bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2026–03–08
33 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Organelle-selective click chemistry for monitoring fatty acid metabolism at the subcellular level.
  2. Imaging intracellular lipid heterogeneity with fluorogen-activating coincidence encounter sensing.
  3. GDF15 Drives Cachexia Through Multisystem Feed-Forward Loop.
  4. Lipid imaging using bifunctional lipid probes.
  5. A closed tumor-immune-brain circuit in cancer cachexia.
  6. Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.
  7. Cancer invasion plasticity during the metastatic cascade: strategies to survive and thrive.
  8. Imaging interorganelle membrane contact sites using dimerization-dependent fluorescent proteins.
  9. Galectin-3-Induced Glycan Lattices as Biophysical Modulators of Membrane Phase Behavior in Live Cells.
  10. A shift in the cellular redox state redirects aspartate for export under glucose deprivation.
  11. A Legacy of Enduring Discovery.
  12. Fluorescence lifetime estimation: A practical approach using Flipper-TR FLIM.
  13. Tumor-induced orexigenic imbalance lowers protein appetite and drives early organ wasting symptoms.
  14. Prediction and characterization of lipid-interacting proteins.
  15. In vitro methods for measuring lipid binding, transfer and competitive displacement reactions by peripheral membrane proteins.
  16. A glucocorticoid-FAS axis controls immune evasion during metastatic seeding.
  17. Osmotic forces modify lipid membrane fluctuations.
  18. Genetically encoded assembly recorder temporally resolves cellular history.
  19. The OligoPanc project: an interdisciplinary expert consensus statement on oligometastatic pancreatic cancer.
  20. Purified diets enable experimental rigor through compositional control in animal research.
  21. A hotspot phosphorylation site on SHP2 drives oncoprotein activation and drug resistance.
  22. Dietary restriction in aging and longevity.
  23. A Legacy of Mentorship: A Tribute to Lewis Cantley.
  24. Precancerous niche remodelling dictates nascent tumour persistence.
  25. Copper potentiates PUFA-mediated antitumor activity by activating Lipophagy.
  26. Regulation of phospholipid scramblases by cholesterol.
  27. Acidic niche sugar shield blocks ferroptosis.
  28. The endothelial plasma membrane lipidome and its remodeling under hyperglycemia: an exploratory study.
  29. The S100A8/A9 complex promotes food intake and prevents adipose tissue loss during cancer cachexia in mice.
  30. Glucose metabolism sustains aberrant STAT3 signaling in colorectal cancer through glycosylated local signaling factors.
  31. Phase II Trial of Vemurafenib and Sorafenib Combination in Advanced KRAS-Mutated Metastatic Pancreatic Cancer.
  32. Genome modelling and design across all domains of life with Evo 2.
  33. New frontiers in applied biophysics: advancing drug discovery using single-molecule microscopy.
  1. Methods Enzymol. 2026 ;pii: S0076-6879(26)00024-8. [Epub ahead of print]727 355-371
    Organelle-selective click chemistry for monitoring fatty acid metabolism at the subcellular level.
    Tomonori Tamura, Seita Kawamoto, Itaru Hamachi.
      Fatty acids are vital cellular components, serving as energy sources and building blocks of membranes. Their metabolism involves multiple enzymatic processes localized to specific organelles, suggesting organelle-dependent distribution of fatty acid-containing lipids. Conventional lipidomics methods, while powerful, often lack spatiotemporal resolution due to reliance on bulk extracts or fractionation. To overcome this, we developed an organelle-selective labeling strategy combining metabolic incorporation of azide-modified fatty acids (AFAs) with organelle-directed copper-free click chemistry. Following the metabolic incorporation of azide analogs of palmitate or oleate into mammalian cells, azide-modified lipids in the endoplasmic reticulum (ER)/Golgi apparatus, mitochondria, lysosomes, and plasma membrane could be visualized and profiled through labeling with organelle-targeting clickable dyes. Distinct lipid distributions were observed among organelles, consistent with known metabolic pathways, such as enrichment of polyunsaturated lipids in mitochondria. Pulse-chase experiments enabled the tracking of interorganelle transport, particularly ER-to-mitochondria trafficking of phosphatidylcholine and phosphatidylethanolamine, and they further revealed a transient accumulation of diacylglycerol within mitochondria. Overall, this methodology enables fractionation-free, organelle-level lipidomics with high spatial and temporal resolution, providing unprecedented insights into fatty acid metabolism and offering a versatile platform for future studies of subcellular lipid dynamics. Here we describe detailed protocols for sample preparation and subsequent analyses by thin-layer chromatography and mass spectrometry.
    Keywords:  Fatty acids; Interorganelle lipid transport; Lipids; Organelle-selective click reaction; Organelles; Pulse chase analysis
    DOI:  https://doi.org/10.1016/bs.mie.2026.01.016
  2. Methods Enzymol. 2026 ;pii: S0076-6879(25)00517-8. [Epub ahead of print]727 145-160
    Imaging intracellular lipid heterogeneity with fluorogen-activating coincidence encounter sensing.
    William M Moore, Itay Budin.
      Here we describe techniques for the implementation of fluorogen-activated coincidence sensing (FACES), a new chemical genetic tool for quantitatively imaging lipids in organelle membranes and reporting their transbilayer orientation in living cells. FACES combines bioorthogonal chemistry with genetically encoded fluorogen-activating proteins (FAPs) for reversible proximity sensing of fluorogen-conjugated azido-phospholipids in target membranes. Here, we provide and discuss method details and experimental considerations for the approach. We focus on the investigation of phosphatidylcholine in azido-choline fed HeLa cells, but the techniques described are broadly applicable to other biomolecules labeled with azido-metabolites in live cells.
    Keywords:  Bioorthogonal chemistry; Biosensing; Click chemistry; Fluorogen-activating protein; Lipid imaging
    DOI:  https://doi.org/10.1016/bs.mie.2025.11.015
  3. Cancer Discov. 2026 Mar 05. OF1
    GDF15 Drives Cachexia Through Multisystem Feed-Forward Loop.
      
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2026-029
  4. Methods Enzymol. 2026 ;pii: S0076-6879(26)00027-3. [Epub ahead of print]727 17-45
    Lipid imaging using bifunctional lipid probes.
    Martin Buitrago-Arango, Chia-Yi Chou, André Nadler.
      Mechanistic lipid cell biology requires techniques to faithfully image cellular lipid localization and transport in a species-specific manner. This is only partially possible by employing fluorescent lipid analogues and lipid biosensors, creating a need for more precise techniques. Here we outline techniques for using bifunctional (clickable and crosslinkable) lipid probes to visualize individual lipid species in cells and quantify their inter-organelle dynamics. We provide a detailed overview with regard to the nature of the chemical reporter groups, their effects on biophysical lipid properties, provide experimental details for sample preparation, fluorescence imaging, image analysis strategies and data interpretation. We outline pitfalls, limitations and best practices for control experiments. The lipid imaging strategy is described here for immortalized cell lines, but can easily be adapted for other tissue culture systems.
    Keywords:  Bifunctional lipids; Fluorescence microscopy; Image analysis; Lipid imaging; Lipids
    DOI:  https://doi.org/10.1016/bs.mie.2026.01.019
  5. Cancer Cell. 2026 Mar 05. pii: S1535-6108(26)00105-4. [Epub ahead of print]
    A closed tumor-immune-brain circuit in cancer cachexia.
    Felix Clemens Richter, Joel Xu En Wong, Andreas Bergthaler.
      Cancer-associated cachexia is a complex metabolic syndrome leading to sustained body weight loss and tissue wasting. In this issue of Cancer Cell, Shi et al. identify a novel GDF15-driven tumor-immune-brain crosstalk, resulting in altered systemic metabolism and tissue catabolism.
    DOI:  https://doi.org/10.1016/j.ccell.2026.02.007
  6. Cell. 2026 Feb 27. pii: S0092-8674(26)00115-7. [Epub ahead of print]
    Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.
    Abigail Xie, Julia S Brunner, Sangita Chakraborty, Angela M Montero, Anna E Bridgeman, Katrina I Paras, Ruobing Cui, Maider Fagoaga-Eugui, Monika Komza, Paige K Arnold, Benjamin T Jackson, Santiago Noriega Madrazo, Mohamed I Atmane, Sebastian E Carrasco, Lydia W S Finley.
      The tricarboxylic acid (TCA) cycle couples nutrient oxidation with the generation of reducing equivalents that power oxidative phosphorylation. Nevertheless, the requirement for components of the TCA cycle is context-specific, raising the question of which TCA cycle outputs support cell fitness. Here, we demonstrate that citrate clearance is an essential function of the TCA cycle. As citrate production increases, so do TCA cycle activity and dependence upon aconitase 2 (ACO2), the enzyme that initiates citrate catabolism in the TCA cycle. Disrupting citrate catabolism activates the integrated stress response and impairs cell fitness, and these effects are reversed by preventing citrate production or promoting mitochondrial citrate efflux. In vivo, ACO2 deficiency induces citrate accumulation and triggers tubular degeneration in the kidney, a tissue that physiologically takes up circulating citrate. Thus, intracellular citrate accumulation can be a metabolic liability, and citrate clearance is a major function of ACO2 in the TCA cycle.
    Keywords:  ACO2; TCA cycle; cell metabolism; citrate; integrated stress response
    DOI:  https://doi.org/10.1016/j.cell.2026.01.028
  7. Cancer Lett. 2026 Feb 28. pii: S0304-3835(26)00121-7. [Epub ahead of print]645 218358
    Cancer invasion plasticity during the metastatic cascade: strategies to survive and thrive.
    Aneta Škarková, Daniel Rösel, Jan Brábek.
      The metastatic process is largely inefficient, yet its outcome - the dissemination of cancer cells from the primary tumor to distant sites and the formation of metastases - remains the leading cause of cancer-related death. The individual steps of the metastatic cascade impose major challenges and represent bottleneck steps, eliminating the majority of cancer cells along the way. To overcome these barriers, cancer cells must adapt to diverse environments, ranging from confining spaces to fluid, non-adhesive milieus. Distinct invasion strategies, including collective, mesenchymal and amoeboid, confer specific advantages under such conditions. Cancer cells capable of exploiting features of the invasion modes by switching among them are more likely to survive and thrive throughout all steps of the metastatic cascade. Thus, invasion plasticity represents a key adaptive strategy enabling cancer cells to endure metastatic progression. In this review, we concisely summarize the contribution of collective, mesenchymal and amoeboid invasion features during individual steps of the metastatic cascade, highlight evidence that invasion plasticity fuels metastatic dissemination and discuss how targeting such adaptability may reduce metastatic burden.
    Keywords:  Amoeboid; Collective; Invasion; Mesenchymal; Metastatic cascade
    DOI:  https://doi.org/10.1016/j.canlet.2026.218358
  8. Methods Enzymol. 2026 ;pii: S0076-6879(26)00032-7. [Epub ahead of print]727 321-354
    Imaging interorganelle membrane contact sites using dimerization-dependent fluorescent proteins.
    Victoria H Williams, Chih-Hsuan Hsu, Gregory E Miner, Sarah Cohen.
      Membrane contact sites (MCSs), sites of close apposition between membrane-bound organelles, mediate key intracellular processes to coordinate organelle function and are implicated in a wide range of human diseases. Because MCSs can span as little as 10 nm of distance, the limited resolution of light microscopy can hamper the ability to study these structures in live cells. Dimerization-dependent fluorescent proteins consist of a weakly fluorescent and non-fluorescent monomer that produce greater signal when the two monomers interact, thereby allowing the user to identify sites of proximity through protein-protein interaction. Here, we describe a protocol using Contact-FP - our suite of organelle-targeted dimerization-dependent fluorescent proteins - to study MCSs using confocal or Airyscan microscopy in live cells. The protocol includes guidance for transfection, imaging, and analysis of Contact-FP biosensors. It includes instructions on how to leverage this tool to study a single MCS type, identify two MCSs involving the same organelle, or induce MCSs using high levels of transfection of Contact-FP probes. We also suggest troubleshooting steps for transfection, imaging, and analysis. This protocol provides a specific example for using this tool in U-2 OS osteosarcoma cells but is amenable to adjustment for other cell types.
    Keywords:  Biosensors; Endoplasmic reticulum; Fluorescent proteins; Lipid droplets; Lysosomes; Membrane contact sites; Mitochondria; Organelles; Peroxisomes; Plasma membrane
    DOI:  https://doi.org/10.1016/bs.mie.2026.01.024
  9. ACS Chem Biol. 2026 Mar 06.
    Galectin-3-Induced Glycan Lattices as Biophysical Modulators of Membrane Phase Behavior in Live Cells.
    Gil-Suk Yang, Abigail E Reeves, Jia Meng Pang, Shaheen A Farhadi, Arun Wanchoo, Gregory Hudalla, Mia L Huang.
      The plasma membrane is an important interface that integrates extracellular biochemical input with biophysical organization to regulate cell behavior. Galectin-3, a multivalent glycan-binding protein, can influence both events through the formation of extracellular glycan lattices on the surfaces of glycosylated cells. Although such lattices have been proposed to reshape membrane organization, their impact on nanoscale membrane phase behavior has remained difficult to quantify. Here, we establish a link between Galectin-3 lattice formation and the remodeling of plasma membranes by using imaging fluorescence correlation spectroscopy (ImFCS) to measure diffusion coefficients of a series of fluorescently labeled probes that partition into ordered or disordered regions of the cell membrane. Across several human cell types (BeWo, BxPC3, THP-1, and HEK293T), we observed that Galectin-3 induced significant changes in the lateral mobility of membranes in a manner dependent on the capacity of Galectin-3 to oligomerize and bind glycans, and that specific glycoproteins can play outsized contributing roles. Membrane regions enriched in Galectin-3 exhibited reduced diffusion, suggesting glycan lattices can serve as nucleation sites for ordered, raft-like microdomains. Finally, we also reveal that these Galectin-3-induced changes to membrane dynamics significantly amplifies Ca2+ triggered scrambling of phosphatidylserine exposure. Together, these findings identify Galectin-3 as an extracellular phase organizer that translates glycan recognition into nanoscale mechanical remodeling of the plasma membrane, potentially serving as a generalizable mechanism for fine-tuning cell behavior.
    DOI:  https://doi.org/10.1021/acschembio.5c00986
  10. Cancer Metab. 2026 Mar 03. pii: 4. [Epub ahead of print]14(1):
    A shift in the cellular redox state redirects aspartate for export under glucose deprivation.
    Barbara Konrad, Gabriele Bluemel, Theresa Haitzmann, Tobias Frech, Anke Vandekeere, Mélanie Planque, Visnja Bubalo, Katharina Schindlmaier, Vanessa Jäger, Michael A Dengler, Sarah Stryeck, Luka Brcic, Jörg Lindenmann, Philipp Stiegler, Doruntina Bresilla, Corina T Madreiter-Sokolowski, Tobias Madl, Thomas O Eichmann, Nikolaus Kneidinger, Sarah-Maria Fendt, Katharina Leithner.
      
    Keywords:  Adaptation; Aspartate; Aspartic acid; Cancer; Glucose deprivation; Metabolism
    DOI:  https://doi.org/10.1186/s40170-026-00420-x
  11. Cancer Discov. 2026 Mar 02. 16(3): 419-420
    A Legacy of Enduring Discovery.
    Lewis C Cantley.
      
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-1758
  12. Methods Enzymol. 2026 ;pii: S0076-6879(26)00026-1. [Epub ahead of print]727 179-232
    Fluorescence lifetime estimation: A practical approach using Flipper-TR FLIM.
    Tithi Mandal, Aurélien Roux, Juan Manuel García-Arcos.
      Flipper-TR is a membrane dye sensitive to lipid packing widely used to probe membrane tension in live cells via fluorescence lifetime imaging microscopy (FLIM). However, no consensus currently exists on the optimal strategy for extracting lifetime values, particularly across varying experimental setups and biological systems. Here, we systematically compare multiple approaches to estimate Flipper-TR lifetime, including multi-exponential reconvolution fitting, tail fitting, mean photon arrival time (first moment), and phasor analysis. These estimators are tested against changes in photon budget, sample characteristics, microscope manufacturer, and laser frequency. This analysis offers a comprehensive benchmark and decision-making framework for quantitative FLIM analysis of Flipper dyes in various contexts.
    Keywords:  Cell mechanics; FLIM; Flipper-TR; Fluorescence lifetime imaging microscopy; Frequency-domain lifetime analysis; Membrane biophysics; Membrane tension; Phasor analysis; Time-domain lifetime analysis
    DOI:  https://doi.org/10.1016/bs.mie.2026.01.018
  13. Nat Commun. 2026 Mar 06.
    Tumor-induced orexigenic imbalance lowers protein appetite and drives early organ wasting symptoms.
    Afroditi Petsakou, Elizabeth Filine, Matthew Li, Yuchen Chen, Alice Zheng, Norbert Perrimon.
      Cancer cachexia (CC) is characterized by organ wasting and ensuing involuntary weight loss. Despite advances, underlying mechanisms initiating CC remain unclear, including early symptoms like anorexia. Here, we use a fly gut-tumor model with a precise time-window before organ wasting starts. We show that tumor-induced factors involved in inflammation (unpaired 3/ Interleukin-6-like) and reduced insulin signaling (ImpL2/ Insulin Growth Factor Binding Protein) decrease NPF (Neuropeptide F/ Neuropeptide Y) in the brain prior to organ wasting. This early NPF decrease triggers low protein-specific food appetite and anorexia. We find that ImpL2 reduces NPF signaling while upd3 helps by concurrently affecting the blood brain barrier. Tumor-induced NPF decrease, and early reduction of protein appetite drive the onset of weight loss and exacerbate the risk of death during organ wasting. Altogether, we provide evidence for an early orexigenic brain imbalance causing low protein appetite that regulates the onset and outcome of organ wasting.
    DOI:  https://doi.org/10.1038/s41467-026-70074-2
  14. Methods Enzymol. 2026 ;pii: S0076-6879(25)00515-4. [Epub ahead of print]727 253-289
    Prediction and characterization of lipid-interacting proteins.
    Sebastian Alfonso, Cassandra M Decosto, Poulami Chatterjee, Timothy Precord, Laura M K Dassama.
      Lipids are essential to all life forms. These molecules serve diverse purposes that range from cell membrane formation to energy storage and inter-cellular signaling. Lipids can be natively synthesized or sourced from the environment, often through the action of proteins engaging with specific lipid molecules. Characterizing lipid-interacting proteins is a key frontier in therapeutic science, as dysfunction in lipid metabolism is implicated in a range of human diseases. A substantial bottleneck that precludes the identification and characterization of lipid-interacting proteins pertains to the nature of the lipid substrates: they are not genetically encoded, their hydrophobic nature results in non-specific interactions, they exist in complex cellular environments, and they are structurally diverse. Regardless, the identification, characterization, and specific targeting of proteins that maintain proper lipid homeostasis is important for efforts to restore dysregulated metabolism. In this chapter, we outline bioinformatic and experimental approaches employed by our research group and others to study lipids and the proteins that directly bind them. The chapter covers methods for proteome-wide computational screening to reveal lipid binding proteins, characterization of total lipid composition in mammalian and bacterial cells, and the use of analytical and biophysical methods to study target protein-lipid interactions.
    Keywords:  Bioinformatics; Lipid-protein interaction; Lipids; Liposomes; Mass spectrometry; Microscale thermophoresis
    DOI:  https://doi.org/10.1016/bs.mie.2025.11.013
  15. Methods Enzymol. 2026 ;pii: S0076-6879(26)00047-9. [Epub ahead of print]727 373-416
    In vitro methods for measuring lipid binding, transfer and competitive displacement reactions by peripheral membrane proteins.
    Vytas A Bankaitis, Xiaohan Yu, Xiao-Ru Chen, Max Lönnfors, Tatyana I Igumenova.
      Biological membranes represent versatile platforms that reduce the dimensionality of biochemical reactions involved in signal transduction. In so doing, membranes effectively concentrate proteins and other molecules to ensure that biochemical reactions can take place even in the face of relatively weak interactions between binding partners. Key factors in specifying organelle identities in the eukaryotic cell are the unique lipid compositions of the cytoplasmic leaflets of organelle membranes. It is these compositions, and their modifications, that determine the peripheral membrane protein cohort that will be recruited to each membrane system. In this chapter, we describe a set of quantitative approaches to characterize lipid binding, transfer and displacement reactions for soluble lipid transfer proteins (LTPs) or for soluble domains of otherwise insoluble (e.g., contact site) proteins. LTPs execute trafficking and sorting lipids between intracellular compartments and are essential for cells to achieve organelle identity. The presented approaches provide a template that can be more generally applied to experimental inquires of peripheral membrane proteins that are involved in lipid metabolism, trafficking and lipid-mediated signal transduction.
    Keywords:  Isotopes; Membrane; Peripheral; Proteins/lipids/lipid; Transfer/fluorescence/
    DOI:  https://doi.org/10.1016/bs.mie.2026.01.039
  16. Nature. 2026 Mar 04.
    A glucocorticoid-FAS axis controls immune evasion during metastatic seeding.
    Monica Cassandras, Xavier Sanchez, Lauren Hsu, Yu Huang, Adam J Getzler, Debolina Ganguly, Pilar Baldominos, Ia Codinachs, Jeffrey Chuong, Elizabeth E Martin, Blake E Smith, Eleonora Marina, Milos Spasic, Xingping Qin, Heather A Parsons, Erica L Mayer, Kristopher A Sarosiek, Stephanie K Dougan, Elizabeth A Mittendorf, Sandra S McAllister, Ya-Chieh Hsu, Judith Agudo.
      Metastasis is the major cause of death for patients with triple-negative breast cancer and other solid malignancies. Metastases arise from cancer cells that disseminate from the original tumour, survive systemic immune surveillance and colonize new organs1. Little is known about how initial disseminated tumour cells (DTCs) overcome anti-tumour immunity after seeding a new organ. Here we use a visible antigen in a model of triple-negative breast cancer with cognate CD8+ T cells to study the mechanisms of immune evasion in early metastatic seeding. Analysis of surviving DTCs revealed glucocorticoid receptor (GR) activation as a key driver of resistance to both CD8+ T cells and natural killer cells. Niche profiling using an optimized labelling tool identified FAS-FASL as a key pan-cytotoxic pathway against DTCs, which is repressed by GR activation. Pharmacological inhibition of GR in combination with immunotherapy reduced metastatic burden and expanded lifespan in mice. Thus, we identified a mechanism of immune evasion that operates specifically in DTCs, illustrating the unique immune-cancer interactions at this stage in the metastatic cascade. Our findings suggest that there are therapeutic opportunities to eliminate DTCs, separately from treatments aimed at primary tumours, and GR inhibition is one promising target.
    DOI:  https://doi.org/10.1038/s41586-026-10222-2
  17. Soft Matter. 2026 Mar 02.
    Osmotic forces modify lipid membrane fluctuations.
    Amaresh Sahu.
      In hydrodynamic descriptions of lipid bilayers, the membrane is often approximated as being impermeable to the surrounding, solute-containing fluid. However, biological and in vitro lipid membranes are influenced by their permeability and the resultant osmotic forces-whose effects remain poorly understood. Here, we study the dynamics of a fluctuating, planar lipid membrane that is ideally selective: fluid can pass through it, while solutes cannot. We find that the canonical membrane relaxation mode, in which internal membrane forces are balanced by fluid drag, no longer exists over all wavenumbers. Rather, this mode only exists when it is slower than solute diffusion-corresponding to a finite range of wavenumbers. The well-known equipartition result, quantifying the size of membrane undulations due to thermal perturbations, is consequently limited in its validity to the aforementioned range. Moreover, this range shrinks as the membrane surface tension is increased, and above a critical tension, the membrane mode vanishes. Our findings are relevant when interpreting experimental measurements of membrane fluctuations, especially in vesicles at moderate to high tensions.
    DOI:  https://doi.org/10.1039/d5sm01094b
  18. Nature. 2026 Mar 03.
    Genetically encoded assembly recorder temporally resolves cellular history.
    Yuqing Yan, Jiaxi Lu, Zhe Li, Zuohan Zhao, Timothy F Shay, Shunzhi Wang, Yaping Lei, Yimei Wang, Wei Chen, Patrick Parker, Hongru Yang, Aileen Qi, Yongzhi Sun, Dwight E Bergles, David Baker, Dingchang Lin.
      Cells constantly change their molecular state in response to internal and external cues1. Mapping cellular activity in tissues with spatiotemporal precision is essential for understanding organ physiology, pathology, and regenerative processes. Current cell-sensing modalities primarily rely on either endpoint analysis that takes static snapshots, or real-time sensing that monitors a small subset of cells3,4. Here, we introduce Granularly Expanding Memory for Intracellular Narrative Integration (GEMINI), an in cellulo recording platform that leverages a computationally designed protein assembly as an intracellular memory device to record the history of individual cells. GEMINI grows predictably within live cells, capturing cellular events as tree-ring-like fluorescent patterns for imaging-based retrospective readout. Absolute chronological information of activity histories is attainable with hour-level accuracy. GEMINI effectively maps differential NFκB-mediated transcriptional changes, resolving fast dynamics of 15 minutes and providing quantifiable signal amplitudes. In a xenograft model, GEMINI records inflammation-induced signaling dynamics across tissue, revealing spatial heterogeneity linked to vascular density. When expressed in the mouse brain, GEMINI minimally impacts neuronal functions and can resolve both transcriptional changes and activity patterns of neurons. Together, GEMINI provides a robust and generalizable means for spatiotemporal mapping of cell dynamics underlying physiological and pathological processes in both culture and intact tissues.
    DOI:  https://doi.org/10.1038/s41586-026-10323-y
  19. Lancet Oncol. 2026 Mar;pii: S1470-2045(25)00714-4. [Epub ahead of print]27(3): e141-e149
    The OligoPanc project: an interdisciplinary expert consensus statement on oligometastatic pancreatic cancer.
    Carl-Stephan Leonhardt, Mustapha Adham, Shouki Bazarbashi, Irit Ben-Aharon, Regina G H Beets-Tan, Ugo Boggi, Thomas B Brunner, Francesco Cellini, Arturo Chiti, Lois Daamen, Berardino De Bari, Sara De Dosso, Michel Ducreux, Cathy Eng, Massimo Falconi, Cristina R Ferrone, Isabella Frigerio, Ingrid Garajova, Sabine Gerum, Michael Ghadimi, Thomas Gruenberger, Pascal Hammel, Karin Haustermans, Maria Hawkins, Jin He, Hanne D Heerkens, Florence Huguet, Martijn P W Intven, Ulla Klaiber, Tiuri E Kroese, Pierre Laurent-Puig, Florian Lordick, Ethan B Ludmir, Teresa Macarulla, Oscar Matzinger, Alessio G Morganti, Somnath Mukherjee, Eileen M O'Reilly, Joon Oh Park, Demetris Papamichael, Per Pfeiffer, José M Ramia, Falk Roeder, Erika Ruiz-García, Sohei Satoi, Marta Scorsetti, Martin Schneider, Thomas Seufferlein, Alejandro Serrablo, Shailesh V Shrikhande, Elizabeth C Smyth, Magali Svrcek, Kyoichi Takaori, Margaret A Tempero, Natalia S Tissera, Jeanne Tie, Orlando J M Torres, Anthony Turpin, Eric Van Cutsem, Eva Versteijne, Caterina Vivaldi, Zev A Wainberg, Ralph R Weichselbaum, Juergen Weitz, Christopher L Wolfgang, Gerald W Prager, Oliver Strobel.
      Currently, no consensus exists regarding the definition of oligometastatic pancreatic ductal adenocarcinoma, its necessary diagnostic measures, and potential treatment approaches. To address these knowledge gaps, the OligoPanc project brought together an interdisciplinary group of experts to establish consensus using a modified Delphi process and clinical vignettes. Participants agreed that the number of metastatic lesions and the number of affected organs are key elements in defining oligometastatic pancreatic ductal adenocarcinoma. Specifically, up to three lesions in a single organ, either the liver or the lung, define oligometastatic pancreatic ductal adenocarcinoma and could be either synchronous or metachronous. Necessary diagnostics include a triple-phase contrast-enhanced CT scan of the chest and abdomen and MRI of the liver with a hepatocyte-specific contrast agent. In unclear cases, [18F]fluorodeoxyglucose-PET CT or MRI can be considered. A multidisciplinary tumour board is essential. Patient-intrinsic factors, including age, do not define oligometastatic disease but should be considered for any treatment decision. Systemic treatment before any local consolidative treatment, including surgery, stereotactic ablative radiotherapy, or other locally ablative techniques, is mandatory. The proposed definition should be incorporated into future trials to improve comparability and enable validation.
    DOI:  https://doi.org/10.1016/S1470-2045(25)00714-4
  20. Cell Metab. 2026 Feb 27. pii: S1550-4131(26)00010-0. [Epub ahead of print]
    Purified diets enable experimental rigor through compositional control in animal research.
    Fangtao Chi, Shixun Han, Ömer H Yilmaz.
      Purified diets offer compositionally defined platforms that improve causal inference in nutrition studies. When aligned with the biological question, they enable targeted nutrient loss- and gain-of-function experiments, systematic lipid-source swaps, and the discovery of diet-microbiome-drug interactions. We recommend complementary validation in grain-based chow or human-relevant diets to maximize translational relevance.
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.010
  21. Nat Commun. 2026 Mar 03.
    A hotspot phosphorylation site on SHP2 drives oncoprotein activation and drug resistance.
    Prashath Karunaraj, Remkes Scheele, Malcolm L Wells, Ruchita Rathod, Ipek S Gokulu, Sophia R Abrahamson, Lila Taylor, Lamia Chowdhury, Abiha Kazmi, Weixiao Song, Peter V Hornbeck, Jing Li, Anum Glasgow, Neil Vasan.
      SHP2 is a phosphatase and a critical mediator of receptor tyrosine kinase (RTK)-driven RAS/mitogen-activated protein kinase (MAPK) signaling. Despite promising preclinical data, SHP2 inhibitors have shown minimal clinical efficacy, with no defined clinical mechanisms of primary resistance. Here, we elucidate phosphorylation of SHP2 at tyrosine 62 (pY62) as a hotspot phosphorylation site in the proteome and RTK-driven tumor types in patients. We demonstrate that SRC family kinases directly phosphorylate SHP2 at Y62, downstream of but not directly phosphorylated by RTKs. Using biochemical and biophysical analyses, we show that SHP2Y62D enforces an open, active conformation, resulting in constitutive phosphatase activation that is sufficient to activate MAPK signaling and confer resistance to allosteric SHP2 inhibitors. These findings establish that SHP2 pY62 is a phosphorylation hotspot phenocopying mutational activation, a mechanism of primary resistance to SHP2 inhibitors, and a cancer drug target distinct from wildtype SHP2.
    DOI:  https://doi.org/10.1038/s41467-026-70060-8
  22. Nat Aging. 2026 Mar 06.
    Dietary restriction in aging and longevity.
    Tomas Schmauck-Medina, Sofie Lautrup, Andrea Di Francesco, Sarah J Mitchell, Christoffer Clemmensen, Linda Partridge, George S Roth, Rozalyn M Anderson, Julie A Mattison, Rafael de Cabo, John R Speakman, Arlan Richardson, Donald K Ingram, Richard Weindruch, Mark P Mattson, Evandro F Fang.
      Different types of dietary restriction (DR) have been practiced by humans for religious and medical purposes for millennia, but only during the past three decades has the scientific study of DR at cellular and molecular levels proliferated. Here we review the evidence testing a variety of DR paradigms in the context of aging, focusing on mammalian findings. We discuss potential DR mimetics that modulate autophagy, FGF21, AMPK, mTORC1, NAD+ metabolism, SIRTs, GLP-1R and other pathways as well as organismal and cellular adaptations to DR, including the roles of fasting, hunger, changes in body temperature and fat loss. We also consider the potential negative effects of DR such as increased vulnerability to infections and impaired wound healing. Further, we discuss preclinical evidence evaluating the potential of DR to improve healthspan and treat, prevent or delay age-related diseases including cancer, cardiovascular diseases and neurodegeneration. Finally, we consider the future opportunities for translation, and the challenges inherent to this complex research field.
    DOI:  https://doi.org/10.1038/s43587-026-01091-5
  23. Cancer Discov. 2026 Mar 02. 16(3): 431-438
    A Legacy of Mentorship: A Tribute to Lewis Cantley.
    Heather R Christofk, Gina M DeNicola, Brooke M Emerling, Jeffrey A Engelman, David A Fruman, Marcus D Goncalves, Katja A Lamia, Costas A Lyssiotis, Brendan D Manning, Reuben J Shaw, Alex Toker, Matthew G Vander Heiden, Michael B Yaffe.
      
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-1792
  24. Nature. 2026 Mar 04.
    Precancerous niche remodelling dictates nascent tumour persistence.
    G Skrupskelyte, J E Rojo Arias, H Ajith, Y Dang, D Rossetti, S Han, M K S Tang, M T Bejar, B Colom, J C Fowler, K Murai, W Knight, D Aust, M H H Schmidt, J Jászai, S Zeki, A Noorani, P H Jones, S Rulands, B D Simons, M P Alcolea.
      Interactions between mutant cells and their environment have a key role in determining cancer susceptibility1-3. However, understanding of how the precancerous microenvironment contributes to early tumorigenesis remains limited. Here we show that newly emerging tumours at their most incipient stages shape their microenvironment in a critical process that determines their survival. Analysis of nascent squamous tumours in the upper gastrointestinal tract of the mouse reveals that the stress response of early tumour cells instructs the underlying mesenchyme to form a supportive 'precancerous niche', which dictates the long-term outcome of epithelial lesions. Stimulated fibroblasts beneath emerging tumours activate a wound-healing response that triggers a marked remodelling of the underlying extracellular matrix, resulting in the formation of a fibronectin-rich stromal scaffold that promotes tumour growth. Functional heterotypic 3D culture assays and in vivo grafting experiments, combining carcinogen-free healthy epithelium and tumour-derived stroma, demonstrate that the precancerous niche alone is sufficient to confer tumour properties to normal epithelial cells. We propose a model in which both mutations and the stromal response to genetic stress together define the likelihood of early tumours to persist and progress towards more advanced disease stages.
    DOI:  https://doi.org/10.1038/s41586-026-10157-8
  25. Cell Signal. 2026 Feb 28. pii: S0898-6568(26)00104-X. [Epub ahead of print]142 112454
    Copper potentiates PUFA-mediated antitumor activity by activating Lipophagy.
    Xiangyang He, Qianqian Yang, Xiaowen Lin, Ziyuan Chen, Kaixuan Ren, Jiao Yang, Xiaoqin An, Shangzhu Yang, Li Yang, Qian Xue, Xi Chen, Yuan Wang, Guifang Yu, Ding Yan, Xin Chen.
      Polyunsaturated fatty acids (PUFAs) have demonstrated promising anticancer properties by inducing cancer cell death and inhibiting cancer metastasis. As dynamic organelles, lipid droplets (LDs) may protect cells from PUFA-induced lipotoxicity by sequestering excess fatty acids. However, the underlying mechanisms regulating LDs dynamics in PUFA-mediated tumor cytotoxicity remain poorly understood. In this study, we report that inhibition of LDs synthesis enhances PUFA-induced cancer cell death, suggesting that LDs formation protects against PUFA cytotoxicity. We further demonstrate that copper ions potentiate the antitumor effects of PUFAs across multiple cancer cell lines primarily by promoting apoptosis rather than cuproptosis or ferroptosis. Mechanistically, copper ions significantly reduce intracellular LDs accumulation by promoting LDs degradation via activation of ATGL-dependent lipophagy. Collectively, these findings uncover a novel mechanism whereby copper ions enhance PUFA-induced tumor cell death through promoting lipophagy, which provides valuable insights for optimizing PUFA-based cancer therapies by targeting lipid metabolism and copper homeostasis.
    Keywords:  Copper; Lipophagy; PUFA; Tumor
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112454
  26. Methods Enzymol. 2026 ;pii: S0076-6879(26)00028-5. [Epub ahead of print]727 1-16
    Regulation of phospholipid scramblases by cholesterol.
    Sabita Chourasia, Haodong Wang, Anant K Menon.
      The activity of membrane proteins is often regulated by their lipid environment, either via physical properties of the membrane or by direct interaction with specific lipids. Testing these effects with purified proteins reconstituted into lipid vesicles is challenging because of the compositional heterogeneity of the vesicle sample. Cholesterol influences membrane properties and binds to a variety of membrane proteins, thereby regulating their activity. To study the effect of cholesterol on the phospholipid scramblase activity of G protein-coupled receptors (GPCRs), we developed a protocol to introduce cholesterol into vesicles after reconstituting the protein. This approach sidesteps the problem of having to account for the possible effect of cholesterol on the reconstitution process itself, enabling direct evaluation of the effect of cholesterol on activity. Here we describe the cholesterol loading protocol and how to quantify the amount loaded by colorimetric assays and membrane fluidity measurements. We provide sample data on the effect of cholesterol on GPCRs. Our protocol is broadly applicable and can be used in any study of the effect of cholesterol on a reconstituted membrane protein.
    Keywords:  G protein-coupled receptor; cholesterol; cyclodextrin; liposome; membrane fluidity; phospholipid; scramblase
    DOI:  https://doi.org/10.1016/bs.mie.2026.01.020
  27. Nat Cell Biol. 2026 Mar 05.
    Acidic niche sugar shield blocks ferroptosis.
    Mario Palma, Jessalyn M Ubellacker.
      
    DOI:  https://doi.org/10.1038/s41556-026-01899-8
  28. Front Mol Biosci. 2025 ;12 1701375
    The endothelial plasma membrane lipidome and its remodeling under hyperglycemia: an exploratory study.
    Ana Reis, Yahya Sohrabi, Lorena Diaz-Sanchez, Ana Rita Dias Araújo, Merle Leffers, Bruno Antonny, Alisa Rudnitskaya, Rui Vitorino, Irundika H K Dias.
       Introduction: At the interface between blood and blood vessels, the endothelial plasma membrane is the first point of contact to external stimuli, triggering the cascade of intracellular events responsible for proper vascular function. However, the endothelial plasma membrane lipidome and its remodeling in pathological conditions remain largely unknown.
    Methods: To address this gap, we present a comprehensive lipidomic analysis of cell-derived giant plasma membrane vesicles isolated from primary human umbilical vein endothelial cells cultured in vitro under normoglycemic conditions and their lipid remodeling in adaptation to hyperglycemia.
    Results: Using targeted mass spectrometry-based strategies, 251 lipids and 13 oxidized lipids from 20 subclasses were identified and quantified. Cholesterol accounted for almost half (45 mol%) of the membrane's composition. In adaptation to hyperglycemia, the noticeable decrease in the total phospholipids extracted resulted in an increased cholesterol-to-phospholipid (Chol/PL) ratio, which is consistent with increased membrane stiffening. Several other lipid subclasses, namely, lysolipids, phosphatidylcholines, aminophospholipids, polyunsaturated sphingomyelins, and other polyunsaturated phospholipids, showed a decreasing trend. Oxysterols displayed a shift toward the predominance of enzymatic (tail-oxidized) in hyperglycemia, whereas truncated oxidized phosphatidylcholines (oxPC) with a terminal aldehyde moiety exhibited a decreasing trend, suggesting the formation of lipid-protein cross-linking modification.
    Discussion: The hyperglycemia-induced alterations provide insights into the endothelial membrane lipid environment and the biophysical dynamics that are likely to deregulate protein-lipid interactions involved in sugar and lipid metabolism. The high amount of Chol found in our work serves as the basis for future in silico simulations crucial for drug design and drug response evaluation.
    Keywords:  cholesterol; giant plasma membrane vesicles; human umbilical vein endothelial cells; oxidized phospholipids; oxysterols; shotgun mass spectrometry
    DOI:  https://doi.org/10.3389/fmolb.2025.1701375
  29. Cell Metab. 2026 Mar 03. pii: S1550-4131(26)00048-3. [Epub ahead of print]
    The S100A8/A9 complex promotes food intake and prevents adipose tissue loss during cancer cachexia in mice.
    Lin Gao, Ying Liu, Ying Yu, Yingga Wu, Huanan Zhang, Cui Wang, Xinrui Gao, Yang Chen, Tingjie Zhang, Sixian Huang, Zhonghui Zhang, Zengguang Jin, Jie Chen, Haiyang Jing, Dehuang Kong, Yanlin Tian, Jacques Togo, Yong Lei, Yi Huang, Fan Xia, Min Li, Anyongqi Wang, Chao Jia, Sumei Hu, Di Chen, Xina Xie, Lu Wang, Jie Liu, Xiaomeng Wu, Changyong Tang, Chaoqun Niu, Zesong Li, John R Speakman.
      Cancer cachexia is a wasting syndrome characterized by reduced food intake and lean and fat tissue loss. In mice, cancer cachexia involved marked reductions in host fat and lean mass (particularly skeletal muscle), which were balanced by tumor growth. Using 15N tracing, the tumor gets protein (nitrogen) from both food intake and host tissue breakdown. Total energy expenditure remained unchanged due to metabolic compensation among the tumor, brown adipose tissue (BAT), and other organs, a phenomenon also observed in people with cancer. The decrease in leptin caused by fat loss did not stimulate food intake or reduce energy expenditure. We show that S100 calcium-binding protein A8 and A9 (S100A8/A9) and complement 3 (C3) in the hypothalamus play a key role in the reduction of food intake and fat mass during cancer cachexia. The peripheral administration of S100A8/A9 inhibitors and the hypothalamic knockdown of C3 significantly increased food intake and partially rescued fat and lean tissue loss.
    Keywords:  C3; S100A8/A9; cancer cachexia; energy balance; fat loss; food intake; mice; muscle loss
    DOI:  https://doi.org/10.1016/j.cmet.2026.02.005
  30. Sci Signal. 2026 Mar 03. 19(927): eadz6443
    Glucose metabolism sustains aberrant STAT3 signaling in colorectal cancer through glycosylated local signaling factors.
    Kathryn Buscher, Kelsey Temprine, Christopher Mays, Noora Aabed, Samuel A Kerk, Hannah N Bell, Joseph A Nieto Carrion, Harrison S Greenbaum, Zheng Hong Lee, Varun Ponnusamy, Sadeesh K Ramakrishnan, Costas A Lyssiotis, Xiang Xue, Yatrik M Shah.
      The JAK-STAT3 signaling pathway is a key driver of colorectal cancer (CRC) progression. STAT3 is a transcription factor that is canonically activated by cytokines, such as IL-6, in a transient manner because of negative feedback mechanisms. However, STAT3 is aberrantly and persistently activated in CRC, promoting tumor cell proliferation and survival. Here, we demonstrated that glucose sustained STAT3 activation independently of cytokine availability. We manipulated glucose metabolism, which showed that both glucose and its downstream metabolite GlcNAc were essential to maintain STAT3 activation. Moreover, cells with high basal STAT3 activity produced proteins that were glycosylated in a glucose-dependent manner and that activated STAT3 in neighboring cells through paracrine signaling. Proteomic analysis identified multiple candidate proteins involved in this process; however, no single protein was sufficient to fully activate STAT3, suggesting that this activation process requires several glycosylated proteins. In a syngeneic mouse model of CRC, inhibition of glycolysis reduced STAT3 activation in tumors, and genetic deletion of STAT3 substantially decreased tumor growth. Together, these findings show how glucose metabolism supports sustained STAT3 activation in CRC, highlighting a potential metabolic vulnerability for therapeutic targeting.
    DOI:  https://doi.org/10.1126/scisignal.adz6443
  31. J Immunother Precis Oncol. 2026 Feb;9(1): 17-24
    Phase II Trial of Vemurafenib and Sorafenib Combination in Advanced KRAS-Mutated Metastatic Pancreatic Cancer.
    Muhammad Rizwan Khawaja, Gayle Jameson, Derek Cridebring, Patricia Shannon, Haiyong Han, Jaeger Moore, Daniel Von Hoff, Richard G Posner, William S Hlavacek, Walter Kolch, Boris N Kholodenko, Oleksii S Rukhlenko, Denise J Roe, Betsy C Wertheim, Erkut Borazanci.
       Introduction: Prognosis of metastatic pancreatic cancer remains poor. KRAS mutations are common in pancreatic cancer and are an attractive therapeutic target. Based on a next-generation mechanistic dynamic model, we hypothesized that a combination of type I½ RAF inhibitor (vemurafenib) and type II RAF inhibitor (sorafenib) would have clinical activity in KRAS-mutated advanced pancreatic cancer.
    Methods: We conducted an open-label pilot phase II trial of vemurafenib and sorafenib combination in advanced pancreatic cancer with KRAS mutations. Eligible patients had progressed on two or more prior treatment regimens, had adequate performance status, adequate organ function and measurable disease, and were able to swallow oral medication. The primary objective was disease control rate (partial or complete response or stable disease ≥ 16 weeks). Secondary objectives included safety, progression-free (PFS) and overall survival (OS), and changes in plasma phospho-ERK and phospho-AKT.
    Results: Nine patients with KRAS-mutated pancreatic cancer were enrolled. The median age was 62.8 years and the median prior lines of treatment was 3. Four of the initial five patients had treatment interruption due to adverse events, and the subsequent four patients were treated at a reduced dose. Three grade 3 adverse events were reported and included anemia (n = 1), hypophosphatemia (n = 1), and maculopapular rash (n = 1); rash and anemia were deemed treatment related. Disease control rate was 0%. Median PFS was 1.6 months (95% CI, 0.5-not available), and median OS was 2.9 months (95% CI, 0.6-5.4). Compared to baseline, the best response for relative plasma phospho-ERK levels were -39 to +11% and -32 to +49% for plasma phospho-AKT levels.
    Conclusion: The combination of vemurafenib and sorafenib in KRAS-mutated refractory pancreatic cancer did not yield disease control in this pilot phase II study. The lack of clinical efficacy may be due to inadequate inhibition of RAS-to-ERK signaling as toxicities necessitated dose reduction.
    Clinicaltrialsgov ID: NCT05068752.
    Keywords:  KRAS mutation; RAF inhibitors; pancreatic cancer; sorafenib; vemurafenib
    DOI:  https://doi.org/10.36401/JIPO-25-20
  32. Nature. 2026 Mar 04.
    Genome modelling and design across all domains of life with Evo 2.
    Garyk Brixi, Matthew G Durrant, Jerome Ku, Mohsen Naghipourfar, Michael Poli, Gwanggyu Sun, Greg Brockman, Daniel Chang, Alison Fanton, Gabriel A Gonzalez, Samuel H King, David B Li, Aditi T Merchant, Eric Nguyen, Chiara Ricci-Tam, David W Romero, Jonathan C Schmok, Ali Taghibakhshi, Anton Vorontsov, Brandon Yang, Myra Deng, Liv Gorton, Nam Nguyen, Nicholas K Wang, Michael T Pearce, Elana Simon, Etowah Adams, Zachary J Amador, Euan A Ashley, Stephen A Baccus, Haoyu Dai, Steven Dillmann, Stefano Ermon, Daniel Guo, Michael H Herschl, Rajesh Ilango, Ken Janik, Amy X Lu, Reshma Mehta, Mohammad R K Mofrad, Madelena Y Ng, Jaspreet Pannu, Christopher Ré, John St John, Jeremy Sullivan, Joseph Tey, Ben Viggiano, Kevin Zhu, Greg Zynda, Daniel Balsam, Patrick Collison, Anthony B Costa, Tina Hernandez-Boussard, Eric Ho, Ming-Yu Liu, Thomas McGrath, Kimberly Powell, Sudarshan Pinglay, Dave P Burke, Hani Goodarzi, Patrick D Hsu, Brian L Hie.
      All of life encodes information with DNA. Although tools for genome sequencing, synthesis and editing have transformed biological research, we still lack sufficient understanding of the immense complexity encoded by genomes to predict the effects of many classes of genomic changes or to intelligently compose new biological systems. Artificial intelligence models that learn information from genomic sequences across diverse organisms have increasingly advanced prediction and design capabilities1,2. Here we introduce Evo 2, a biological foundation model trained on 9 trillion DNA base pairs from a highly curated genomic atlas spanning all domains of life to have a 1 million token context window with single-nucleotide resolution. Evo 2 learns to accurately predict the functional impacts of genetic variation-from noncoding pathogenic mutations to clinically significant BRCA1 variants-without task-specific fine-tuning. Mechanistic interpretability analyses reveal that Evo 2 learns representations associated with biological features, including exon-intron boundaries, transcription factor binding sites, protein structural elements and prophage genomic regions. The generative abilities of Evo 2 produce mitochondrial, prokaryotic and eukaryotic sequences at genome scale with greater naturalness and coherence than previous methods. Evo 2 also generates experimentally validated chromatin accessibility patterns when guided by predictive models3,4 and inference-time search. We have made Evo 2 fully open, including model parameters, training code5, inference code and the OpenGenome2 dataset, to accelerate the exploration and design of biological complexity.
    DOI:  https://doi.org/10.1038/s41586-026-10176-5
  33. Biophys Rev. 2025 Dec;17(6): 1807-1833
    New frontiers in applied biophysics: advancing drug discovery using single-molecule microscopy.
    Francis Stabile, Cynthia Shaheen, Sabrina Leslie.
       Abstract: Since the last event of a drug interacting with its target occurs one molecule at a time, it stands to reason that the ability to observe the structures, time courses, and interactions of individual molecules will be important to optimizing drug properties. While bulk measurements provide ensemble-average properties of molecules, important information is often obscured from view. Recently, single-molecule methods have emerged in the field of drug discovery and development to fill in these gaps. Benefits of single-molecule resolution include reduced sample consumption, higher detection sensitivity, and enabling direct visualization of multi-step molecular interactions. In this review, we attempt to bridge the gap between the fields of biophysics and drug discovery to increase the interaction between these fields and drive progress together. First, we give a brief overview of the drug discovery process, which is intended for the biophysics community. Then, we review a series of single-molecule techniques, including both well-established and newly emerging technologies, highlighting key drug discovery insights and possible future applications of each technique. Looking forward, we are inspired to see the advent and application of single-molecule methods and biophysical approaches to drive real-world impacts in drug discovery by providing crucial and complementary information to bulk measurements. Looking ahead, we are excited about the widespread impact that bringing the fields of biophysics and drug discovery together will have on myriad classes of emerging medicines and energizing the required research.
    Graphical abstract:
    Keywords:  Biophysics; Drug discovery process; Microscopy
    DOI:  https://doi.org/10.1007/s12551-025-01396-6
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