Diao S, Zou JY, Wang S
… +13 more, Chan JE, Kortlever RM, Poulain N, Ghaddar N, Kim H, Evan GI, Koumenis C, Hatzoglou M, Walter P, Sonenberg N, Le Quesne J, Tammela T, Koromilas AE
Tumour progression towards dedifferentiated cell clusters plays a critical role in intratumour heterogeneity and therapy resistance. While tumour microenvironmental stress has been implicated, the underlying mechanisms r...Tumour progression towards dedifferentiated cell clusters plays a critical role in intratumour heterogeneity and therapy resistance. While tumour microenvironmental stress has been implicated, the underlying mechanisms remain poorly defined. Using mouse models of lung adenocarcinoma, we demonstrate that activation of the integrated stress response (ISR)-marked by phosphorylation of eIF2 (p-eIF2) and ATF4 induction-drives tumour heterogeneity. ISR activation facilitates the emergence of high-plasticity, undifferentiated and pre-epithelial-to-mesenchymal transition clusters characterized by elevated ATF4 and MYC activity. This process is MYC dependent and involves ISR-mediated repression of NKX2-1, a key determinant of alveolar identity, and induction of CHCHD10, a regulator of mitochondrial integrity and metabolic fitness. Disruption of the p-eIF2-ATF4 axis induces mitochondrial dysfunction, limits dedifferentiation and suppresses tumour growth. In human lung adenocarcinoma, ISR-driven dedifferentiation correlates with advanced disease and poor prognosis, identifying the ISR as a central driver of lineage reprogramming and metabolic fitness in tumour progression.
Bassot A, Violy L, Gorka L
… +32 more, Cigalotto L, Namasivayam B, Mikaelian I, St Johnston E, Han C, Gadet R, Alpha-Bazin B, Moindrot L, Clement E, Dragic H, Crépin M, Berdeaux O, Vanbelle C, Gautier M, Cariou A, Larrouquere L, Wei C, Gudermann T, Sarkaria JN, Zito E, Dietrich PY, Walker PR, Nemazanyy I, Lincet H, Armengaud J, Rieusset J, Mischel PS, Mammadova-Bach E, Simmen T, Martinvalet D, Castets M, Cosset E
Despite the wealth of data generated in the omics era to investigate molecular drivers, glioblastoma (GBM) remains one of the most incurable cancers with a poor median of survival. Here we unravelled the dynamic crosstal...Despite the wealth of data generated in the omics era to investigate molecular drivers, glioblastoma (GBM) remains one of the most incurable cancers with a poor median of survival. Here we unravelled the dynamic crosstalk between the endoplasmic reticulum and mitochondria, known as mitochondria-associated membranes (MAMs) and define how modulation of calcium fluxes and MAM structure influences GBM cell plasticity and metabolic flexibility. We identified ERO1α, whose expression is significantly associated with poor GBM patient survival, as a critical MAM protein that regulates MAM structure, dynamics and calcium-mediated functions. Our data demonstrate that ERO1α activity and expression promotes GBM aggressiveness in vitro and in vivo and enhances mitochondrial oxidative phosphorylation. By establishing a direct link between ERO1α-mediated MAM modulation and the antitumour effects of ERO1α inhibition, this work highlights a context-dependent, druggable vulnerability that can be exploited for GBM therapy.
TEA domain transcription factor 1 (TEAD1), a Hippo pathway transcription factor important in cellular homeostasis and development, is increasingly implicated in cancer biology. Here we reveal an unexpected role for TEAD1...TEA domain transcription factor 1 (TEAD1), a Hippo pathway transcription factor important in cellular homeostasis and development, is increasingly implicated in cancer biology. Here we reveal an unexpected role for TEAD1 in organizing nuclear condensates, independent of active transcription. Using high-resolution imaging, ChIP-seq, RNA sequencing and proximity-based proteomics, we demonstrate that in patient-derived renal cell carcinoma cells, TEAD1 forms micrometre-sized condensates by binding to heterochromatic pericentromeric regions using its DNA-binding domain. TEAD-specific MCAT motifs selectively enrich and cluster in the pericentromeric region to specifically seed TEAD1 condensates. TEAD1 condensates do not activate transcription but instead serve as depots for excess TEAD1, and disruption of TEAD1 condensates leads to increases in YAP and TEAD target gene expression. This organization of TEAD1 contrasts with that observed in other genomic regions of both renal cell carcinoma and normal kidney cells, in which TEAD1 associates with markers of active transcription. Our findings provide a mechanistic framework for the dual regulatory roles of TEAD1 and offer new insights into its contribution to transcriptional dysregulation and tumour progression.
Advances in proteomics are transforming our understanding of mammalian oocyte maturation and preimplantation embryo development. These resources and their findings provide unprecedented insights into the molecular underp...Advances in proteomics are transforming our understanding of mammalian oocyte maturation and preimplantation embryo development. These resources and their findings provide unprecedented insights into the molecular underpinnings of developmental competence. Here we summarize the ongoing development of proteomic methodologies and highlight the stage-specific reprogramming events of the proteome in both humans and mice, underscoring the unique utility of proteomics in deciphering oocyte maturation and early embryonic development. Furthermore, we discuss the clinical implications of these findings, highlighting the translational potential of proteomics in understanding reproductive ageing, improving oocyte quality, and refining the outcomes of assisted reproductive technology.
DRP1 is a dynamin-related large GTPase responsible for mitochondrial fission, which ensures proper mitochondrial distribution, morphology and quality control. Despite its relevance, the mechanism of mitochondrial divisio...DRP1 is a dynamin-related large GTPase responsible for mitochondrial fission, which ensures proper mitochondrial distribution, morphology and quality control. Despite its relevance, the mechanism of mitochondrial division, especially regarding the dynamic regulation of DRP1, remains elusive. Here we report that DRP1 oligomers diffuse in helical-like trajectories along mitochondria, browsing the organelle surface and stalling at preconstricted fission sites, in what we call 'mito-scanner' motion. Molecular dynamics simulations support a geometry-mediated diffusion mechanism emerging from surface confinement. Perturbation of DRP1 motility results in elongated mitochondria, underscoring the functional importance of DRP1 scanning dynamics in mitochondrial division. We also show that DRP1 dynamics on mitochondria are differentially regulated by interactions with its adaptors, where co-diffusion of MID49/MID51 with DRP1 promotes its motility. Our findings support a model in which receptor-regulated mitochondrial surveillance by DRP1 enables balanced organelle division, with potential implications for targeting this process in disease.
De Belly H, Gallén AF, Strickland E
… +8 more, Estrada DC, Godinez DS, Neiva E, Zager PJ, Nagy TL, Burkhardt JK, Turlier H, Weiner OD
Nat Cell Biol
· 2026 Jun · PMID 42270977
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In migrating cells, the GTPase Rac organizes a protrusive front, whereas Rho organizes a contractile back. How these GTPases are positioned at opposite poles remains unclear. We leverage optogenetics, mechanical perturba...In migrating cells, the GTPase Rac organizes a protrusive front, whereas Rho organizes a contractile back. How these GTPases are positioned at opposite poles remains unclear. We leverage optogenetics, mechanical perturbations, and mathematical modelling to reveal a surprising mechanochemical long-range mutual activation between front and back polarity programmes that complements their well-known local mutual inhibition. Rac-based protrusions elevate membrane tension, stimulating an mTORC2-dependent activation of Rho at the opposite side of the cell. Conversely, Rho-mediated contractility induces cortical-flow-based regulation of phosphoinositide signalling that triggers Rac activation distally. We develop a minimal mechanochemical model to explain how long-range facilitation, together with local inhibition, enables robust Rho and Rac partitioning. Our findings demonstrate how the actin cortex and plasma membrane interact as an integrated mechanochemical system for long-range Rac-Rho patterning. This circuit is required for efficient polarity and migration in primary human T cells and is conserved in epithelial cells, highlighting the generality of this mechanism.
Oshio H, Shiiba I, Ito N
… +12 more, Okada N, Yamaguchi F, Ishikawa Y, Nagashima S, Fujikawa Y, Umezawa K, Miura Y, Shimizu M, Saito Y, Yamaguchi T, Inatome R, Yanagi S
Mitochondrial iron dynamics are essential for cellular respiration and metabolic homeostasis, yet the molecular mechanisms governing iron supply to mitochondria remain poorly understood. Here we identify a pathway in whi...Mitochondrial iron dynamics are essential for cellular respiration and metabolic homeostasis, yet the molecular mechanisms governing iron supply to mitochondria remain poorly understood. Here we identify a pathway in which haem serves as an iron source for mitochondria, maintaining mitochondrial iron homeostasis and mitochondrial supercomplex integrity, regulated at mitochondria-endoplasmic reticulum contact sites (MERCs). We demonstrate that haem oxygenase 2 (HMOX2), an ER-resident enzyme, is also localized to MERCs and facilitates the supply of haem-derived iron to mitochondria. This process is orchestrated by the mitochondrial ubiquitin ligase MITOL (also known as MARCH5/MARCHF5), which ubiquitinates HMOX2 at K68 with K63-linked polyubiquitin chains, enhancing its haem-degrading activity. Notably, loss of HMOX2 or disruption of MITOL-mediated ubiquitination impairs mitochondrial iron homeostasis and mitochondrial respiration. These findings establish a paradigm in which MERCs function as an iron supply hub, integrating haem metabolism with mitochondrial iron utilization.
Hoslett G, Tribble S, Lascaux P
… +21 more, Koukouravas S, Torrecilla I, Song W, Hou CX, Li J, González-Fernández M, De Gregoriis G, Dagg RA, O'Brien D, Pierangelini A, Martial T, Ng AWT, Raimundo N, Milosevic I, Freire R, Li Y, Rottenberg S, Krastev DB, Lord CJ, Tarsounas M, Ramadan K
Nat Cell Biol
· 2026 Jun · PMID 42230924
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Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) induce cytotoxicity in homologous recombination repair (HR)-deficient (HRD) cancers by trapping PARP1 on chromatin, thereby causing irreparable replication-associated...Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) induce cytotoxicity in homologous recombination repair (HR)-deficient (HRD) cancers by trapping PARP1 on chromatin, thereby causing irreparable replication-associated DNA damage. Although increased clearance of trapped PARP1 from chromatin reduces the sensitivity of cancer cells to PARPi, details surrounding this process remain unclear. PARPi exposure is known to cause increased autophagy flux, whereas autophagy inhibition can hypersensitize cells to PARPi. Our study reveals that trapped PARP1 is cleared via nucleophagy, with the selective autophagy receptor TEX264 and its partner segregase p97 (also known as VCP) orchestrating this process. TEX264 interacts directly with trapped PARP1, linking it to the autophagosomal protein LC3 for degradation. Disrupting this pathway, either chemically or genetically, increases PARP1 trapping, resulting in protein aggregates, DNA damage and cell lethality, ultimately re-sensitizing PARPi-resistant cells. We conclude that nucleophagy serves a cytoprotective role by targeting PARPi-induced trapped PARP1 for degradation.
The proper development of the human female reproductive tract (FRT) is essential for reproductive competence. However, the mechanisms underlying its segmental specialization remain underexplored. This gap limits our know...The proper development of the human female reproductive tract (FRT) is essential for reproductive competence. However, the mechanisms underlying its segmental specialization remain underexplored. This gap limits our knowledge of congenital anomalies and adult reproductive disorders. Herein, we build a spatiotemporal transcriptomic atlas of the distinct human FRT segments development from gestational week (GW) 10 to 25, capturing cellular composition and lineage dynamics. We discovered that the upper and lower segments of FRT are composed of distinct mesenchymal and epithelial cell subpopulations starting from as early as GW10. Mesenchymal lineages in different segments arise from distinct mesenchymal stem cell (MSC)-like cells and undergo critical differentiation between GW13 and GW22, giving rise to fibroblasts and smooth muscle cells. TGF-β and PDGF signalling pathways seem to play a pivotal role in guiding these distinct fate transitions. Concurrently, epithelial development exhibits region-specific trajectories: upper and lower FRT epithelial cells originate from different stem-like populations and undergo key transitions between GW14 and GW22. Specifically, we identify MSC-like1 and MSC-like2 as regulatory populations that may influence epithelial differentiation via WNT5A-FZD and IGF1-IGF1R signalling pathways in the upper and lower FRT, respectively. This finding highlights a spatially specific mesenchymal-epithelial crosstalk that shapes regional epithelial identity. Altogether, our work provides a comprehensive insight into the segmental specification and coordinated lineage decisions that offer foundational resource for understanding FRT development, congenital anomalies and tissue engineering.
Mani SK, Tardif N, Rossier O
… +17 more, Khater IM, Zhou X, Breton V, Nunes Vicente F, Radhakrishnan AV, Gracia C, Gonzalez Troncoso P, Brito I, Ruez R, Dewulf M, Hamarneh G, Nabi IR, Cuniasse P, Sens P, Giannone G, Blouin CM, Lamaze C
Caveolae are invaginated plasma membrane nanodomains traditionally associated with membrane trafficking and signalling. These multifunctional organelles are also essential mechanosensors mediating the cell response to me...Caveolae are invaginated plasma membrane nanodomains traditionally associated with membrane trafficking and signalling. These multifunctional organelles are also essential mechanosensors mediating the cell response to mechanical stress. We investigated the role of caveolae mechanics in regulating various signalling pathways. Single-molecule imaging and super-resolution microscopy revealed that mechanical stress rapidly triggers caveolae disassembly and the release of caveolin-1 scaffolds, which then exhibit enhanced diffusion at the plasma membrane. This promoted direct interaction between the caveolin-1 scaffolding domain and the tyrosine kinase JAK1, leading to the inhibition of its catalytic activity. A similar process was observed for eNOS, PTEN and PTP1B. The control of signalling by diffusing Cav1 scaffolds was further validated by a theoretical model based on caveolae thermodynamics. These findings establish a mechanotransduction paradigm in which signalling information is decoded remotely from the initial mechanosensing caveola, through dynamic and reversible assembly of tension-controlled complexes between signalling effectors and caveolin-1 scaffolds.
Cao S, Lin L, Feng H
… +33 more, Chen P, Wu G, Cai B, Pan M, Shen Q, Chen H, Zhai X, Cai Q, Feng Z, Zhao Y, Li D, Wu C, Jiang F, Liang W, Mai Y, Ke J, Zhang Y, Zhu P, Liu Y, Zeng M, Ke M, Lu F, Yu Y, Liu H, Quan X, Pang W, Chu S, Cui G, Qu F, Gu S, Peng G, Chen J, Pei D
Current single-cell atlases of mouse embryos are limited in temporal resolution and cellular or sequencing depth coverage. Here we report the mouse developmental Cell and Lineage Atlas (mdCLA), which covers 37 time point...Current single-cell atlases of mouse embryos are limited in temporal resolution and cellular or sequencing depth coverage. Here we report the mouse developmental Cell and Lineage Atlas (mdCLA), which covers 37 time points across the entire embryonic development from the 2-cell stage (E1.5) to birth (E19.0), with two million cells and a median of 4,500 genes detected per cell. The temporal coverage and data quality of mdCLA surpass the existing mouse embryonic atlases, enabling the identification of organ-specific cell type and gene expression. Using mdCLA, we uncovered divergent gene expression profiles between early and late-stage metanephric progenitor populations, marked by the upregulation of epithelial differentiation and immune response pathways in the late-stage population. Moreover, by analysing the newly generated cell types over time, we revealed an epithelium-specific accelerated differentiation process that occurs after E14.5. The transcription factor upregulated during late developmental stages was validated, where specific ablation of the Tub gene in the pituitary epithelium led to a reduction in the populations producing follicle-stimulating hormone. Consequently, this genetic modification resulted in postnatal obesity in mice. Together, mdCLA offers a comprehensive and high-quality reference, providing critical insights into the dynamic processes and mechanisms underlying mammalian embryogenesis.
The brain offers a unique environment for cancer, with limited access to nutrients and highly regulated immune surveillance. Here we explore the role of ferroptosis, a form of metabolically regulated cell death driven by...The brain offers a unique environment for cancer, with limited access to nutrients and highly regulated immune surveillance. Here we explore the role of ferroptosis, a form of metabolically regulated cell death driven by iron-mediated lipid peroxidation, in shaping immune-cell composition and function in glial tumours. We review the complex metabolic crosstalk between cell populations regulating ferroptosis in the glioma milieu. Ferroptosis induces polarization of resident microglia and controls the cytotoxic roles of CD8 T cells and the immunosuppressive effects of regulatory T cells. We discuss recently uncovered mechanisms of ferroptosis-driven immune evasion and the impact on tumour evolution. Additionally, we analyse mechanisms of synergy in combinations incorporating ferroptosis-inducing agents and immunotherapies, including immune checkpoint blockade and adoptive cell therapies, which aim to induce effective immune responses and durable control in gliomas.
Valdivieso K, Rozmaric T, Victorelli S
… +32 more, Jadhav V, Ring NAR, Machcińska-Zielińska S, Schädl B, Dworak H, Klinaki E, Fischer I, Gadecka A, Moskalevska I, Kostrebic S, Kienberger M, Marzec E, Efraimoglou C, Zanchetta A, Cherfils-Vicini J, Lushchak O, Löscher A, Kolbe T, Dahlhoff M, Pirius NE, Gutasi A, Takacs S, Ferguson J, Podesser BK, Slezak P, Monroe D, Zhou B, Khosla S, Grillari J, Redl H, Jurk D, Ogrodnik M
Nat Cell Biol
· 2026 Jun · PMID 42209725
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Cellular senescence plays key roles in tissue repair, tumour suppression and ageing. Here we identify a rapid, transcription‑independent senescence response in skin following injury. Within minutes to hours after woundin...Cellular senescence plays key roles in tissue repair, tumour suppression and ageing. Here we identify a rapid, transcription‑independent senescence response in skin following injury. Within minutes to hours after wounding, skin cells at the edge of injury display hallmark features of senescence. This response involves the utilization of pre‑existing Cdkn1a mRNA through the removal of nuclear export inhibitors, which enables Cdkn1a transcript translation and rapid p21 protein accumulation. These cells enter stable cell‑cycle arrest and secrete pro‑migratory and pro‑inflammatory factors that promote tissue repair, including re‑epithelialization. Experimental suppression of this rapid senescence, either genetically or pharmacologically, markedly delays wound closure, whereas inhibition during later phases of repair has no effect. Our findings establish rapid‑onset senescence as a mechanistic requirement for efficient tissue regeneration.