bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2026–03–22
thirty papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Catabolism of extracellular glutathione supplies cysteine to support tumours.
  2. Ca²⁺ leakage is a conserved signal for non-canonical ATG8/LC3 lipidation and membrane repair.
  3. Not Just Soft: Cell Viscosity Emerges as a Driver of Tumor Cell Dissemination.
  4. Ferroptosis: The Demise of Cells Through Phospholipid Peroxidation.
  5. Phospholipid Glutathione Peroxidase Overexpression Mitigates Cancer Cachexia by Protecting Muscle Mass and Lowering Inflammation.
  6. Cell Clustering Promotes a Metabolic Switch that Supports Metastatic Colonization.
  7. Engineering synthetic cells with intramembrane domains possessing distinct bilayer asymmetries.
  8. Visualizing suborganellar lipid distribution using correlative light and electron microscopy.
  9. ATG8 and protein ATG8ylation - more than just Another TaG?
  10. Transport of sphingolipids by yeast Npc2 supports phase separation of the vacuole membrane.
  11. Effect of very long-chain lipids on the organization of biological membranes: A simulation study.
  12. Lysosomal phosphoinositide turnover acts upstream of RagGTPase-mTORC1 and controls muscle growth.
  13. Impaired Adipose Anabolism in Pancreatic Cancer Cachexia Is Reversed by HuR Inhibition.
  14. Targeting dormant cancer cells: ferroptosis as a precision therapeutic strategy.
  15. Phase 2 Study of Azacitidine plus Pembrolizumab as Second-Line Treatment in Patients with Locally Advanced or Metastatic Pancreatic Ductal Adenocarcinoma.
  16. MRTX1133 suppresses ERK signaling but elicits context-dependent antiproliferative responses in KRAS (G12C) cancer cells.
  17. FAK/SRC-JNK axis promotes ferroptosis via upregulating ACSL4 expression.
  18. Lethal toxin-equipped effector cells for the potential treatment of cancer.
  19. LazySlide: accessible and interoperable whole-slide image analysis.
  20. DGAT1 mediates sex-specific CD8+ T cell antitumour responses.
  21. CXCR2 blockade overcomes the NETosis-mediated resistance to MEK inhibition in pancreatic cancer models.
  22. Three-dimensional high-content imaging of unstained soft tissue with subcellular resolution using a laboratory-based X-ray microscope.
  23. Adipogenic transdifferentiation reprograms EMT-high PDAC cells into a post-mitotic adipocyte-like state and limits metastasis.
  24. Fundamental mechanism of ferroptosis: Three unanswered questions.
  25. Proteasome-guided haem signalling axis contributes to T cell exhaustion.
  26. MolViewStories: Interactive molecular storytelling.
  27. Autophagy is essential for survival and function of polyploid giant cancer cells under therapeutic stress.
  28. What is quantum biology?
  29. Targeting ubiquitin signaling vulnerabilities in KEAP1-inactivated lung cancer.
  30. Cancer in 4D: toward Spatiotemporal Hallmark Ecosystems.
  1. Nature. 2026 Mar 18.
    Catabolism of extracellular glutathione supplies cysteine to support tumours.
    Fabio Hecht, Marco Zocchi, Emily T Tuttle, Nathan P Ward, Fatemeh Alimohammadi, Amal Afzal Khan, Veronica C Gomes, Bradley Smith, Jennifer J Twardowski, Bradley N Mills, Kevin A Welle, Sina Ghaemmaghami, Zhuoran Zhou, Yuhan Gan, Yun Pyo Kang, Juliana Cazarin, Zamira G Soares, Mete Emir Ozgurses, Huiping Zhao, Colin Sheehan, Guillaume Cognet, Lila D Munger, Dhvani Trivedi, Gloria Asantewaa, Sara K Blick-Nitko, Jason J Zoeller, Ying Chen, Vasilis Vasiliou, Bradley M Turner, Stephano S Mello, Brian J Altman, Alexander Muir, Jonathan L Coloff, Joshua Munger, Gina M DeNicola, Isaac S Harris.
      Restricting amino acids from tumours is an emerging therapeutic strategy with substantial promise1. Although typically considered an intracellular antioxidant with tumour-promoting capabilities2, glutathione (GSH), as a tripeptide of cysteine, glutamate and glycine, can be catabolized to release amino acids. The extent to which GSH-derived amino acids are essential to cancers is unclear. Here we show that depletion of intracellular GSH does not alter tumour growth and extracellular GSH is highly abundant in the tumour microenvironment, highlighting the potential importance of GSH outside tumours. Supplementation with GSH rescues cancer cell survival and growth in cystine-deficient conditions, and this rescue depends on the catabolic activity of γ-glutamyltransferases. Finally, pharmacological targeting of the activity of γ-glutamyltransferases prevents the breakdown of circulating GSH, reduces tumour cysteine levels and slows tumour growth. Our findings indicate a non-canonical role for GSH in supporting tumours by acting as a reservoir of amino acids. Depriving tumours of extracellular GSH or inhibiting its breakdown is potentially a therapeutically tractable approach for patients with cancer. Furthermore, these findings change our view of GSH and how amino acids, including cysteine, are supplied to cells.
    DOI:  https://doi.org/10.1038/s41586-026-10268-2
  2. EMBO J. 2026 Mar 20.
    Ca²⁺ leakage is a conserved signal for non-canonical ATG8/LC3 lipidation and membrane repair.
    Di Chen, Antony Fearns, Christopher J Peddie, Maximiliano G Gutierrez.
      Endomembrane damage of intracellular vesicles triggers signals that activate membrane repair in mammalian cells to restore homeostasis. However, the signals that drive diverse membrane repair recruitment at the individual organelle level are unknown. Here by recording Ca2+ leakage history with a newly developed Ca2+ probe in human macrophages, we discovered that Ca²⁺ leakage serves as a conserved signal that triggers ATG8/LC3 lipidation after different types of sterile membrane damage. The damaged compartments consisted of both single membrane and multilayered membrane structures undergoing extensive membrane remodelling. We show the complexity and acidification of these ATG8/LC3-positive compartments depends on the nature of the membrane damage trigger. Functionally, the formation of these multimembrane ATG8/LC3-positive compartments restricted membrane damage independently of canonical autophagy and the recruitment of ESCRT components CHMP2A/CHMP4B. Altogether, we show that endolysosomal Ca²⁺ leakage triggers non-canonical LC3 lipidation on damaged membranes to promote membrane repair in human macrophages.
    Keywords:  Ca2+ Leakage; Lysosome Damage; Macrophages; Membrane Repair; Non‑canonical LC3 Lipidation
    DOI:  https://doi.org/10.1038/s44318-026-00741-z
  3. Cancer Res. 2026 Mar 16.
    Not Just Soft: Cell Viscosity Emerges as a Driver of Tumor Cell Dissemination.
    Sanjiban Nath, Debanik Choudhury, Alice Amitrano, Konstantinos Konstantopoulos.
      The mechanical properties of cells and tissues have emerged as important biophysical markers for distinguishing between healthy and diseased states. In cancer, mechanical heterogeneity spans multiple scales, from tissue-level variations to substantial differences between individual tumor cells. The prevailing notion is that metastatic cancer cells are typically elastically softer than their non-malignant counterparts, a feature attributed to their ability to deform, remodel their shape, and navigate dense extracellular matrices and constricting blood vessels. However, cells are not purely elastic materials, but instead they exhibit viscoelastic behavior, in which deformation depends not only on instantaneous stiffness but also on time-dependent internal flow. In this context, Gensbittel and colleagues find that cellular viscosity, rather than elasticity, is a key determinant of cancer cell dissemination and extravasation, providing new insights into the mechanical underpinnings of cancer metastasis.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-1081
  4. Adv Sci (Weinh). 2026 Mar 20. e24387
    Ferroptosis: The Demise of Cells Through Phospholipid Peroxidation.
    Shaojie Cui, Jin Ye.
      Ferroptosis is a form of regulated cell death driven by iron-dependent peroxidation of polyunsaturated phospholipids. The susceptibility of cells to ferroptosis is often strongly shaped by lipid metabolic pathways that determine the abundance, distribution, and redox reactivity of polyunsaturated phospholipids. Enzymes that activate and incorporate polyunsaturated fatty acids into phospholipids generate the substrates whose peroxidation causes ferroptosis, thereby sensitizing cells to ferroptosis. In contrast, synthesis of monounsaturated phospholipids and the presence of lipid-soluble antioxidants limit the accumulation of phospholipid peroxides, thereby protecting cells from ferroptosis. Thus, different tissues may display characteristic ferroptotic responses caused by their unique lipid composition and antioxidant capacity. This review summarizes the metabolic foundations that determine the susceptibility of cells to ferroptosis and discusses the possibility of treating human diseases by modulating cellular sensitivity to ferroptosis.
    Keywords:  GPX4‐glutathione defense; PUFA‐containing phospholipids; ferroptosis; hyperoxidized PRDX3; phospholipid peroxidation
    DOI:  https://doi.org/10.1002/advs.202524387
  5. J Cachexia Sarcopenia Muscle. 2026 Apr;17(2): e70255
    Phospholipid Glutathione Peroxidase Overexpression Mitigates Cancer Cachexia by Protecting Muscle Mass and Lowering Inflammation.
    Elizabeth Duggan, Jordan D Fuqua, Bo Hagy, Constantin Georgescu, Benjamin F Miller, Holly Van Remmen, Jacob L Brown.
       BACKGROUND: Cancer cachexia is a muscle wasting syndrome that occurs in ~80% of cancer patients and is the primary cause of death for 22%-30% of cancer patients. The primary challenge associated with cancer cachexia is that effective therapies to treat the associated muscle loss and dysfunction are lacking. Research exploring whether reactive oxygen species (ROS, i.e., superoxide anion and hydrogen peroxide) contributes to cancer cachexia has had mixed results. Lipid peroxidation is an underexplored component of oxidative stress that may contribute to cancer cachexia as markers of lipid peroxidation such as 4-hydroxyneoneal (4-HNE) and MDA (Malondialdehyde) are higher in muscle from tumour-bearing mice when compared to controls. Phospholipid hydroperoxide glutathione peroxidase (GPx4) is an antioxidant enzyme that reduces lipid hydroperoxides. We hypothesized that reducing lipid peroxidation via GPx4 overexpression would mitigate cancer cachexia in tumour-bearing mice.
    METHODS: One million Lewis lung carcinoma (LLC) cells or phosphate-buffered saline was injected into the hind flank of wildtype or GPx4 transgenic (Tg) mice at 6 months of age and the tumour developed for 4 weeks. Muscle mass, contractile function, mitochondrial respiration, RNA-sequencing, inflammation and the oxylipin profile were assessed.
    RESULTS: Muscle mass and myofiber cross-sectional area were reduced ~25% in wildtype tumour-bearing mice compared to control mice but not changed in GPx4 Tg tumour-bearing mice. GPx4 overexpression (~3-fold) did not raise maximal or specific muscle force generation in LLC-tumour-bearing mice. Muscle mitochondrial respiration was reduced in wildtype tumour-bearing mice by ~40% when compared to control mice but not altered in tumour-bearing GPx4 Tg mice. Quadricep RNA seq analysis revealed that expression of inflammatory genes was elevated in wildtype tumour-bearing mice when compared to control mice, and the expression of these genes was reduced in tumour-bearing GPx4 Tg mice compared to wildtype tumour-bearing mice. Next, we found that protein content of IL-6 was ~5-fold greater in muscle from wildtype tumour-bearing mice compared to control mice, and GPx4 overexpression prevented this increase in IL-6. We assessed the muscle oxylipin profile and found that many oxylipins generated by 12/15-Lox were elevated in tumour-bearing mice but not impacted by GPx4 overexpression.
    CONCLUSIONS: Our results show that GPx4 overexpression protected muscle mass and mitochondrial respiration in tumour-bearing mice, possibly by reducing muscle inflammation. Future studies will explore the potential mechanisms for the protective effect of GPx4 in cancer cachexia.
    Keywords:  GPx4; atrophy; lipid peroxidation; lipoxygenase; oxylipin; skeletal muscle
    DOI:  https://doi.org/10.1002/jcsm.70255
  6. Cell Metab. 2026 Mar 18. pii: S1550-4131(26)00102-6. [Epub ahead of print]
    Cell Clustering Promotes a Metabolic Switch that Supports Metastatic Colonization.
    Christiaan F Labuschagne, Eric C Cheung, Julianna Blagih, Marie-Charlotte Domart, Karen H Vousden.
      
    DOI:  https://doi.org/10.1016/j.cmet.2026.03.008
  7. Nat Commun. 2026 03 19. pii: 2620. [Epub ahead of print]17(1):
    Engineering synthetic cells with intramembrane domains possessing distinct bilayer asymmetries.
    Naresh Yandrapalli, Tina Seemann, Reinhard Lipowsky, Tom Robinson.
      Our understanding of how membrane asymmetry governs biological function is limited by the lack of techniques to produce model membranes which can reliably and accurately mimic cellular membrane asymmetry. Not only in terms of asymmetric lipid distribution, but also how that asymmetry can be confined to specific lateral locations across the membrane. Here we present an inverted emulsion method that can be used to produce synthetic cells with symmetric and asymmetric bilayers, as well as phase separation where the intermembrane domains possess distinct bilayer asymmetries. We assess the degree of lipid asymmetry using protein-lipid interaction and quenching assays. Surprisingly, the synthetic cells with asymmetric and phase separated membranes displayed pronounced curvature of the domains and resulted in membrane budding and division. Overall, this work develops biomimetic membranes with lipid compositions akin to natural biomembranes - an essential element in the development of functional synthetic cells.
    DOI:  https://doi.org/10.1038/s41467-026-68997-x
  8. Nat Cell Biol. 2026 Mar 20.
    Visualizing suborganellar lipid distribution using correlative light and electron microscopy.
    H Mathilda Lennartz, Suman Khan, Weihua Leng, Kristin Böhlig, Gunar Fabig, Yannick Kieswald, Falk Elsner, Nadav Scher, Michaela Wilsch-Bräuninger, Ori Avinoam, André Nadler.
      Lipids and proteins compartmentalize biological membranes into nanoscale domains, which are crucial for signalling, intracellular trafficking and many other cellular processes. Studying nanodomain function requires the ability to measure protein and lipid localization at the nanoscale. Current methods for visualizing lipid localization do not meet this requirement. Here we introduce a correlative light and electron microscopy workflow to image lipids (Lipid-CLEM), combining near-native lipid probes and on-section labelling by click chemistry. This approach enables the quantification of relative lipid densities in membrane nanodomains. We find differential partitioning of sphingomyelin into intraluminal vesicles, recycling tubules and the boundary membrane of the early endosome, representing a degree of nanoscale organization previously observed only for proteins. We anticipate that our Lipid-CLEM workflow will greatly facilitate the mechanistic analysis of lipid functions in cell biology, allowing for the simultaneous investigation of proteins and lipids during membrane nanodomain assembly and function.
    DOI:  https://doi.org/10.1038/s41556-026-01915-x
  9. Autophagy. 2026 Mar 20. 1-9
    ATG8 and protein ATG8ylation - more than just Another TaG?
    Fabian Gerth, Simone Kosol, Natasha Aley, Alexander Agrotis, Robin Ketteler.
      Since its discovery as a key component of the autophagosome membrane, the small ubiquitin-like protein ATG8 and its mammalian homologs (ATG8s) have garnered a lot of attention. Many researchers use it as a marker for autophagosome number, size and composition. A lot of research has focussed on its function in forming complexes required for autophagosome-lysosome fusion or generally, its interaction with other proteins via the ATG8-family interacting motif/AIM. Many additional functions have been discovered, for instance in non-canonical autophagy processes and in the nucleus. The list of known functions of ATG8 are ever expanding, and, most recently, evidence has emerged that, similar to ubiquitin, ATG8 can modify proteins by covalent attachment to a lysine residue (protein ATG8ylation). In this review, we aim to summarize the current literature on protein ATG8ylation and highlight the currently known substrates. We propose strategies to investigate this modification and provide an outlook for its possible cellular function.Abbreviations: ATG: autophagy related; DUBs: de-ubiquitinating enzymes; GABARAPL: GABA type A receptor associated protein like; GIR: GABARAP-interacting region; LIR: LC3-interacting region; MAP1LC3: microtubule associated protein 1 light chain 3; RMSD: root mean square; UBL: ubiquitin-like; UPS: ubiquitin-proteasome-system.
    Keywords:  ATG4B; ATG8; ATG8ylation; LC3ylation; autophagy; ubiquitin-like
    DOI:  https://doi.org/10.1080/15548627.2026.2642981
  10. J Biol Chem. 2026 Mar 16. pii: S0021-9258(26)00240-1. [Epub ahead of print] 111370
    Transport of sphingolipids by yeast Npc2 supports phase separation of the vacuole membrane.
    Hyesoo Kim, Nicolas-Frédéric Lipp, Israel Juarez-Contreras, Adrian M Wong, Itay Budin.
      The yeast vacuole membrane forms ordered microdomains that facilitate micro-lipophagy under nutrient limitation. We previously found that this process involves the intracellular sorting of sphingolipids to the vacuole. While multiple vacuole protein pathways have been identified, corresponding mechanisms for lipid sorting remain undefined. Here we use a range of approaches to identify how endocytic sorting and intraluminal transport of sphingolipids contribute to the formation of vacuole domains. To visualize sphingolipid trafficking, we employed the ceramide analogue BODIPY C12-ceramide (BODIPY-Cer), which is internalized by cells and stains the vacuole. We observed that cells lacking Vps29 and Vps30, proteins involved in endosomal sorting, show altered vacuole domains and accumulate BODIPY-Cer at sites proximal to the plasma membrane. Subsequent incorporation of endocytic-derived ceramide into the vacuole is dependent on the Niemann-Pick Type C 2 protein (Npc2). Loss of Npc2 reduces domain formation and causes BODIPY-Cer to accumulate within the vacuole lumen. Both intra-vacuole trafficking of BODIPY-Cer and membrane phase separation were not dependent on Npc2's canonical receptor, Ncr1. Lipidomics of isolated vacuoles confirmed that Npc2 independently mediates sphingolipid sorting under micro-lipophagy conditions. In liposome assays, yeast Npc2 - but not its human homologue - robustly transports an analogue of inositol phosphorylceramide, a complex sphingolipid that is enriched in phase-separated vacuoles. We propose that the enlarged binding cavity of yeast Npc2 is specialized for the incorporation of sphingolipids into the vacuole membrane to support its phase separation.
    DOI:  https://doi.org/10.1016/j.jbc.2026.111370
  11. Biophys J. 2026 Mar 13. pii: S0006-3495(26)00192-X. [Epub ahead of print]
    Effect of very long-chain lipids on the organization of biological membranes: A simulation study.
    Annemarie Quas, Clara Rickhoff, Roland Wedlich-Söldner, Andreas Heuer.
      Lipids in all biological membranes are distributed heterogeneously across the bilayer. A particularly striking example of this asymmetry is the yeast plasma membrane (PM), which exhibits a high concentration of very long-chain tail-asymmetric sphingolipids (SL) in its outer leaflet. Experimental observations indicate the existence of highly ordered gel-like PM domains that are enriched in SL but depleted of the major yeast sterol ergosterol. For a better mechanistic understanding of these unusual domains we have performed coarse-grained molecular dynamics simulations with membranes containing varying concentrations of very long-chain tail-asymmetric lipids. In agreement with experimental results we observed the formation of a gel phase, with a high order parameter of the acyl chains and hexagonal arrangement of lipid tails, at higher concentrations of these long-chain lipids. By systematically varying the lipid number asymmetry between the two leaflets, we demonstrate that the observed gel phase in asymmetric membranes is a robust feature and not an artifact of membrane construction. Our simulations also show that ergosterol is excluded from these gel regions and that, even when embedded into a liquid disordered phase, gels remain stable on the simulation time scale.
    DOI:  https://doi.org/10.1016/j.bpj.2026.03.020
  12. Nat Metab. 2026 Mar 18.
    Lysosomal phosphoinositide turnover acts upstream of RagGTPase-mTORC1 and controls muscle growth.
    Melanie Picot, Nesrine Hifdi, Mathilde Vaucourt, Melanie Mansat, Peng Li, Isabel Singer, Gaëtan Chicanne, Alexandre Stella, Shen Kuang, Caterina Miceli, Nathaniel F Henneman, Bernard Payrastre, Marie Vandromme, Odile Schiltz, Ivan Nemazanyy, Mariana E G de Araujo, Ganna Panasyuk, Julien Viaud, Michael Lämmerhofer, Karim Hnia.
      Lysosomes act as metabolic signalling hubs that integrate nutrient availability to coordinate anabolic and catabolic programmes. Mechanistic target of rapamycin complex 1 (mTORC1) is activated at the lysosomal surface by amino acids through RagGTPases recruited by the lysosomal adaptor and MAPK and mTOR activator complex, yet the contribution of lysosomal lipid composition to this pathway remains unclear. Here we identify lysosomal phosphoinositides, PI3P and PI(3,5)P2, as key regulators of lysosomal adaptor and MAPK and mTOR activator complex stability and dynamics at the lysosome. These lipid pools are controlled by the phosphoinositide 3-phosphatase MTM1, mutated in myotubular myopathy, via endoplasmic reticulum-lysosome membrane contact sites. Under endoplasmic reticulum stress, MTM1-dependent phosphoinositide remodelling suppresses RagGTPase-mTORC1 signalling, thereby regulating anabolic-catabolic balance during myogenic differentiation. Restoring mTORC1 activity or lysosomal phosphoinositide homeostasis rescues Rag-dependent signalling and muscle growth in cellular and mouse models of myopathy, uncovering a lysosome-centred metabolic checkpoint with direct disease relevance.
    DOI:  https://doi.org/10.1038/s42255-026-01484-1
  13. J Cachexia Sarcopenia Muscle. 2026 Apr;17(2): e70253
    Impaired Adipose Anabolism in Pancreatic Cancer Cachexia Is Reversed by HuR Inhibition.
    Paige C Arneson-Wissink, Katherine Pelz, Beth Worley, Heike Mendez, Peter Pham, Parham Diba, Peter R Levasseur, Grace McCarthy, Alex Chitsazan, Jonathan R Brody, Aaron J Grossberg.
       BACKGROUND: Cachexia is defined by chronic loss of fat and muscle, is a frequent complication of pancreatic ductal adenocarcinoma (PDAC) and negatively impacts patient outcomes. Nutritional supplementation cannot fully reverse tissue wasting, and the mechanisms underlying this phenotype are unclear. This work aims to define the relative contributions of catabolism and anabolism to adipose wasting in PDAC-bearing mice. Human antigen R (HuR) is an RNA-binding protein recently shown to suppress adipogenesis. We hypothesize that fat wasting results from a loss of adipose anabolism driven by increased HuR activity in adipocytes of PDAC-bearing mice.
    METHODS: Adult C57BL/6J mice received orthotopic PDAC cell (KrasG12D; p53R172H/+; Pdx1-cre) (PDAC) or PBS (sham) injections. Mice exhibiting moderate cachexia (9 days after injection) were fasted for 24 h, or fasted 24 h and refed 24 h before euthanasia. A separate cohort of PDAC mice were treated with an established HuR inhibitor (KH-3, 100 mg/kg) and subjected to the fast/refeed paradigm. We analysed body mass, gross fat pad mass and adipose tissue mRNA expression. We quantified lipolytic rate as the normalized quantity of glycerol released from 3T3-L1 adipocytes in vitro and gonadal fat pads (gWAT) ex vivo.
    RESULTS: 3T3-L1 adipocytes treated with PDAC cell conditioned media (CM) had lower expression of lipolysis and lipogenesis genes than control cells and did not display elevated lipolysis as measured by liberated glycerol. PDAC gWAT cultured ex vivo displayed decreased lipolysis compared to sham gWAT (-54.7%). PDAC and sham mice lost equivalent fat mass after a 24 h fast; however, PDAC mice could not restore inguinal fat pads (iWAT) (-40.5%) or gWAT (-31.8%) mass after refeeding. RNAseq revealed 572 differentially expressed genes in gWAT from PDAC compared to sham mice. Downregulated genes (n = 126) were associated with adipogenesis (adj p = 0.05), and expression of adipogenesis master regulators Pparg and Cebpa were reduced in gWAT from PDAC mice. Immunohistochemistry revealed increased HuR staining in gWAT (+74.9%) and iWAT (+41.2%) from PDAC mice. Inhibiting HuR binding restored lipogenesis in refed animals with a concomitant increase in iWAT mass (+131.7%).
    CONCLUSIONS: Our work highlights deficient adipose anabolism as a driver of reduced lipid content in 3T3-L1 adipocytes treated with PDAC conditioned media and PDAC mice. The small molecule KH-3, which disrupts HuR binding, restored adipose anabolism in PDAC mice. This highlights HuR as a potentially targetable regulatory node for adipose anabolism in cancer cachexia.
    Keywords:  HuR; adipogenesis; adipose; cachexia; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1002/jcsm.70253
  14. Cell Mol Biol Lett. 2026 Mar 20.
    Targeting dormant cancer cells: ferroptosis as a precision therapeutic strategy.
    Sijia Hao, Yulu Guo, Qiaozhen Huang, Lu Gan, Cheng Chen, Qiang Li, Cuixia Di, Jing Si.
      
    Keywords:  Autophagy; Cancer dormancy; Ferroptosis; Lipid metabolism; Oxidative stress; TGF-β signaling
    DOI:  https://doi.org/10.1186/s11658-026-00895-y
  15. Oncologist. 2026 Mar 17. pii: oyag091. [Epub ahead of print]
    Phase 2 Study of Azacitidine plus Pembrolizumab as Second-Line Treatment in Patients with Locally Advanced or Metastatic Pancreatic Ductal Adenocarcinoma.
    Rachael A Safyan, Ruth A White, Tamas A Gonda, Shing M Lee, Jiying Han, Nadine Kuriakose, Naomi K Yamamoto, Sita Kugel, Jacob K Jamison, Gulam A Manji, Gary J Schwartz, Paul E Oberstein, Susan E Bates.
       BACKGROUND: Epigenetic regulators represent a novel strategy to modulate the tumor immune microenvironment in pancreatic ductal adenocarcinoma (PDAC). In preclinical models, DNA hypomethylating agents enhance cytotoxic T-cell infiltration, synergize with PD-1 blockade, and improve survival when combined with immune checkpoint blockade. This single-institution, phase II study evaluated the safety, efficacy, and biomarkers of azacitidine plus pembrolizumab in patients with previously treated PDAC.
    METHODS: Patients with locally advanced or metastatic PDAC after one prior regimen received 50 mg/m2 subcutaneous azacitidine on days 1-5 of a 28-day cycle, starting week 1, and pembrolizumab 200 mg intravenously every 3 weeks starting week 3. Baseline and on-treatment blood and tumor was collected for exploratory biomarker analysis.
    RESULTS: Thirty-six patients enrolled between October 2017 and September 2021 (median age: 62.5 years); 34 were evaluable for safety; 31 for efficacy. Treatment was generally well-tolerated, with Grade 1-2 fatigue and diarrhea most common AEs. Three patients (9.7%) had a partial response, and the disease control rate was 35.5%. Median progression-free and overall survival was 1.51 and 4.83 months, respectively. Exploratory analysis suggested higher baseline CD8+ T cells and lower tumor Ki-67 was associated with response, whereas low baseline CD8+ T cell and Granzyme B infiltration correlated with higher exponential tumor growth rate. PD-L1 and CD68 expression were not predictive of benefit.
    CONCLUSION: Azacitidine plus pembrolizumab demonstrated limited clinical activity in second line, locally advanced or metastatic PDAC. Biomarker analysis suggests higher baseline CD8+ T-cell infiltration and lower proliferative index may identify patients more likely to benefit. (NCT03264404).
    Keywords:  Pancreatic cancer; azacitidine; pembrolizumab; tumor immune microenvironment
    DOI:  https://doi.org/10.1093/oncolo/oyag091
  16. Mol Cancer Ther. 2026 Mar 14.
    MRTX1133 suppresses ERK signaling but elicits context-dependent antiproliferative responses in KRAS (G12C) cancer cells.
    Abraham C Sianoya, Yan Zuo, Cynthia V Pagba, Jacob L Jakubec, Stephanie A Planque, Jeffrey A Frost, Paul Mark B Medina, Alemayehu A Gorfe.
      KRAS is a high-value therapeutic target for the treatment of cancer. Two covalent inhibitors, sotorasib and adagrasib, which target a specific codon 12 mutation (G12C), had received accelerated approvals for clinical use. Studies of these inhibitors ushered in the development of new inhibitors such as MRTX1133 that had entered clinical trials as a KRAS (G12D)-selective, non-covalent inhibitor. However, the subsequent failure of sotorasib as monotherapy and the recent termination of an early-phase clinical trial for MRTX1133 indicate that developing clinically effective allele-specific KRAS inhibitors remains a challenge, and that there is a need for further evaluation of KRAS inhibition mechanisms. Here, we show that the KRAS (G12D)-selective MRTX1133 also binds to G12C mutant KRAS with high affinity and suppresses nucleotide exchange and MAPK signaling in cancer cell lines harboring KRAS (G12C). However, its effect on the proliferation of KRAS (G12C) cancer cells is context-dependent; MRTX1133 robustly inhibits the proliferation of the pancreatic cancer cell line MIA PaCa-2 as well as the tumor growth of MIA PaCa-2 mouse xenografts but it has minimal effect in lung and colorectal cancer cells. This appears to be due to a lack of effect on downstream KRAS effectors such as the ribosomal protein S6, highlighting the need for strategies that take into account potential context-dependent processes. Together with other recent reports on high-affinity binding of MRTX1133 to other non-G12D KRAS mutants, our findings further reveal the usefulness of MRTX1133 as a chemical probe that continues to provide novel insights on KRAS biology and inhibition mechanisms.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-25-1087
  17. Cell Death Dis. 2026 Mar 20.
    FAK/SRC-JNK axis promotes ferroptosis via upregulating ACSL4 expression.
    Jianhua Qin, Shuang Ma, Junyang Wang, Siyuan Huang, Jing Luan, Jiyuan He, Guoyuan Hou, Na Sun, Wei Zhang, Minghui Gao.
      Ferroptosis, an iron-dependent form of programmed cell death driven by toxic lipid peroxide accumulation, plays a critical role in various diseases, making its modulation a promising therapeutic strategy. In this study, we identified defactinib, a specific inhibitor of FAK as a novel ferroptosis suppressors. We demonstrate that FAK/SRC-JNK signaling positively regulates ferroptosis by upregulating ACSL4, a critical mediator of ferroptosis. We reveal that a subset of JNK downstream transcription factors, including ATF2, NFATC1, NFATC3, and SMAD4, promote ferroptosis through direct binding to the ACSL4 promoter and activation of its expression. In contrast, another subset of JNK-associated transcription factors, including c-Jun, STAT3, ELK1, and HSF1, inhibit ferroptosis by binding to the ACSL4 promoter and repressing its expression. The net effect of FAK/SRC-JNK signaling in our models is a significant upregulation of ACSL4 and promotion of ferroptosis. Notably, elevated FAK/SRC-JNK signaling sensitizes cancer cells to ferroptosis-inducing therapies, while inhibition of the FAK/SRC-JNK signaling pathway protects against acute pancreatitis by suppressing ferroptosis. These findings highlight the central role of FAK/ SRC-JNK signaling in controlling ferroptotic cell death and underscore the therapeutic potential of targeting FAK/ SRC-JNK mediated ferroptosis, offering new avenues for the treatment of cancer and acute pancreatitis.
    DOI:  https://doi.org/10.1038/s41419-026-08570-y
  18. Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2506991123
    Lethal toxin-equipped effector cells for the potential treatment of cancer.
    Alexander H Pearlman, Brian J Mog, Michael S Hwang, Jordina Rincon-Torroella, Sarah R DiNapoli, Suman Paul, Jacqueline Douglass, Emily Han-Chung Hsiue, Stephanie A Glavaris, Drew M Pardoll, Nickolas Papadopoulos, Kenneth W Kinzler, Chetan Bettegowda, Shibin Zhou, Bert Vogelstein, Maximilian F Konig.
      Lethal toxins could become potent therapies against cancer, but their clinical utility is limited by adverse events upon systemic administration. These could be reduced if the toxins were delivered by effector cells that specifically infiltrate cancers, thereby releasing toxins locally into the tumor microenvironment. One of the challenges underlying this strategy is that cells delivering toxins would have to be resistant to them. We address this obstacle by showing that effectors derived from transformed human cell lines genetically engineered for resistance to bacterial adenosine diphosphate ribosylating toxins (ADPRTs), including Pseudomonas aeruginosa exotoxin A (PE), can produce targeted immunotoxins that specifically kill cancer cells expressing cognate tumor-associated antigens. Resistance to immunotoxins was achieved by knockout of genes in the diphthamide biosynthesis pathway (DPH1-4) required for the posttranslational modification of eukaryotic elongation factor 2 (EEF2) that is the target of ADPRTs or by mutation of EEF2 itself. We show that engineering resistance to ADPRTs, one of the most potent toxins acting on human cells, is essential to achieve robust function of armored effector cell lines. This work establishes a critical step on the path to equip effector cells with the ability to deliver powerful toxins to cancer cells and introduces a platform to investigate extension to primary autologous or allogeneic therapeutic cell types.
    Keywords:  cancer; cell engineering; immunotherapy; immunotoxin
    DOI:  https://doi.org/10.1073/pnas.2506991123
  19. Nat Methods. 2026 Mar 20.
    LazySlide: accessible and interoperable whole-slide image analysis.
    Yimin Zheng, Ernesto Abila, Eva Chrenková, Iva Buljan, Juliane Winkler, André F Rendeiro.
      Histopathological data are foundational in both biological research and clinical diagnostics but remain siloed from modern multimodal and single-cell frameworks. Here we introduce LazySlide, an open-source Python package built on the scverse ecosystem for efficient whole-slide image analysis and multimodal integration. By leveraging vision-language foundation models and adhering to scverse data standards, LazySlide bridges histopathology with omics workflows. It supports tissue and cell segmentation, feature extraction, cross-modal querying and zero-shot classification, with minimal setup.
    DOI:  https://doi.org/10.1038/s41592-026-03044-7
  20. Nat Metab. 2026 Mar 20.
    DGAT1 mediates sex-specific CD8+ T cell antitumour responses.
    Alaa Madi, Hui Shi, Min Su, Ahmed Mady, Boqiong Lv, Haiyan Wang, Bing Yang, Zhenni Yan, Xiaomeng Jin, Lingling Wu, Mengyue Lv, Marvin Hering, Sicong Ma, Alessa Mieg, Ferdinand Zettl, Xin Yan, Kerstin Mohr, Nora Knabe, Gernot Poschet, Karsten Richter, Nikolai Schleußner, Rene-Filip Jackstadt, Sonja Loges, F Nina Papavasiliou, Xi Wang, Jingxia Wu, Guoliang Cui.
      Fatty acid (FA) oxidation plays an important role in T cell responses. However, whether DGAT1-mediated FA esterification to triacylglycerol also regulates T cell function remains unclear. Here we uncover a sexually dimorphic requirement for DGAT1 expression in CD8+ tumour-infiltrating lymphocyte function. In female mice, T cell-specific Dgat1 deficiency improves mitochondrial metabolic fitness and expands the pool of progenitor exhausted CD8+ T (Tex) cells to sustain antitumour responses. In male mice, however, Dgat1 deficiency leads to FA peroxidation, endoplasmic reticulum (ER) stress and CD8+ Tex cell death. We show that these effects are mediated by androgen receptor (AR) signalling. Deletion of Ar, overexpression of glutathione peroxidase 4, or inhibition of ER stress-induced cell death rescues Dgat1-deficient CD8+ T cell survival and promotes antitumour responses in male mice. Overall, this study suggests that DGAT1 detoxifies AR signalling in male mice to protect against ER stress-induced cell death and maintain T cell stemness, and uncovers sex-specific metabolic adaptations in the tumour microenvironment.
    DOI:  https://doi.org/10.1038/s42255-026-01462-7
  21. J Clin Invest. 2026 Mar 19. pii: e196622. [Epub ahead of print]
    CXCR2 blockade overcomes the NETosis-mediated resistance to MEK inhibition in pancreatic cancer models.
    Brian Herbst, Alex B Blair, Yiming Li, Elizabeth M Jaffee, Lei Zheng.
      Single-agent anti-PD-1 antibody is ineffective for pancreatic ductal adenocarcinoma (PDAC) due to its immunosuppressive tumor-microenvironment (TME). KRAS-mutations contribute to the inflammatory TME and therapeutic resistance by upregulating IL-8 via MAPK pathways. Thus, this study attempted to overcome the resistance to anti-PD-1 antibody by targeting downstream KRAS-effectors. The study found that the resistance to anti-PD-1 antibody can be overcome through MEK1/2-inhibition. The combination of anti-PD-1 antibody and MEK inhibitor displayed antitumor activity in Krasmut (mutated) KPC mouse tumors, but not KrasWT (wild-type) Panc02 tumors. The combination of anti-PD-1 antibody and MEK inhibitor induced recruitment of tumor-associated neutrophils (TANs) via CXCR2, an IL-8 receptor, and increased memory CD8+ T cells and IFNgamma production in treatment-sensitive tumors. However, larger tumors still resisted to the combination of anti-PD-1 antibody and MEK inhibitor likely due to hypoxia/necrosis-induced NETosis and associated paucity of CD8+ T cells. The subsequent addition of anti-CXCR2 antibody overcame this resistance by blocking TAN-infiltration to hypoxic/necrotic areas. Consistently, a risk-score based on the NETosis-MAPK signaling interaction is significantly associated with poorer survival in human PDACs. This study thus provides a new venue for overcoming resistance to strategies targeting KRAS signaling.
    Keywords:  Cancer; Cancer immunotherapy; Drug therapy; Immunology; Oncology
    DOI:  https://doi.org/10.1172/JCI196622
  22. Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2525239123
    Three-dimensional high-content imaging of unstained soft tissue with subcellular resolution using a laboratory-based X-ray microscope.
    Michela Esposito, Alberto Astolfo, Yang Zhou, Ian Buchanan, Alexei Teplov, John Ciaran Hutchinson, Marco Endrizzi, Alexandra Egido Vinogradova, Olga Makarova, Ralu Divan, Cha-Mei Tang, Yukako Yagi, Peter D Lee, Claire L Walsh, Joseph D Ferrara, Alessandro Olivo.
      With increasing interest in studying biological systems across spatial scales-from centimeters down to nanometers-histology continues to be the gold standard for tissue imaging at cellular resolution, providing an essential bridge between macroscopic and nanoscopic analysis. However, its inherently destructive and two-dimensional nature limits its ability to capture the full three-dimensional complexity of tissue architecture. Here, we show that phase-contrast X-ray microscopy can enable three-dimensional virtual histology with subcellular resolution. This technique provides direct quantification of electron density without restrictive assumptions, allowing for direct characterization of cellular nuclei in a standard laboratory setting. By combining high spatial resolution and soft tissue contrast, with automated segmentation of cell nuclei, we demonstrated virtual Hematoxylin and Eosin (H&E) staining using machine learning-based style transfer, yielding volumetric datasets compatible with existing histopathological analysis tools. Furthermore, by integrating electron density and the sensitivity to nanometric features of the dark field contrast channel, we achieve stain-free, high-content imaging capable of distinguishing nuclei and extracellular matrix.
    Keywords:  3D virtual histology; X-ray dark field imaging; X-ray microscopy; X-ray phase contrast CT; cell imaging
    DOI:  https://doi.org/10.1073/pnas.2525239123
  23. Cell Death Dis. 2026 Mar 20.
    Adipogenic transdifferentiation reprograms EMT-high PDAC cells into a post-mitotic adipocyte-like state and limits metastasis.
    Yunzhen Qian, Zhixiu Yan, Junjie Wang, Qi An, Jiamei Luo, Musitaba Mutailifu, Aziguli Tulamaiti, Xue-Li Zhang, Zhi-Gang Zhang, Dong-Xue Li.
      Pancreatic ductal adenocarcinoma (PDAC) is a notoriously lethal malignancy with high epithelial-mesenchymal transition (EMT) baseline. EMT is associated with enhanced cell plasticity and contributes to tumor adaption and evolution. EMT programs fuel PDAC invasion, metastasis, and treatment resistance, but directly targeting EMT has yielded limited clinical benefits. Transdifferentiation therapy that exploits cell plasticity and redirects malignant cell fate offers an orthogonal approach beyond pathway inhibition. To validate the feasibility of transdifferentiation in epithelial malignancies such as PDAC, we applied an adipogenesis protocol in seven human PDAC cell lines and distinguished AsPC-1 with intensified adipocyte features (intracellular lipid droplets accumulation, elevated adiponectin, CEBPA, PPARG, FABP4 expression). AsPC-1 was converted into adipocyte-like, post-mitotic cells with lipometabolic (enhanced adiponectin secretion and lipolysis) and phenotypic reprogramming (proliferation inhibition, G1 cell cycle arrest, and EMT key transcription factors downregulation). Multi-omics showed global chromatin compaction and transcriptome-wide repression of EMT and metastatic programs in induced AsPC-1 cells, with suppressed MMPs and TGF-β, indicating diminished metastatic potential. Therefore, we further evaluated the possibility of clinical translation by murine orthotopic and hepatic metastasis models, finding adipogenesis induction reduced primary tumor burden and slowed metastatic progression. The adipocyte-like phenotype in vivo was sustained through one-month observation period following induction drug withdrawal. This study establishes a plasticity-oriented "convert-instead-of-kill" strategy for EMT-high PDAC, suggesting a potential for future studies to investigate rational combinations (e.g., transdifferentiation therapy combined with targeted or immunotherapy) to exploit lineage conversion.
    DOI:  https://doi.org/10.1038/s41419-026-08613-4
  24. Ferroptosis Oxid Stress. 2026 ;pii: 202512. [Epub ahead of print]2(2):
    Fundamental mechanism of ferroptosis: Three unanswered questions.
    Hanna Feinsod, Brent R Stockwell.
      Ferroptosis, an iron-dependent form of regulated cell death (RCD) driven by lipid peroxidation, has been extensively studied since its conceptualization in 2012 and has been suggested as a therapeutic target in many cancers and degenerative diseases. However, three fundamental questions remain unanswered about ferroptosis. First, the mechanisms by which cells execute death during ferroptosis remain elusive: The key role of lipid peroxides in triggering ferroptosis is established, but how this results in the death of a cell remains unclear. Second, the physiological role of ferroptosis throughout the human life cycle is unclear; currently, there is evidence for ferroptosis in early development, immunity, aging, and tumor suppression, but not in many other aspects of physiology. Third, and finally, the intersection between ferroptosis and other RCD modalities, such as apoptosis, necroptosis, pyroptosis, and autophagic cell death, is necessary for understanding how ferroptosis integrates into networks controlling cellular fate. Addressing these gaps in knowledge is essential for building a comprehensive understanding of this mode of cell death, as well as translating ferroptosis knowledge into effective therapeutics.
    Keywords:  Ferroptosis; ROS; iron; lipid; metabolism; peroxidation
    DOI:  https://doi.org/10.70401/fos.2026.0015
  25. Nature. 2026 Mar 18.
    Proteasome-guided haem signalling axis contributes to T cell exhaustion.
    Yingxi Xu, Yangtao Shangguan, Yu-Ming Chuang, Tzu-Hsuan Chang, Wenbing Liu, Jhan-Jie Peng, Josep Garnica, Leling Xie, Pei-Chun Hsueh, Mei-Chun Lin, Yi-Hao Wang, Karina Lobo Hajdu, Yibo Wu, Maryam Akrami, Chen Wang, Anna Kohl, Alfred Zippelius, Wei Qi, Min Wang, Bugi Ratno Budiarto, Shih-Yu Chen, Zhengtao Xiao, Panagiota Vardaka, Rahul Roychoudhuri, Zhiliang Bai, Rong Fan, Santiago Carmona, Yi-Ru Yu, Christoph Scheiermann, Jianxiang Wang, Ping-Chih Ho.
      The accumulation of depolarized mitochondria commits T cells to exhaustion1-3, yet the precise mechanism remains unclear. Here we find that exhausted CD8+ T cells increase proteasome activity owing to the accumulation of depolarized mitochondria, which drives the selective degradation of mitochondrial proteins and the release of regulatory haem through haemoprotein breakdown. In turn, increased regulatory haem disrupts BACH2-mediated transcriptional regulation, thereby exacerbating T cell exhaustion and compromising stemness-like properties. Inhibition of nuclear import of regulatory haem prevents BACH2 degradation and enhances the anti-tumour efficacy of antigen-specific T cells. We find that the therapeutic efficacy of human CD19+ chimeric antigen receptor (CAR)-T cells in patients with B cell acute lymphoblastic leukaemia negatively correlates with the proteasome gene signature in their CAR-T cells. Manufacturing CAR-T cells in the presence of bortezomib, an FDA-approved proteasome inhibitor, prevents T cell exhaustion and improves therapeutic efficacy. Our findings identify a proteasome-guided haem signalling axis, governed by mitochondrial integrity, as a regulator of CD8+ T cell exhaustion and propose innovative therapeutic strategies that exploit this pathway to optimize adoptive cellular immunotherapy.
    DOI:  https://doi.org/10.1038/s41586-026-10250-y
  26. Protein Sci. 2026 Apr;35(4): e70540
    MolViewStories: Interactive molecular storytelling.
    Terézia Slanináková, Zachary Charlop-Powers, Viktoriia Doshchenko, Alexander S Rose, Adam Midlik, Anna Sekuła, Neli Fonseca, Kyle L Morris, Stephen K Burley, Sameer Velankar, Jennifer Fleming, Brinda Vallat, Ludovic Autin, David Sehnal.
      Effectively communicating knowledge related to molecular structures and their associated data remains a challenge, as traditional static figures limit interactivity and professional visualization tools often require substantial expertise. MolViewStories addresses these limitations by providing an open-source, web-based platform for creating and sharing interactive, narrative-driven molecular visualizations. The platform uses the MolViewSpec standard for reproducible scene specification, extended to support animations, interactive descriptions, and synchronized audio commentary. Visualization is powered by the Mol* Viewer, which leverages Web Graphics Library (WebGL) for efficient 3D rendering and WebXR for immersive virtual and augmented reality experiences. Users can construct molecular narratives through an intuitive graphical interface or a command-line workflow, enabling both exploratory and automated use. Completed stories can be shared online, exported locally, or distributed as self-contained packages that remain functional indefinitely. Each story is assigned a persistent uniform resource locator (URL) and can be modified or reused as a template, promoting collaboration and community-driven content creation. We demonstrate the capabilities of MolViewStories through a diverse set of narratives illustrating its broad applicability to research communication, education, and public outreach. Together, these examples highlight how interactive, web-based storytelling can make molecular data more accessible, reproducible, and engaging. MolViewStories is freely available at https://molstar.org/mol-view-stories with open-source code accessible at https://github.com/molstar/mol-view-stories.
    Keywords:  Mol* Viewer; MolViewSpec; PDB; interactive molecular visualization; molecular storytelling; open‐source software; reproducible visualization; structural biology; web‐based tools
    DOI:  https://doi.org/10.1002/pro.70540
  27. Cancer Lett. 2026 Mar 14. pii: S0304-3835(26)00194-1. [Epub ahead of print] 218431
    Autophagy is essential for survival and function of polyploid giant cancer cells under therapeutic stress.
    D Ghosh, B White, X Lu, M Perricone, M Zhou, B Xuan, Y Li, Y Wang, M R Dawson.
      Polyploid giant cancer cells (PGCCs) are enlarged, multinucleated tumor cells that arise in response to stressors such as chemotherapy and are increasingly recognized as key drivers of recurrence and metastasis in aggressive cancers. Found in triple-negative breast cancer (TNBC) and ovarian cancer (OC), PGCCs can survive cytotoxic therapy in a dormant state and later produce chemoresistant progeny through amitotic budding. Here, we investigated the role of autophagy in paclitaxel (PTX)-induced PGCC survival, nuclear maintenance, and migration. PGCCs generated from MDA-MB-231 and HEY cells were significantly larger, more heterogeneous, and more resistant to PTX than parent cells. Transcriptomic profiling revealed enrichment of metabolic and cytoskeletal pathways, with strong upregulation of autophagy-related genes, including SQSTM1 (P62), LC3, and LAMP1. PGCCs exhibited elevated oxidative stress and marked induction of mitochondrial superoxide dismutase 2 (SOD2). p62 was localized near micronuclei, and prolonged autophagy inhibition with Bafilomycin A1 reduced nuclear size, heterogeneity, and micronuclei number. PGCCs also displayed a dispersed vimentin intermediate filament network that scaffolded autophagic structures; autophagy inhibition impaired migration in PGCC-derived daughter cells. These findings identify autophagy as a critical process sustaining PGCC survival, structural integrity, and motility, and suggest that targeting autophagy may disrupt PGCC-driven recurrence in aggressive cancers.
    Keywords:  Autophagy; Daughter cells; Micronuclei; PGCC; Paclitaxel; Vimentin; p62
    DOI:  https://doi.org/10.1016/j.canlet.2026.218431
  28. Proc Natl Acad Sci U S A. 2026 Apr 07. 123(14): e2531134123
    What is quantum biology?
    Gregory D Scholes, Graham R Fleming.
      Quantum biology is the field at the intersection of quantum-related physics and the biology of living systems. The goal of the field is to determine if quantum phenomena underpin biological function at the macroscale. Such results, supported by compelling experimental evidence, will be important because they will show how quantum effects can have functional relevance, even in very complex and nominally classical systems. Here, we attempt to define the scope of quantum biology with a forward-facing view to help focus the research agenda. To that end, we propose open questions fundamental to consolidating the field of quantum biology. These open questions highlight the importance of developing suitable probes at the quantum scale, the possibility that classical biological machinery might simply mimic quantum systems, and of elucidating the ways quantum function can be amplified to the macroscale.
    Keywords:  coherence; quantum biology; quantum mimics; quantum probes
    DOI:  https://doi.org/10.1073/pnas.2531134123
  29. EMBO J. 2026 Mar 20.
    Targeting ubiquitin signaling vulnerabilities in KEAP1-inactivated lung cancer.
    Varun Jayeshkumar Shah, Oliver Hartmann, Martin Wegner, Cristian Prieto-Garcia, Rubina Kazi, Viktoria von Heyl Zu Herrnsheim, Amin Wanli, Igor Mačinković, Bianka Bohnacker, Koraljka Husnjak, Dmitry Namgaladze, Mathias Rosenfeldt, Manuel Kaulich, Markus E Diefenbacher, Ivan Dikic.
      Lung cancer cells rely on protein homeostasis regulators, particularly the ubiquitin-proteasome system (UPS), to sustain malignancy. Genetic alterations in UPS components, such as E3 ubiquitin ligases (E3s) and deubiquitinating enzymes (DUBs), are common and create context-dependent therapeutic dependencies. To investigate how these genetic alterations drive tumor formation, we conducted CRISPR screens on metabolically stressed murine lung cancer models and identified specific cancer dependencies, including ubiquitin ligase subunit KEAP1. Although KEAP1 is frequently mutated in aggressive non-small cell lung cancers (NSCLC, ~15%), our findings reveal an unexpected proto-oncogenic role for KEAP1 in a genetically defined subset of NSCLC. Mechanistically, Keap1 deletion activated Nrf2 and upregulated Aldh3a1. This led to elevated reductive stress and suppressed tumor growth. Given the poor prognosis of KEAP1-mutated patients, combinatorial CRISPR dropout screens revealed druggable E3s and DUBs as Keap1-dependent co-vulnerabilities. Notably, depleting these co-dependencies, such as the E3 ligases Herc2, Ubr4 and Huwe1 ablated the in vivo development of Keap1-inactivated tumors. We demonstrate that targeting the UPS represents an underexplored, promising therapeutic approach for patients with KEAP1-inactivated tumors, especially under metabolic stress.
    Keywords:  CRISPR/Cas9; Keap1; NSCLC; Reductive Stress; Ubiquitin-Proteasome System
    DOI:  https://doi.org/10.1038/s44318-026-00737-9
  30. Trends Cancer. 2026 Mar 16. pii: S2405-8033(26)00004-X. [Epub ahead of print]
    Cancer in 4D: toward Spatiotemporal Hallmark Ecosystems.
    Mustafa Sibai, Martin Zacharias, Nicholas McGranahan, Mariam Jamal-Hanjani, Eduard Porta-Pardo.
      The Hallmarks of Cancer framework provided a unifying description of tumor capabilities, but in its static form, it cannot capture where in a tumor these traits occur, when they arise, or how they reorganize under selection pressure. Here, we propose Spatiotemporal Hallmark Ecosystems as a new lens that redefines the functional unit of selection in cancer evolution. In this view, hallmarks are not fixed consequences of mutations but context-dependent phenotypes that are enabled or constrained by local tissue and microenvironmental conditions. This perspective resolves critical paradoxes, explaining why identical mutations yield divergent outcomes, why premalignant states persist without transformation, and how therapeutic resistance emerges not just from clonal selection but also from 'ecological buffering' by the tumor architecture. By shifting the analysis from the individual cell to the ecosystem, we outline a path toward predictive biomarkers and spatially aware strategies that target the structural stability of the tumor.
    DOI:  https://doi.org/10.1016/j.trecan.2026.01.004
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