel, reduced 2,3-BPG synthesis alters hemoglobin-oxygen affinity, exacerbating hypoxia. Together, these mechanisms provide a biochemical explanation for the normocytic-normochromic anemia frequently observed in cancer. Importantly, cancer-associated anemia is multifactorial, and CILLO-E should be viewed not as a comprehensive explanation but as a complementary mechanism acting through lactate-induced erythrocyte dysfunction.
    Conclusions: The CILLO-E hypothesis reframes erythrocytes as active metabolic targets in the TME rather than passive oxygen carriers. By linking lactate-driven metabolic stress to erythrocyte dysfunction, anemia, and systemic hypoxia, it suggests a feedback loop that promotes tumor progression and highlights opportunities for erythrocyte-based biomarkers and therapeutic strategies.
    Keywords:  CILLO-E Hypothesis; cancer-associated anemia; eryptosis; erythrocyte metabolism; lactate shuttle; metabolic adaptation; redox regulation; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2025.1697588
  34. Cell Death Discov. 2025 Nov 06. 11(1): 503
    Acinar-specific loss of activating transcription factor 3 restricts KRASG12D mediated transcriptional changes and PanIN progression.
    Mickenzie B Martin, Fatemeh Mousavi, Gavin Goebel, Domenic Di Stasi, Alesia Mano, Andrei Glogov, Liena Zhao, Gianni Di Guglielmo, Parisa Shooshtari, Christopher L Pin.
      Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer deaths in North America with ~12% survival 5 years after diagnosis. Risk factors for PDAC, including smoking and chronic pancreatitis, trigger the unfolded protein response (UPR). Global deletion of Activating Transcription Factor 3 (ATF3), a UPR mediator, restricts preneoplastic progression in mice expressing oncogenic KRAS (KRASG12D). However, ATF3 is expressed in malignant and non-malignant cells suggesting it may affect multiple cell compartments in PDAC. Therefore, the goal of this study was to determine if ATF3 has epithelial-specific roles during PDAC initiation. Epithelial cells from mice expressing KRASG12D with (Ptf1acreERT/+KRASG12D/+) or without ATF3 (Atf3-/-Ptf1acreERT/+KRASG12D/+; APK) were characterized before and after pancreatic injury. Additionally, mice allowing acinar-specific Atf3 deletion and KRASG12D expression (AacinarPK) were compared to Ptf1acreERT/+KRASG12D/+ and APK mice following injury. RNA-seq revealed reduced oncogenic pathways in APK acinar cells consistent with reduced ADM formation in APK cultures. Ptf1acreERT/+KRASG12D/+ and APK organoids showed differential gene expression and morphology, with APK organoids exhibiting reduced viability. In vivo, APK and AacinarPK tissue showed restricted neoplastic progression and KRAS signaling compared to Ptf1acreERT/+KRASG12D/+ mice. This study indicates ATF3 works in a cell autonomous fashion, and its absence restricts KRASG12D-mediated PDAC.
    DOI:  https://doi.org/10.1038/s41420-025-02777-2
  35. Traffic. 2025 Oct;26(10-12): e70022
    Beyond the Secretory Pathway: New Insights Into Protein Release.
    Ruey-Hwa Chen, Antonio J Costa-Filho, Jayanta Debnath, Thierry Galli, Liang Ge, Deborah Goberdhan, Wei Guo, Kangmin He, Ralf Jacob, Tiebang Kang, Min Goo Lee, Lian Li, Fabio Lolicato, Jun Lu, Vivek Malhotra, Walter Nickel, Vassiliki Nikoletopoulou, Stacey K Ogden, Georgia Maria Sagia, Feng Shao, Anbing Shi, Clotilde Thery, Christel Vérollet, Julien Villeneuve, Frederik Verweij, Yanzhuang Wang, Juan Wang, Shenjie Wu, Yihong Ye, Hang Yin, Li Yu, Min Zhang, Ying Zhang, Xin Zhou, Chiara Zurzolo.
      In eukaryotes, protein secretion plays essential roles in intercellular communications and extracellular niche-building. Protein secretion generally requires a signal sequence that targets cargos to the canonical secretory pathway consisting of the endoplasmic reticulum (ER), the Golgi apparatus, plasma membrane, and vesicles moving between these compartments. However, cytoplasmic proteins lacking signal sequences (e.g., IL1β, Acb1, FGF2) have been detected, and many have defined functions in the extracellular space, suggesting unconventional protein secretion (UcPS) via alternative pathways. In recent years, scientists have uncovered many new UcPS paradigms, reporting a plethora of mechanisms that collectively form a new field. The inaugural Cold Spring Harbor Asia (CSHA) conference on "Molecular Mechanisms and Physiology of Unconventional Secretion" is the first meeting to bring these researchers together, providing a collegial platform for information sharing at this exciting frontier of cell biology research.
    Keywords:  CUPS; autophagy; extracellular vesicle; lysosome; stress adaptation; unconventional protein secretion
    DOI:  https://doi.org/10.1111/tra.70022
  36. Mol Omics. 2025 Nov 04.
    Hypoxia-induced alterations in lipid polyunsaturation and associated proteins drive aggressive metastasis in pancreatic cancer via the PPAR/hypoxia pathway.
    Prema Kumari Agarwala, Avinash Singh, Sanjeeva Srivastava, Shobhna Kapoor.
      In pancreatic ductal adenocarcinoma, hypoxia is a crucial component of the tumour microenvironment and is associated with worse clinical outcomes. Adaptation to extreme hypoxic settings is based on abnormal lipid metabolism, but insights into how hypoxia-regulated lipid changes link with aggressive migratory potential in pancreatic cancer are lacking. This study investigates the molecular processes, pathways, and critical proteins involved in hypoxia-induced lipidic and polyunsaturated fatty acid alterations in pancreatic cancer. Our findings elucidate increased multilayer unsaturation in FA chains of major lipid classes associated with greater migration and invasion, as well as higher abundances of particular desaturases. The expression of these proteins was verified in clinical tumour samples by unsaturated fatty acid biosynthesis-related gene enrichment score. High unsaturated fatty acid clusters were shown to be associated with a low survival rate. Pathway correlation and protein-protein interaction analysis indicated that the PPAR-hypoxia axis and SCD/FADS2/APOC3-HDLBP protein network are implicated in mediating the observed alterations in lipid pools and poly-unsaturation levels in pancreatic cancer under hypoxia. These results provide novel therapeutic targets in pancreatic cancer while improving our understanding of hypoxia-induced migratory potential in pancreatic cancer.
    DOI:  https://doi.org/10.1039/d5mo00111k
  37. Nano Lett. 2025 Nov 06.
    Buried Nanopore Membranes with Enhanced Mechanical Robustness for High-Resolution Single-Molecule Sensing.
    Simran Nasa, Manoj Varma.
      The mechanical fragility of ultrathin membranes limits the broader deployment of solid-state nanopores for high-resolution single-molecule sensing. Here, we introduce a buried nanopore architecture in which silicon nitride (SiNx) membranes are recessed within the silicon substrate using a time-controlled double-sided, anisotropic, wet etching process. This buried geometry enables sub-micrometer lateral membrane dimensions and achieves more than an order-of-magnitude improvement in impact resistance relative to conventional membranes formed at the wafer surface. Electrical conductance measurements reveal a reduced effective membrane thickness, suggesting enhanced ionic confinement and spatial resolution. We demonstrate the sensing capability of these buried nanopores through translocation measurement of double-stranded DNA, as short as 22 base pairs, confirming the high signal resolution of the buried membrane nanopores for label-free molecular analysis. The proposed fabrication method enhances mechanical durability, measurement resolution, and device yield, offering a scalable route for robust high-resolution nanopore biosensors.
    Keywords:  biosensors; buried SiNx membranes; ion current; single-molecule translocation; solid-state nanopores
    DOI:  https://doi.org/10.1021/acs.nanolett.5c03778
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