Luciani A, Villella VR, Esposito S
… +15 more, Brunetti-Pierri N, Medina D, Settembre C, Gavina M, Pulze L, Giardino I, Pettoello-Mantovani M, D'Apolito M, Guido S, Masliah E, Spencer B, Quaratino S, Raia V, Ballabio A, Maiuri L
Lipid metabolism has recently regained considerable attention in neuroscience, as disturbances in lipid metabolic pathways have been linked to neurodevelopmental and neurodegenerative diseases. Here we examine brain lipi...Lipid metabolism has recently regained considerable attention in neuroscience, as disturbances in lipid metabolic pathways have been linked to neurodevelopmental and neurodegenerative diseases. Here we examine brain lipid metabolism from a cellular perspective, focusing on lipid uptake, de novo synthesis, storage, breakdown and intercellular transfer. We cover the recent literature showing how these processes are important during brain development and how they occur in diverse brain cell types, including astrocytes, oligodendrocytes, neural stem and progenitor cells, microglia and neurons in the adult brain. We further discuss the consequences of disrupted lipid metabolism and highlight emerging insights into neuron-glia lipid exchange, as well as the importance of lipid droplets for brain health and disease.
Wang JH, Zheng YQ, Qian ZY
… +18 more, Pan YQ, Tian T, Duan XT, Wang RB, Wang LY, Peng JH, Mo HY, Zhang YY, Han Y, Liao K, Li T, Yang W, Shi GJ, Wu J, Liu ZX, Lin JZ, Xu RH, Ju HQ
Nat Cell Biol
· 2026 Mar · PMID 41714703
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Although peritumoural visceral adipose tissue (tVAT) is anatomically close to tumours such as colorectal cancer, the immune landscape of this tissue and its functional contribution to tumour immunity remain poorly define...Although peritumoural visceral adipose tissue (tVAT) is anatomically close to tumours such as colorectal cancer, the immune landscape of this tissue and its functional contribution to tumour immunity remain poorly defined. Here, we performed single-cell RNA analysis on the tVAT from patients with colorectal cancer to map its immune landscape and observed that tVAT exhibited a highly immune-infiltrated microenvironment enriched with lymphocytes, especially tumour-specific CD8⁺ T cells. Mechanistically, tVAT competes with the tumour for these immunocytes by activating the CXCL12-CXCR4 axis to promote tumour immune escape. Moreover, tumour-derived factors induce an adipose-mesenchymal transformation process where the adipose stromal cells trans-differentiated into adipose-derived cancer-associated fibroblasts, which secrete large amounts of CXCL12 in tVAT. Clinically, targeting adipose-tumour interaction substantially enhances diagnostic and therapeutic efficacy of anti-PD-1 therapy. These findings offer an understanding of the dynamic crosstalk between tVAT and tumour immune escape, highlighting the tVAT as a potential target for cancer immunotherapy.
Rao L, Liu X, Arnold M
… +6 more, Okada K, McKenney RJ, Stengel K, Sidoli S, Berger F, Gennerich A
Nat Cell Biol
· 2026 Mar · PMID 41699082
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Cytoplasmic dynein is an essential microtubule motor protein that powers organelle transport and mitotic spindle assembly. Its activity depends on dynein-dynactin-cargo adaptor complexes, such as dynein-dynactin-BicD2, w...Cytoplasmic dynein is an essential microtubule motor protein that powers organelle transport and mitotic spindle assembly. Its activity depends on dynein-dynactin-cargo adaptor complexes, such as dynein-dynactin-BicD2, which typically function with two dynein motors. We show that mechanical tension recruits a third dynein motor via an auxiliary BicD2 adaptor binding the light intermediate chain of the third dynein, stabilizing multidynein assemblies and enhancing force generation. Lis1 prevents dynein from transitioning into a force-limiting phi-like conformation, allowing single-dynein dynein-dynactin-BicD2 to sustain forces up to approximately 4.5 pN, whereas force generation often ends at about 2.5 pN without Lis1. Complexes with two or three dyneins generate 7 pN and 9 pN, respectively, consistent with a staggered motor arrangement that enhances collective output. Under load, dynein-dynactin-BicD2 primarily takes 8-nm steps, challenging existing dynein coordination models. These findings reveal adaptive mechanisms that enable robust intracellular transport under varying mechanical demands.
Langstein-Skora I, Schmid A, Huth F
… +18 more, Shabani D, Spechtenhauser L, Likhodeeva M, Kunert F, Metzner FJ, Emenecker RJ, Richardson MO, Aftab W, Götz MJ, Payer SK, Pietrantoni N, Valka V, Ravichandran SK, Bartke T, Hopfner KP, Gerland U, Korber P, Holehouse AS
Nat Cell Biol
· 2026 Feb · PMID 41688823
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Intrinsically disordered regions (IDRs) pervasively engage in essential molecular functions, yet they are often poorly conserved as assessed by sequence alignment. To explore the seeming paradox of how sequence variabili...Intrinsically disordered regions (IDRs) pervasively engage in essential molecular functions, yet they are often poorly conserved as assessed by sequence alignment. To explore the seeming paradox of how sequence variability is compatible with persistent function, we examined the functional determinants for a poorly conserved but essential IDR. We show that IDR function depends on two distinct but related properties: sequence and chemical specificity. Whereas sequence specificity operates via binding motifs and depends on the precise order and identity of residues, chemical specificity reflects the sequence-encoded chemistry of multivalent interactions across an IDR and depends on local and global chemical properties. Unexpectedly, a binding motif essential in the wild-type IDR can be removed when compensatory changes to the sequence chemistry are introduced, highlighting the orthogonality and interoperability of these properties, and expanding the sequence space compatible with function. Our results provide a general framework for the functional constraints on IDR evolution.
Morales-Sanfrutos J, Etxeberria-Ugartemendia J, Barroso-Gomila O
… +8 more, González E, Sendino M, Ximénez-Embún P, García F, Zarzuela E, Falcón-Pérez JM, Peinado H, Muñoz J
Nat Cell Biol
· 2026 Mar · PMID 41688734
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Extracellular vesicles (EVs) are key mediators of intercellular communication and promising biomarkers. However, their molecular characterization remains challenging due to the heterogeneity of EV subtypes and co-isolate...Extracellular vesicles (EVs) are key mediators of intercellular communication and promising biomarkers. However, their molecular characterization remains challenging due to the heterogeneity of EV subtypes and co-isolated non-vesicular components. Here we leverage protein correlation profiling along density gradients to systematically analyse over 9,000 proteins in human cancer cell lines and biofluids, providing a rigorous reassessment of virtually all protein constituents associated with small EVs (sEVs) and non-vesicular entities. We show that sEVs primarily incorporate plasma membrane proteins via selective cargo-loading mechanisms, with low inclusion of intraluminal soluble proteins. By contrast, the abundant cytosolic proteins frequently detected in sEV preparations are not encapsulated within vesicles but are externally associated, probably originating from copurifying cellular debris and aggregates. Our work provides a reference resource for understanding the biogenesis, molecular determinants of cargo selection and functional roles of sEVs.
Whether a distinct subset of cancer stem cells (CSCs) is exclusively responsible for metastasis and how this process occurs remain unresolved. Through multi-omics, pan-cancer analysis and multiple tumour-bearing models,...Whether a distinct subset of cancer stem cells (CSCs) is exclusively responsible for metastasis and how this process occurs remain unresolved. Through multi-omics, pan-cancer analysis and multiple tumour-bearing models, we identify THY1⁺ CSCs as the key drivers of metastasis and uncover a previously unrecognized 'pseudohypoxic' state (independent of classical hypoxia) as a central regulatory factor. The self-renewal of THY1⁺ CSCs is maintained by IL-6-MYC signalling. Upon encountering neutrophils, THY1⁺ CSCs activate the THY1-Mac1 axis, triggering the Src-Akt/Erk pathway, Rac1 activation and a migrasome-dependent process that induces neutrophils to expel reactive oxygen species-enriched damaged mitochondria. THY1 signalling further enhances macropinocytosis, enabling CSCs to internalize these mitochondria and adopt a pseudohypoxic state, thereby facilitating CSC metastasis. Notably, targeting the IL-6-Myc, THY1-Mac1 or Src-Akt/Erk signalling pathways effectively suppresses pseudohypoxia-driven CSC metastasis. These findings unveil previously unexplored mechanisms by which CSCs undergo metastasis, offering potential strategies to combat tumour metastasis and improve cancer prognosis.
Jacquemyn J, Marriott B, Chang J
… +15 more, Iftikhar E, Chik K, Lee NYJ, Rubio Atonal LF, Green C, Wong J, Acevedo-Morantes C, Chen CX, Nicouleau M, You Z, Deneault E, Abdian N, Durcan TM, Jackson J, Ioannou MS
The intercellular transmission of α-synuclein contributes to Parkinson's disease pathology. Yet, the mechanisms of α-synuclein spread are not fully understood. Here we used live-cell microscopy to examine the impact of P...The intercellular transmission of α-synuclein contributes to Parkinson's disease pathology. Yet, the mechanisms of α-synuclein spread are not fully understood. Here we used live-cell microscopy to examine the impact of Parkinson's disease associated lipid alterations on α-synuclein release. We discovered that increased glucosylceramides as a consequence of reduced β-glucocerebrosidase activity induce ectosome shedding from primary neurons and from dopaminergic neurons derived from induced pluripotent stem cells of a patient with Parkinson's disease harbouring mutations in GBA1 (N370S, L444P and W378G) and LRRK2 (G2019S and R1441H) compared with their isogenic control. We show that elevated glucosylceramide and the pharmacological inhibition of β-glucocerebrosidase similarly increase vesicle release and uptake by other neurons in mouse brains. Finally, we show that ectosomes are loaded with α-synuclein and lead to the transmission of α-synuclein pathology to neighbouring neurons. These data reveal ectosomes as a major route for α-synuclein transmission in Parkinson's disease.
Bång-Rudenstam A, Cerezo-Magaña M, Horvath M
… +20 more, Talbot H, Gustafsson E, Jonathan S, Chakraborty C, Nissen I, Gonçalves de Oliveira K, Boukredine A, Beyer S, Perez JE, Johansson MC, Kjellén L, Tykesson E, Malmström A, van Kuppevelt TH, Forsberg-Nilsson K, Esko JD, Remeseiro S, Bengzon J, Governa V, Belting M
Nat Cell Biol
· 2026 Mar · PMID 41673170
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Aggressive tumours are defined by microenvironmental stress adaptation and metabolic reprogramming. Within this niche, lipid droplet accumulation has emerged as a key strategy to buffer toxic lipids and suppress ferropto...Aggressive tumours are defined by microenvironmental stress adaptation and metabolic reprogramming. Within this niche, lipid droplet accumulation has emerged as a key strategy to buffer toxic lipids and suppress ferroptosis. Lipid droplet formation can occur via de novo lipogenesis or extracellular lipid-scavenging. However, how tumour cells coordinate these processes remains poorly understood. Here we identify a chondroitin sulfate (CS)-enriched glycocalyx as a hallmark of the acidic microenvironment in glioblastoma and central nervous system metastases. This CS-rich glycocalyx encapsulates tumour cells, limits lipid particle uptake and protects against lipid-induced ferroptosis. Mechanistically, we demonstrate that converging hypoxia-inducible factor and transforming growth factor beta signalling induces a glycan switch on syndecan-1-replacing heparan sulfate with CS-thereby impairing its lipid-scavenging function. Dual inhibition of CS biosynthesis and diacylglycerol O-acyltransferase-1, a critical enzyme in lipid droplet formation, triggers catastrophic lipid peroxidation and ferroptotic cell death. These findings define glycan remodelling as a core determinant of metabolic plasticity, positioning the dynamic glycocalyx as a master regulator of nutrient access, ferroptotic sensitivity and therapeutic vulnerability in cancer.
Erdem A, Morganti C, Totani H
… +2 more, van Gastel N, Ito K
Nat Cell Biol
· 2026 Mar · PMID 41673169
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Haematopoietic stem cells (HSCs) rely on precisely coordinated metabolic programs to preserve their functionality, adapt to environmental cues, and sustain lifelong haematopoiesis. Here we analyse recent advances in unde...Haematopoietic stem cells (HSCs) rely on precisely coordinated metabolic programs to preserve their functionality, adapt to environmental cues, and sustain lifelong haematopoiesis. Here we analyse recent advances in understanding the metabolic landscape of HSCs, emphasizing how their intrinsic bioenergetic programs facilitate quiescence, self-renewal and differentiation. We also summarize the dynamic metabolic interactions with the bone marrow microenvironment, including stromal cells, osteoblasts, endosteal cells and adipose tissue, highlighting how they support proper HSC fate. In addition, we discuss how alterations in metabolic homeostasis in healthy and aged HSCs are linked to haematological disorders, particularly leukaemogenesis. We discuss metabolic dysregulation in leukaemic cells that maintains malignant persistence by mimicking certain intrinsic-extrinsic key HSC metabolic features, while simultaneously activating distinct metabolic pathways to support their growth and survival. Understanding the complex role of metabolism in HSC biology will be essential to advance regenerative medicine and blood cancer prevention strategies.
Huang ME, Qin Y, Shang Y
… +27 more, Hao Q, Zhan C, Lian C, Luo S, Liu LD, Zhang S, Zhang Y, Wo Y, Li N, Wu S, Gui T, Wang B, Luo Y, Cai Y, Liu X, Xu Z, Dai P, Li S, Zhang L, Dong J, Wang J, Zheng X, Xu Y, Sun Y, Wu W, Yeap LS, Meng FL