bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2025–06–29
thirty-one papers selected by
Kıvanç Görgülü, Technical University of Munich



  1. J Hepatol. 2025 Jun 19. pii: S0168-8278(25)02273-1. [Epub ahead of print]
       BACKGROUND & AIMS: Mucosal-associated invariant T (MAIT) cells constitute a highly abundant innate-like T cell population in the human liver that is critical for immune surveillance of hepatic cancers but often dysfunctional in human hepatocellular carcinoma (HCC) for unclear reasons. Here, we sought to determine mechanisms that drive MAIT cells dysfunction in metabolic dysfunction-associated steatotic liver disease (MASLD), a chronic liver disease predisposing patients for HCC development.
    METHODS: We studied MAIT cell functionality, metabolism and anti-cancer activity directly ex vivo in patients with MASLD, as well as in co-culture models mimicking MASLD. (Single-cell) RNA sequencing was used for translation into clinical cohorts of patients with MASLD and MASLD-associated HCC.
    RESULTS: We show that MAIT cells have lost their effector functions in patients with MASLD. We uncover that MAIT cell dysfunction is caused by MASLD-associated polyunsaturated fatty acids (PUFAs), which selectively accumulate in MAIT cells but not conventional CD8+ T cells or NK cells. Mechanistically, PUFAs drive MAIT cell dysfunction through intracellular formation of lipid peroxides that promote a state of 'metabolic exhaustion' characterised by compromised mitochondrial respiration and glycolysis in MAIT cells. Excessive signalling through this MASLD-PUFA-lipid peroxide axis results in MAIT cell death by ferroptosis. Interference with PUFA-induced lipid peroxide formation in MAIT cells reversed their metabolic exhaustion and prevented ferroptotic MAIT cell death, thereby restoring MAIT cell effector function and anti-cancer activity. In patients with HCC, high enrichment of the MAIT cell-PUFA gene signature linked to MAIT cell dysfunction was associated with poor survival.
    CONCLUSIONS: Our findings uncover a novel immunometabolic axis that serves as a functional barrier for MAIT cell-mediated anti-cancer immunity and could be exploited for enhancement of immunotherapy. IMPACT AND IMPLICATIONS: ; This study identifies a novel immunometabolic axis by which polyunsaturated fatty acids (PUFAs) accumulating in MASLD liver tissue drive MAIT cell dysfunction through lipid peroxide-induced metabolic exhaustion and ferroptosis, thereby impairing their anti-tumour activity. These findings reveal how MASLD creates an immune-permissive environment that may facilitate HCC development and -progression. Targeting the PUFA-lipid peroxide axis could restore MAIT cell function and enhance current immunotherapeutic anti-cancer strategies.
    Keywords:  HCC; MAIT cells; MASLD; ferroptosis; immunometabolism; lipid peroxidation
    DOI:  https://doi.org/10.1016/j.jhep.2025.06.006
  2. Nature. 2025 Jun 25.
      
    Keywords:  Cancer; Cell biology; Metabolism; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-01941-z
  3. Nat Metab. 2025 Jun 27.
      Genetic and dietary cues are known drivers of obesity, yet how they converge at the molecular level is incompletely understood. Here we show that PPARγ supports hypertrophic expansion of adipose tissue via transcriptional control of LPCAT3, an endoplasmic reticulum (ER)-resident O-acyltransferase that selectively enriches diet-derived omega-6 polyunsaturated fatty acids (n-6 PUFAs) in the membrane lipidome. In mice fed a high-fat diet, lowering membrane n-6 PUFA levels through genetic or dietary interventions results in aberrant adipose triglyceride (TG) turnover, ectopic fat deposition and insulin resistance. Additionally, we detail a non-canonical adaptive response in 'lipodystrophic' Lpcat3-/- adipose tissues that engages a futile lipid cycle to increase metabolic rate and offset lipid overflow to ectopic sites. Live-cell imaging, lipidomics and molecular dynamics simulations reveal that adipocyte LPCAT3 activity enriches n-6 arachidonate in the phosphatidylethanolamine (PE)-dense ER-lipid droplet interface. Functionally, this localized PE remodelling optimizes TG storage by driving the formation of large droplets that exhibit greater resistance to adipose TG lipase activity. These findings highlight the PPARγ-LPCAT3 axis as a mechanistic link between dietary n-6 PUFA intake, adipose expandability and systemic energy balance.
    DOI:  https://doi.org/10.1038/s42255-025-01320-y
  4. Biophys J. 2025 Jun 23. pii: S0006-3495(25)00386-8. [Epub ahead of print]
      Plasma membranes (PMs) exhibit asymmetry between their two leaflets in terms of phospholipid headgroups, unsaturation, and resulting membrane properties such as packing and fluidity. Lateral heterogeneity, including the formation of lipid domains, is another crucial aspect of PMs with significant biological implications. However, the nature and even the existence of lipid domains in the two leaflets of PMs remain elusive, hindering a complete understanding of the significance of lipid asymmetry. Using coarse-grained molecular dynamics simulation of the asymmetric PM, we find that the outer leaflet lipids are highly ordered and largely uniformly distributed, whereas the inner leaflet separates into nanoscale (≈10 nm) highly ordered and more disordered domains, exhibiting highly dynamic domain fusion and fission events. This structural asymmetry is further reinforced by asymmetric lateral stress resulting from a cholesterol bias toward the outer leaflet. These findings suggest distinct functional roles for the two leaflets, modulated by asymmetric lateral stress. Additionally, comparing the phase behavior of asymmetric and fully scrambled PMs reveals a key determinant of domain size: intact PMs maintain nanoscale domains, while cell-derived giant PM vesicles, which have lost the strict lipid asymmetry, exhibit microscale domains.
    Keywords:  Coarse-grained molecular simulation; Lipid asymmetry; Lipid domains; Plasma membrane
    DOI:  https://doi.org/10.1016/j.bpj.2025.06.026
  5. Nature. 2025 Jun 25.
      The nervous system has a pivotal role in cancer biology, and pathological investigations have linked intratumoural nerve density to metastasis1. However, the precise impact of cancer-associated neurons and the communication channels at the nerve-cancer interface remain poorly understood. Previous cancer denervation models in rodents and humans have highlighted robust cancer dependency on nerves, but the underlying mechanisms that drive nerve-mediated cancer aggressivity remain unknown2,3. Here we show that cancer-associated neurons enhance cancer metabolic plasticity by transferring mitochondria to cancer cells. Breast cancer denervation and nerve-cancer coculture models confirmed that neurons significantly improve tumour energetics. Neurons cocultured with cancer cells undergo metabolic reprogramming, resulting in increased mitochondrial mass and subsequent transfer of mitochondria to adjacent cancer cells. To precisely track the fate of recipient cells, we developed MitoTRACER, a reporter of cell-to-cell mitochondrial transfer that permanently labels recipient cancer cells and their progeny. Lineage tracing and fate mapping of cancer cells acquiring neuronal mitochondria in primary tumours revealed their selective enrichment at metastatic sites following dissemination. Collectively, our data highlight the enhanced metastatic capabilities of cancer cells that receive mitochondria from neurons in primary tumours, shedding new light on how the nervous system supports cancer metabolism and metastatic dissemination.
    DOI:  https://doi.org/10.1038/s41586-025-09176-8
  6. bioRxiv. 2025 Apr 26. pii: 2025.04.23.650241. [Epub ahead of print]
      Branched-chain amino acid (BCAA) catabolism contributes prominently to the TCA cycle in the healthy pancreas but is suppressed in pancreatic ductal adenocarcinoma (PDA). The impact of this metabolic remodeling on cancer phenotypes remains poorly understood. Here, we find that the BCAA isoleucine is a primary source of propionyl-CoA in PDA cells. Reduction of propionyl-CoA availability by either genetic perturbation or isoleucine and valine starvation decreases histone propionylation (Kpr) without impacting histone acetylation on specific lysine sites, correlating with reduced transcription of certain lipid- and immune-related genes. Mechanistically, we find that multiple enzymes of isoleucine catabolism unexpectedly localize to and carry out multi-step isoleucine oxidation within the nuclei of PDA cells. Importantly, nuclear localization of the rate-limiting branched-chain alpha ketoacid dehydrogenase (BCKDH) complex is essential for isoleucine-dependent Kpr and gene regulation. Moreover, we demonstrate that isoleucine-sensitive Kpr and its associated gene expression are driven by the MYST family of lysine acyltransferases (KATs), and that the BCKDHA subunit of the BCKDH complex interacts with KAT7 within the nuclear compartment. BCAA catabolism enzymes are apparent in the nuclei of PanIN lesions in mice and PDA tumors in patients, contrasting that in healthy pancreatic acinar and ductal cells. Collectively, these findings unveil a nuclear isoleucine catabolism pathway and highlight its role in controlling histone Kpr and tumorigenic transcriptional programs in PDA.
    DOI:  https://doi.org/10.1101/2025.04.23.650241
  7. Nature. 2025 Jun 25.
      The endosomal sorting complex required for transport (ESCRT) is a multicomplex machinery comprising proteins that are conserved from bacteria to humans and has diverse roles in regulating the dynamics of cellular membranes. ESCRT functions have far-reaching consequences for cell biological processes such as intracellular traffic, membrane repair, cell signalling, metabolic regulation, cell division and genome maintenance. Here we review recent insights that emphasize the pathophysiological consequences of ESCRT dysfunctions, including infections, immune disorders, cancers and neurological diseases. We highlight the possibilities of using our knowledge about ESCRT structures and functions for drug discovery.
    DOI:  https://doi.org/10.1038/s41586-025-08950-y
  8. JCI Insight. 2025 Jun 26. pii: e191595. [Epub ahead of print]
      Pancreatic ductal adenocarcinoma (PDAC) has a poor survival rate due to late detection. PDAC arises from precursor microscopic lesions, termed pancreatic intraepithelial neoplasia (PanIN), that develop at least a decade before overt disease--this provides an opportunity to intercept PanIN-to-PDAC progression. However, immune interception strategies require full understanding of PanIN and PDAC cellular architecture. Surgical specimens containing PanIN and PDAC lesions from a unique cohort of five treatment-naïve patients with PDAC were surveyed using spatial-omics (proteomic and transcriptomic). Findings were corroborated by spatial proteomics of PanIN and PDAC from tamoxifen-inducible KPC (tiKPC) mice. We uncovered the organization of lymphoid cells into tertiary lymphoid structures (TLSs) adjacent to PanIN lesions. These TLSs lacked CD21+CD23+ B cells compared to more mature TLSs near the PDAC border. PanINs harbored mostly CD4+ T cells with fewer Tregs and exhausted T cells than PDAC. Peri-tumoral space was enriched with naïve CD4+ and central memory T cells. These observations highlight the opportunity to modulate the immune microenvironment in PanINs before immune exclusion and immunosuppression emerge during progression into PDAC.
    Keywords:  Adaptive immunity; Cancer immunotherapy; Gastric cancer; Immunology; Inflammation; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.191595
  9. Oncotarget. 2025 Jun 25. 16 532-544
      Ferroptosis is a mode of cell death that relies on iron metabolism and lipid peroxidation. Preclinical and clinical studies indicate that ferroptosis suppresses tumor growth, and dysregulation of ferroptosis promotes treatment resistance in cancer. Hypoxia is a universal feature of solid tumors that is particularly relevant to prostate cancer (PCa), which arises in the hypoxic peripheral zone of the organ. Hypoxia has been implicated in resistance to ferroptosis and other forms of cell death, but how hypoxia impacts the sensitivity of PCa to ferroptosis inducing agents (FINs) has not been well studied. Here, we show that hypoxia dramatically reduces the sensitivity of PCa cell lines to mechanistically distinct FINs, Erastin (xCT inhibitor) and RLS3 (GPX4 inhibitor) by inducing lipid droplet (LD) accumulation. Transcriptomic analysis revealed that hypoxia significantly reduced the expression of genes related to incorporating polyunsaturated fatty acids into phospholipids (ACSL4, LPCAT3), and parallel lipidomic analysis demonstrated that hypoxia significantly decreased the levels of the ferroptosis-prone lipid class, phosphatidylethanolamine (PE) and increased production of neutral lipid species, cholesteryl ester (ChE (22:5)) and triglycerides (TG(48:1), TG:(50:4), and TG(58:4)). Targeting LD biogenesis and de novo lipogenesis did not alter sensitivity to RSL3 under hypoxia. These findings suggest that hypoxia promotes ferroptosis resistance in PCa by altering lipid metabolism at the transcriptional level, by producing lipids that are less susceptible to peroxidation, and at the cellular level, by increasing storage in LDs. Thus, manipulating LD dynamics represents a promising strategy to overcome hypoxia-induced resistance to ferroptosis and improve the success of PCa treatment.
    Keywords:  ferroptosis; hypoxia; lipid droplets; prostate; resistance
    DOI:  https://doi.org/10.18632/oncotarget.28750
  10. bioRxiv. 2025 Jan 05. pii: 2025.01.05.631358. [Epub ahead of print]
      Sterols are among the most abundant lipids in eukaryotic cells, yet are synthesized through notoriously long metabolic pathways. It has been proposed that the molecular evolution of such pathways must have required each step to increase the capacity of its product to condense and order phospholipids. Here we carry out a systematic analysis of the ergosterol pathway that leverages the yeast vacuole's capacity to phase-separate as a predictive biophysical readout for each intermediate. In the post-synthetic steps specific to ergosterol biosynthesis, we find that successive modifications act to oscillate ordering capacity, settling on a level that supports phase separation while retaining fluidity of the resulting domains. Simulations carried out with each intermediate showed how conformers in the sterol's alkyl tail are capable of modulating long-range ordering of phospholipids, which could underlie changes in phase behavior. Our results indicate that the complexity of sterol metabolism could have resulted from the need to balance lipid interactions required for membrane organization.
    DOI:  https://doi.org/10.1101/2025.01.05.631358
  11. Sci Adv. 2025 Jun 27. 11(26): eads6132
      Mechanotransduction is essential for living cells to adapt to their extracellular environment. However, it is unclear how the biophysical adaptation of intracellular organelles responds to mechanical stress or how these adaptive changes affect cellular homeostasis. Here, using the tendon cell as a mechanosensitive cell type within a bioreactor, we show that the tension of the plasma membrane (PM) and the endoplasmic reticulum (ER) adaptively increases in response to repetitive external stimuli. Depletion of stromal interaction molecule 1 (STIM1), the highest expressed PM-ER tether protein, interfered with mechanotransduction from the PM to the ER, and affected the ER tension. We found that an optimized mechanical strain increased ER tension in a homeostatic manner, but excessive strain resulted in ER expansion, as well as activating ER stress. Last, we showed that changes in ER tension were linked with ER-mitochondria interactions and associated with cellular energetics and function. Together, these findings identify a PM-ER mechanotransduction mechanism that dose-dependently regulates cellular metabolism.
    DOI:  https://doi.org/10.1126/sciadv.ads6132
  12. Nat Cell Biol. 2025 Jun 27.
      Lipid transport proteins (LTPs) facilitate non-vesicular lipid exchange between cellular compartments and have critical roles in lipid homeostasis. A recently identified family of bridge-like LTPs (BLTPs) is thought to form lipid-transporting conduits between organelles. One of these, BLTP2, is conserved across species but its function is not known. Here we show that BLTP2 regulates plasma membrane (PM) fluidity by increasing phosphatidylethanolamine (PE) levels in the PM. BLTP2 localizes to endoplasmic reticulum (ER)-PM contact sites, and transports PE in vivo, suggesting it drives PE movement from ER to PM. We find that BLTP2 works in parallel with another pathway that regulates intracellular PE distribution and PM fluidity. BLTP2 expression correlates with breast cancer aggressiveness. We found that BLTP2 facilitates growth of a triple negative breast cancer cell line and sustains its aggressiveness in an in vivo model of metastasis, suggesting maintenance of PM fluidity by BLTP2 may be critical for tumorigenesis in humans.
    DOI:  https://doi.org/10.1038/s41556-025-01672-3
  13. Adv Sci (Weinh). 2025 Jun 26. e04470
      Understanding the mechanisms underlying Kirsten rat sarcoma (KRAS) mutation-driven development and progression of pancreatic ductal adenocarcinoma (PDAC) may facilitate the discovery of novel strategies for KRAS-mutant PDAC (KRASmut-PDAC) treatment. Here, it is reported that downregulation of arachidonate 15-lipoxygenase (ALOX15B) significantly correlated with poor outcomes in patients with KRASmut-PDAC. Mechanistically, KRASmut/ERK1-elicited phosphorylation of ABHD17C promotes depalmitoylation and membrane-to-cytoplasm translocation of ALOX15B, facilitating proteasome-dependent degradation of ALOX15B via interaction with the E3 ligase complex CUL4/DDB1/DCAF10. Notably, treatment with methyl protodioscin (MPD), a steroid saponin primarily purified from polygonatum sibiricum rhizome, restored the S-palmitoylation and membrane location of ALOX15B via disruption of the ABHD17C/ALOX15B interaction, consequently resulting in significant inhibition of growth rate of patient-derived KRASmut-PDAC organoids in vitro and KRASmut-PDAC-formed tumor in vivo via induction of ferroptosis. Therefore, these findings unveil a prominent role of ferroptosis evasion in KRASmut-PDAC progression and highlight the potential of targeting KRAS/ERK1/ABHD17C/ALOX15B axis in KRASmut-PDAC treatment.
    Keywords:  ABHD17C; ALOX15B; KRAS mutation; ferroptosis; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1002/advs.202504470
  14. Nat Cell Biol. 2025 Jun 27.
      Autophagy deficiency in breast cancer promotes metastasis through the accumulation of the autophagy cargo receptor NBR1. Here we show that autophagy normally suppresses breast cancer metastasis by enabling the clearance of NBR1-p62/SQSTM1 complexes that instruct p63-mediated pro-metastatic basal differentiation programmes. When autophagy is inhibited, the autophagy cargo receptors NBR1 and p62/SQSTM1 accumulate within biomolecular condensates in cells, which drives basal differentiation in both mouse and human breast cancer models. Mechanistically, these NBR1-p62/SQSTM1 complexes sequester ITCH, a ubiquitin ligase that degrades and negatively regulates p63 in breast cancer cells, thereby stabilizing and activating p63. Accordingly, mutant forms of NBR1 unable to sequester ITCH into NBR1-p62/SQSTM1 complexes do not promote basal differentiation and metastasis in vivo. Overall, our findings illuminate how proteostatic defects arising in the setting of therapeutic autophagy inhibition modulate epithelial lineage fidelity and metastatic progression.
    DOI:  https://doi.org/10.1038/s41556-025-01689-8
  15. Trends Cancer. 2025 Jun 25. pii: S2405-8033(25)00148-7. [Epub ahead of print]
      Cuproptosis is a newly identified form of copper-dependent cell death. Recent studies show that solid tumors evade this process through transcriptional reprogramming, including hypoxia inducible factor 1 subunit alpha (HIF1A) and NFE2 like BZIP transcription factor 2 (NFE2L2) activation and BTB domain and CNC homolog 1 (BACH1) suppression. Targeting these pathways may restore cuproptosis sensitivity, offering a promising strategy to overcome therapy resistance in cancer.
    Keywords:  copper metabolism; cuproptosis; therapy resistance; transcription factor; tumor metabolism
    DOI:  https://doi.org/10.1016/j.trecan.2025.06.006
  16. Nat Mater. 2025 Jun 26.
      Cell migration in mechanically confined environments is a crucial step of metastatic cancer progression. Nonetheless, the molecular components and processes mediating such behaviour are still not fully understood. Here we demonstrate that a pool of the scaffolding protein anillin and its cofactor Ect2, which are both predominantly nuclear proteins and critical mediators of cytokinesis, is present in the cytoplasm of multiple interphase cell types that promote confined cell migration. Confined migration in biomimetic microfluidic models triggers the actomyosin-binding-dependent recruitment of anillin to the plasma membrane at the poles of migrating cells in a manner that scales with microenvironmental stiffness and confinement. The guanine nucleotide exchange activity of Ect2 is required for its RhoA-GTPase-mediated activation of myosin II at the cell poles, enhancing invasion, bleb-based migration and extravasation. Confinement-induced nuclear envelope rupture further amplifies this process due to the release of further anillin and Ect2 into the cytoplasm. Overall, these results show how Ect2 and anillin cooperate to mediate RhoA/ROCK/myosin II-dependent mechanoadaptation and invasive cancer progression.
    DOI:  https://doi.org/10.1038/s41563-025-02269-9
  17. Nature. 2025 Jun 25.
      The dendritic cell (DC)-initiated and sustained cancer immunity cycle is indispensable for effective endogenous and therapeutically mobilized antitumour T cell responses1-8. This necessitates the continuous migration of antigen-carrying DCs from the tumour microenvironment (TME) to the tumour draining lymph nodes (tdLNs)7-13. Here, through longitudinal analysis of human and mouse tumours, we observed a progressive decrease in migratory conventional DCs (mig-cDCs) in the tdLNs during tumour progression. This decline compromised tumour-specific T cell priming and subsequent T cell supply to the TME. Using a genome-wide in vivo CRISPR screen, we identified phosphodiesterase 5 (PDE5) and its substrate cyclic guanosine monophosphate (cGMP) as key modulators of DC migration. Advanced tumours disrupted cGMP synthesis in DCs to decrease their motility, while PDE5 perturbation preserved the cGMP pool to restore DC migration. Mechanistically, cGMP enhanced myosin-II activity through Rho-associated factors, extending the paradigm of cGMP-regulated amoeboid migration from Dictyostelium to mammalian immune cells. Pharmacological inhibition of PDE5 using sildenafil restored mig-cDC homing to late-stage tdLNs and sustained antitumour immunity in a DC-dependent manner. Our findings bridge fundamental DC interstitial motility to antitumour immunity, revealing that its disruption in chaotic TME promotes immune evasion, and its enhancement offers a promising direction for DC-centric immunotherapy.
    DOI:  https://doi.org/10.1038/s41586-025-09202-9
  18. Biophys J. 2025 Jun 25. pii: S0006-3495(25)00385-6. [Epub ahead of print]
      Organelles such as mitochondria have characteristic shapes that are critical to their function. Recent efforts have revealed that the curvature contributions of individual lipid species can be a factor in the generation of membrane shape in these organelles. Inspired by lipidomics data from yeast mitochondrial membranes, we used Martini coarse-grained molecular dynamics simulations to investigate how lipid composition facilitates membrane shaping. We found that increasing lipid saturation increases bending rigidity while reducing the monolayer spontaneous curvature. We also found that systems containing cardiolipin exhibited decreased bending rigidity and increased spontaneous curvature when compared to bilayers containing its precursor, phosphatidylglycerol. This finding contradicts some prior experimental results that suggest that bilayers containing tetraoleoyl cardiolipin have greater rigidity than dioleoyl phosphatidylcholine bilayers. To investigate this discrepancy, we analyzed our simulations for correlations between lipid localization and local curvature. We found that there are transient correlations between curved lipids such as cardiolipin (CDL) and phosphatidylethanolamine (PE) and curvature; these interactions enrich specific bilayer undulatory modes and cause bilayer softening. Furthermore, we show that curvature-localization of some lipids such as cardiolipin can influence lipids in the opposing leaflet. These observations add to the emerging evidence that lipid geometric features give rise to local interactions, which can cause membrane compositional heterogeneities. The cross-talk between composition-driven tuning of membrane properties and membrane shape has implications for membrane organization and its related functions.
    DOI:  https://doi.org/10.1016/j.bpj.2025.06.025
  19. J Mol Biol. 2025 Jun 19. pii: S0022-2836(25)00366-3. [Epub ahead of print] 169300
      
    DOI:  https://doi.org/10.1016/j.jmb.2025.169300
  20. bioRxiv. 2025 Apr 18. pii: 2025.04.16.649000. [Epub ahead of print]
      Residual tumor cells can persist in a dormant state during clinical remissions that may last decades. The mechanisms that lead to such growth control vs. eventual reactivation and macroscopic tumor outgrowth remain unclear. Here, we report data from a mouse model that reveals a key role of host immunity and the cellular and molecular mechanisms that control tumor dormancy. Abrogation of myeloid-specific TGF-βRII expression (TβRII myeKO ) resulted in an IFN-γ rich immune microenvironment. IFN-γ in turn elevated KLF4-mediated SLURP1 production in malignant cells, which is critical to the tumor cell quiescent state through interruption of fibronectin-integrin signaling pathways. The dormant tumor lesions were located in spatially localized immune niches rich in NK cells, cDCs, monocytes, and neutrophils, concomitant with tumor cell inactivation of NK cell immune surveillance through a CD200-CD200R1 mechanism. Our studies identify the IFN-γ-KLF4-SLURP1 and CD200-CD200R1 axes as critical molecular drivers in tumor dormancy regulated by immune-tumor crosstalk. These insights provide enhanced mechanistic understanding of tumor dormancy in a mouse model suitable for further investigation of cancer treatment resistance and prevention of metastatic spread.
    DOI:  https://doi.org/10.1101/2025.04.16.649000
  21. Membranes (Basel). 2025 Jun 17. pii: 182. [Epub ahead of print]15(6):
      Cell membranes contain a variety of biomolecules, especially various kinds of lipids and proteins, which constantly change with fluidity and environmental stimuli. Though Helfrich curvature elastic energy has successfully explained many phenomena for single-component membranes, a new theoretical framework for multicomponent membranes is still a challenge. In this work, we propose a generalized Helfrich free-energy functional describe equilibrium shapes and phase behaviors related to membrane heterogeneity with via curvature-component coupling in a unified framework. For multicomponent membranes, a new but important Laplace-Beltrami operator is derived from the variational calculation on the integral of Gaussian curvature and applied to explain the spontaneous nanotube formation of an asymmetric glycolipid vesicle. Therefore, our general mathematical framework shows a predictive capabilities beyond the existing multicomponent membrane models. The set of new curvature-component coupling EL equations have been derived for global vesicle shapes associated with the composition redistribution of multicomponent membranes for the first time and specified into several typical geometric shape equations. The equilibrium radii of isotonic vesicles for both spherical and cylindrical geometries are calculated. The analytical solution for isotonic vesicles reveals that membrane stability requires distinct elastic moduli among components (kA≠kB, k¯A≠k¯B), which is consistent with experimental observations of coexisting lipid domains. Furthermore, we elucidate the biophysical implications of the derived shape equations, linking them to experimentally observed membrane remodeling processes. Our new free-energy framework provides a baseline for more detailed microscopic membrane models.
    Keywords:  Euler-Lagrange equations; curvature-component coupling; generalized Helfrich free energy; multicomponent membranes
    DOI:  https://doi.org/10.3390/membranes15060182
  22. Dev Cell. 2025 Jun 13. pii: S1534-5807(25)00327-2. [Epub ahead of print]
      Autophagosome formation involves multiple sequential steps that need to be coordinated and linked. Here, we describe in mammalian cells that the transferrin receptor (TfR) links LC3 family conjugation to phagophore membranes, an early step in autophagosome biogenesis, with subsequent autophagosome closure. TfR depletion impairs autophagic flux and its overexpression stimulates this catabolic process in an iron-independent manner. TfR is ubiquitinated by the ubiquitin ligase MARCH8 in the RAB11A-LC3B-positive membranes that are conjugated by LC3 family members from which phagophores emanate. Ubiquitinated TfR recruits the VPS34 component VPS15, enabling phosphatidylinositol 3-phosphate (PI(3)P) synthesis on nascent autophagosome membranes. This PI(3)P is not only important for LC3-lipid conjugation but also for subsequent phagophore closure, where TfR-dependent PI(3)P recruits the endosomal sorting complexes required for transport (ESCRT) complex. This TfR activity occurs after endocytosis of iron-containing transferrin, its canonical function, as TfR only binds VPS15 after iron detachment from transferrin that is enabled by pH lowering in the endocytic compartment.
    Keywords:  ESCRT complex; PI(3)P; autophagosome closure; autophagy; transferrin receptor
    DOI:  https://doi.org/10.1016/j.devcel.2025.05.016
  23. Ann Surg Open. 2025 Jun;6(2): e584
       Objective: To determine the prevalence of new-onset diabetes (NOD) in individuals undergoing pancreatic surgery and to explore the implications of glycaemic status on clinicopathological features and outcomes for patients with pancreatic ductal adenocarcinoma (PDAC).
    Introduction: PDAC is characterized by a high prevalence of NOD. The prevalence of NOD in individuals undergoing pancreatic surgery for other diseases is less well-documented.
    Methods: A retrospective analysis of 483 individuals undergoing pancreatic surgery between 2016 and 2020 was undertaken. For patients with PDAC, associations between glycaemic status and tumor size, cancer stage, grade, postoperative complications, and outcomes were assessed.
    Results: Diabetes status was determined for 433 patients. The prevalence of preoperative NOD was higher in PDAC (34.9%; 58/166) compared to ampullary adenocarcinoma (6.3%; 3/48; P < 0.001), cholangiocarcinoma (5.6%; 2/36; P < 0.001), and intraductal papillary mucinous neoplasms (8.9%; 4/45; P = 0.005), but was similar to chronic pancreatitis (30%; 9/30; P = 0.909). For 22/58 (37.9%) PDAC patients with NOD, diabetes was undiagnosed until preoperative testing. In individuals undergoing pancreaticoduodenectomy, delayed gastric emptying (DGE) was more frequently associated with glucose dysregulation than with normoglycaemia (32.8% vs 8.3%; P = 0.004), while overall postoperative pancreatic fistula (POPF) was less frequently associated with glucose dysregulation than with normoglycaemia (4.7% vs 19.4%; P = 0.02).
    Conclusions: In contrast to PDAC, NOD was infrequently observed in other pancreatic/periampullary tumors. Of clinical importance, in more than one-third of PDAC patients, NOD was undiagnosed until preoperative assessment. Preoperative glucose dysregulation correlated with an increased rate of DGE and a reduced rate of POPF in pancreaticoduodenectomy.
    Keywords:  diabetes; new-onset diabetes; pancreatic cancer; pathology; perioperative care
    DOI:  https://doi.org/10.1097/AS9.0000000000000584
  24. Chem Commun (Camb). 2025 Jun 27.
      Membrane protein-lipid interactions, like other biomolecular interactions, are often temperature-sensitive. Here, we use variable-temperature electrospray ionization mass spectrometry to investigate the temperature dependence of protein-lipids interactions from membranes. The findings reveal that specific lipid binding, and in some cases metal ion binding, to membrane proteins is significantly enhanced at elevated temperatures.
    DOI:  https://doi.org/10.1039/d5cc01576f
  25. Nat Cancer. 2025 Jun 23.
      Prostate epithelium develops from multipotent stem cells, which are replaced in adult life by different lineage-restricted basal and luminal unipotent stem cells. Deletion of Pten re-induces multipotency in basal cells (BCs); however, the molecular mechanisms regulating BC plasticity and tumor initiation are poorly understood. Here we showed that Pten deletion in BCs led to distinct cell fate reprogramming and tumor initiation in a regionalized manner. Single-cell RNA sequencing, ATAC-seq and in situ characterization revealed that following Pten deletion in anterior and dorsolateral prostates, BCs were highly plastic and reprogrammed into a hillock-like state, progressing into a proximal-like luminal state before giving rise to invasive tumors. This BC reprogramming was associated with the activation of innate immunity. Pharmacological targeting of interleukin-1, JAK-STAT and NF-κB as well as genetic deletion of Nfkb inhibit Pten-induced cell plasticity and reprogramming in a cellular autonomous manner, opening new opportunities for prevention and treatment of prostate cancer.
    DOI:  https://doi.org/10.1038/s43018-025-00994-3
  26. Cell. 2025 Jun 26. pii: S0092-8674(25)00675-0. [Epub ahead of print]188(13): 3370-3374
      Virtual cells are an emerging frontier at the intersection of artificial intelligence and biology. A key goal of these cell state models is predicting cellular responses to perturbations. The Virtual Cell Challenge is being established to catalyze progress toward this goal. This recurring and open benchmark competition from the Arc Institute will provide an evaluation framework, purpose-built datasets, and a venue for accelerating model development.
    DOI:  https://doi.org/10.1016/j.cell.2025.06.008
  27. Cancer Epidemiol Biomarkers Prev. 2025 Jun 24.
       BACKGROUND: Muscle loss influences pancreatic ductal adenocarcinoma (PDAC) outcomes, but treatment-related edema may cause overestimation of total skeletal muscle area (tSMA) confounding our understanding of muscle changes. However, no studies have quantified the impact of edema on tSMA and psoas skeletal muscle area (pSMA) changes. Thus, we sought to i) assess the impact of edema on tSMA and pSMA change between diagnosis and follow-up and ii) explore the utility of pSMA as a clinically relevant measure of muscle and muscle loss among PDAC patients.
    METHODS: Body composition was measured using computed tomography scans at diagnosis and follow-up from ninety-five patients enrolled in the Florida Pancreas Collaborative cohort study. Edema was assessed by opacifications in subcutaneous fat, and tSMA and pSMA change were expressed as percent change between diagnosis and follow-up. We used multivariable generalized linear models to estimate mean tSMA and pSMA change overall and by edema status. Spearman correlation was used to measure interrelationships of tSMA and pSMA.
    RESULTS: tSMA increased between diagnosis and follow-up (Δ=0.66) but only in patients with edema (Δ=3.35) while non-edematous patients lost tSMA (Δ=-2.03). Conversely, pSMA decreased regardless of edema status. Further, tSMA and pSMA were strongly correlated overall (r=0.75) and in non-edematous patients (r=0.83).
    CONCLUSIONS: Edema inflated estimates of tSMA at follow-up in PDAC patients, but pSMA was impervious to edema and may represent a suitable proxy for tSMA.
    IMPACT: pSMA is a reliable measure of muscle and muscle loss and should be considered in future studies assessing muscle loss in PDAC patients.
    DOI:  https://doi.org/10.1158/1055-9965.EPI-25-0237
  28. Science. 2025 Jun 26. 388(6754): eadv4314
      During apoptosis, cytosolic BAX monomers are translocated to the mitochondria to permeabilize the outer membrane. Here, we identified a dimer of BAX dimers as the basic repeating unit of its various oligomeric forms: arcs, lines, and rings. Cryo-electron microscopy structure of the BAX repeating unit at 3.2-angstrom resolution revealed the interactions within and between dimers. End-to-end stacking of the repeating units through the protruding α9 pairs yielded lines, arcs, polygons, and rings. We structurally characterized the tetragon, pentagon, hexagon, and heptagon, which comprise 16, 20, 24, and 28 BAX protomers, respectively. Missense mutations at the BAX inter-protomer interface damage pore formation and cripple its proapoptotic function. The assembly principle of the various BAX oligomers reported here provides the structural basis of membrane permeabilization by BAX.
    DOI:  https://doi.org/10.1126/science.adv4314
  29. Cell Death Differ. 2025 Jun 23.
      As cancer cell specific rewiring of metabolic networks creates potential therapeutic opportunities, we conducted a synthetic lethal screen utilizing inhibitors of metabolic pathways. Simultaneous administration of (R)-GNE-140 and BMS-986205 (Linrodostat) preferentially halted proliferation of ovarian cancer cells, but not of their non-oncogenically transformed progenitor cells. While (R)-GNE-140 inhibits lactate dehydrogenase (LDH)A/B and thus effective glycolysis, BMS-986205, in addition to its known inhibitory activity on Indoleamine 2,3-dioxygenase (IDO1), also restricts oxidative phosphorylation (OXPHOS), as revealed here. BMS-986205, which is being tested in multiple Phase III clinical trials, inhibits the ubiquinone reduction site of respiratory complex I and thus compromises mitochondrial ATP production. The energetic catastrophe caused by simultaneous interference with glycolysis and OXPHOS resulted in either cell death or the induction of senescence in tumor cells, with the latter being eliminated by senolytics. The frequent synergy observed with combined inhibitor treatment was comprehensively confirmed through testing on tumor cell lines from the DepMap panel and on human colorectal cancer organoids. These experiments revealed highly synergistic activity of the compounds in a third of the tested tumor cell lines, correlating with alterations in genes with known roles in metabolic regulation and demonstrating the therapeutic potential of metabolic intervention.
    DOI:  https://doi.org/10.1038/s41418-025-01532-5