Ge J, Hirosue S, Castillon L
… +10 more, Patel SA, Wesolowski L, Dyas A, Yong C, de Haan S, Drost J, Stewart GD, Obenauf AC, Muñoz-Espín D, Vanharanta S
EMBO Mol Med
· 2026 Feb · PMID 41420106
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The von Hippel-Lindau tumor suppressor (VHL) is a component of a ubiquitin ligase complex that controls cellular responses to hypoxia. Endogenous VHL is also utilized by proteolysis-targeting chimera (PROTAC) protein deg...The von Hippel-Lindau tumor suppressor (VHL) is a component of a ubiquitin ligase complex that controls cellular responses to hypoxia. Endogenous VHL is also utilized by proteolysis-targeting chimera (PROTAC) protein degraders, a promising class of anti-cancer agents. VHL is broadly essential for cell proliferation, yet it is a key tumor suppressor in renal cell carcinoma. To understand the functional consequences of VHL loss, and to identify targeted approaches for the elimination of VHL null cells, we have used genome-wide CRISPR-Cas9 screening in human renal epithelial cells. We find that, upon VHL loss, the HIF1A/ARNT complex is the central inhibitor of cellular fitness, suppressing mitochondrial respiration, and that VHL null cells show HIF1A-dependent molecular vulnerabilities that can be targeted pharmacologically. Combined VHL/HIF1A inactivation in breast and esophageal cancer cells can also provide resistance to ARV-771, a VHL-based bromodomain degrader that has anti-cancer activity. HIF1A stabilization can thus provide opportunities for early intervention in neoplastic VHL clones, and the VHL-HIF1A axis may be relevant for the development of resistance to the emerging class of PROTAC-based cancer therapies.
Stringer BW, Zhang Y, Taghipour-Sheshdeh A
… +5 more, Goh S, Kölbel H, Farrar MA, Wirth B, Giacomotto J
EMBO Mol Med
· 2026 Jan · PMID 41398093
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Spinal muscular atrophy (SMA) results from SMN1 gene loss-of-function (LOF), with disease severity directly linked to the level of remaining SMN protein. Nusinersen, risdiplam, and onasemnogene abeparvovec are revolution...Spinal muscular atrophy (SMA) results from SMN1 gene loss-of-function (LOF), with disease severity directly linked to the level of remaining SMN protein. Nusinersen, risdiplam, and onasemnogene abeparvovec are revolutionary treatments but should ideally be implemented before clinical symptoms appear. Because of this, prenatal and newborn screenings are increasingly used to identify common SMN1 variants and patients requiring therapy. However, for novel variants, clinicians lack robust analytic tools to predict pathogenicity before irreversible damage occurs. To address this gap, we deployed a zebrafish model presenting smn1-LOF, exhibiting progressive motor defects and death by only six days of age. We evaluated two SMN1-variants of uncertain significance (VUS) identified in newborn infants awaiting definite diagnosis and treatment recommendations. We demonstrated that while known pathogenic variants did not change the disease course, wild-type SMN1 and both infants variants rescued SMA hallmarks in zebrafish, demonstrating the relevance of this approach for VUS-testing within a crucial timeframe for patients. Extending the assay to known SMN1-hypomorphs showed partial rescue, weaker than wild-type or VUS, demonstrating that this approach can also discriminate partial-LOF effects. Both VUS were resolved to be non-pathogenic, and the therapeutic costs of >US$2 million per child were avoided. Beyond SMA, this study provides robust proof-of-principle that the zebrafish represents a powerful translational tool for VUS-analysis, and that such approaches should be considered in clinical settings for supporting diagnosis and treatment decisions.
EMBO Mol Med
· 2026 Feb · PMID 41381808
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Metabolic adaptations are a functional requirement for the heart to accommodate its broad range of physiologic operating conditions. It is increasingly recognized that persistent and exaggerated metabolic alterations pre...Metabolic adaptations are a functional requirement for the heart to accommodate its broad range of physiologic operating conditions. It is increasingly recognized that persistent and exaggerated metabolic alterations precede adverse cardiac remodeling leading to heart failure. These metabolic shifts are coupled with changes in cardiac gene expression, driven in part by chromatin-modifying enzymes, which have recently been identified as both sensors and transducers of metabolic stress and gene regulatory networks, respectively. This review synthesizes the latest evidence implicating chromatin-modifying enzymes as key regulators of metabolic reprogramming in the heart, providing a framework to understand how metabolic stressors are incorporated as epigenetic modifications that regulate cardiac gene expression. We propose a model of 'metabo-epigenetic circuitry' within which energy metabolic perturbations drive transcriptional and epigenetic changes that ultimately contribute to cardiac dysfunction. Although many nodes in these circuits remain unidentified, this viewpoint opens new avenues for investigating chromatin-modifying enzymes as therapeutic targets to halt the metabolic programs that promote heart failure.
Epeslidou E, Scott JS, de Klein B
… +3 more, Cudia JT, Melgert B, Prekovic S
EMBO Mol Med
· 2026 Feb · PMID 41381807
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Human-driven environmental change continues to reshape global patterns of disease, as seen in past pollution-related respiratory crises. Microplastics, persistent synthetic polymer particles, have now emerged as a widesp...Human-driven environmental change continues to reshape global patterns of disease, as seen in past pollution-related respiratory crises. Microplastics, persistent synthetic polymer particles, have now emerged as a widespread airborne contaminant with growing relevance for lung health. Continuous inhalation exposure, particularly in indoor environments rich in synthetic fibers, raises concern about their contribution to respiratory disease. Epidemiological and experimental studies increasingly link microplastic exposure to lung cancer, asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis, yet the underlying mechanisms remain poorly defined. This review integrates current evidence on how particle properties influence biological outcomes and outlines how different polymer types, sizes, and aging states affect lung cells through inflammation, oxidative stress, ferroptosis, epithelial-mesenchymal transition, and epigenetic change. Together, these findings suggest that microplastics may act as environmental modifiers that exacerbate disease progression. Recognizing their complex and persistent nature highlights the need for standardized exposure metrics, mechanistic research at realistic doses, and coordinated scientific and regulatory action.
Heron C, Lemarcis T, Laguerre O
… +15 more, Bourgeois B, Thuilliez C, Valentin C, Dumesnil A, Valet M, Godefroy D, Schapman D, Riou G, Candon S, Derambure C, Zernecke A, Berard C, Dauchel H, Tardif V, Brakenhielm E
EMBO Mol Med
· 2026 Jan · PMID 41381806
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Cardiac lymphatic alterations and insufficient lymphatic drainage have been found in cardiovascular diseases (CVDs). To unravel the mechanisms underlying lymphatic dysfunction, we applied single-cell (sc) analyses in mur...Cardiac lymphatic alterations and insufficient lymphatic drainage have been found in cardiovascular diseases (CVDs). To unravel the mechanisms underlying lymphatic dysfunction, we applied single-cell (sc) analyses in murine heart failure (HF) models. Transaortic constriction (TAC) in C57BL/6J and BALB/c mice modeled chronic pressure -overload-induced cardiac hypertrophy and HF, respectively. Cardiac lymphatic (LEC) and blood vascular endothelial cells (BEC) were analyzed by scRNAseq, and targets validated by immunohistochemistry and human LEC cultures. While LEC profiles were comparable between strains in healthy mice, we found expansion of lymphatic capillaries and loss of valves post-TAC only in BALB/c. Differentially expressed gene (DEG) analysis revealed a reduction post-TAC only in BALB/c of lymphatic junctional components. Conversely, LEC expression of immune cell cross-talk mediators was mostly preserved post-TAC. Interestingly, around 35% of DEGs identified in cardiac LECs post-TAC were similarly altered in interleukin (IL)1β-stimulated human LECs. In conclusion, loss of lymphatic valves and dysregulated lymphatic barrier may underlie poor drainage capacity during pressure-overload-induced HF, despite potent lymphangiogenesis and preserved LEC immune attraction. Our work provides tractable targets to restore lymphatic health in CVDs.
Roos L, Garrido-Charles A, Albrecht N
… +12 more, Vavakou A, Alekseev A, Bleyer M, Thirumalai A, Mittring A, Alvanos T, Huet AT, Bamberg E, Kusch K, Wolf BJ, Moser T, Mager T
EMBO Mol Med
· 2026 Feb · PMID 41366521
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Optogenetics allows versatile control of excitable cell networks, which advances basic science research and drives the development of future medical applications. Fast-closing channelrhodopsins (ChRs) are required for hi...Optogenetics allows versatile control of excitable cell networks, which advances basic science research and drives the development of future medical applications. Fast-closing channelrhodopsins (ChRs) are required for high temporal fidelity of neurostimulation, but their short channel open times require sufficient plasma membrane expression and high light intensity, challenging clinical translation. Here, we addressed the need of high-rate neurostimulation by engineering optimized blue-light-sensitive ChR variants. In particular, we report on the ChR2 variant f-ChR2 TC enabling high frequency stimulation at low light requirements, due to its good plasma membrane targeted expression and balanced closing kinetics. Upon Adeno-associated virus (AAV) mediated f-ChR2 TC expression in spiral ganglion neurons of the inner ear in mice, f-ChR2 TC accordingly enabled optogenetic stimulation of the auditory nerve with sizeable responses beyond 300 Hz and low pulse energy thresholds. Translating the approach to the larger cochlea of gerbils, we tested the utility of f-ChR2 TC for evaluating multichannel optical cochlear implants with blue light emitting diodes and found light-efficient stimulation of the auditory pathway by single LEDs at rates ≥100 Hz.
Chava S, Bugide S, Malvi P
… +8 more, DeMarco KD, Ma B, Parikh CN, Ruscetti M, Zajac A, Cai G, Gupta R, Wajapeyee N
EMBO Mol Med
· 2026 Jan · PMID 41366520
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Natural Killer (NK) cells play a critical role in regulating tumor growth, but our understanding of the mechanisms underlying their anti-tumor activity remains limited. We identified the histone methyltransferase EHMT2 a...Natural Killer (NK) cells play a critical role in regulating tumor growth, but our understanding of the mechanisms underlying their anti-tumor activity remains limited. We identified the histone methyltransferase EHMT2 as a key suppressor of NK cell-mediated cytotoxicity. EHMT2 inhibition in cancer cells enhanced NK cell-mediated elimination of diverse cancers, including uveal melanoma, breast cancer, and pancreatic cancer. EHMT2 loss increased AZGP1 and decreased TGF-β1 levels, resulting in the autocrine elevation of NKG2D ligands MICB and ULBP3, chemokines in cancer cells, and the paracrine stimulation of NK cell function. In a syngeneic pancreatic cancer model, EHMT2 inhibition suppressed tumors in an NK cell-dependent manner, as NK cell depletion restored tumor growth. This effect persisted and remained dependent on NK cells in Rag2 knockout mice (lacking T and B cells), but not in NSG mice (lacking T-, B- and NK-cells). Furthermore, EHMT2 and TGF-β1 inhibitors suppressed tumors in immunocompetent, but not in immunodeficient mice. These findings establish EHMT2 as a suppressor of NK cell-mediated anti-tumor immunity and a promising therapeutic target.
Gao H, Zhan Y, Liu Y
… +18 more, Zhu Z, Zheng Y, Qian L, Xue Z, Cheng H, Nie Z, Ge W, Ruan S, Liu J, Zhang J, Sun Y, Zhou L, Xun D, Wang Y, Xu H, Miao H, Zhu Y, Guo T
EMBO Mol Med
· 2026 Jan · PMID 41350775
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Circulating blood proteomics enables minimally invasive biomarker discovery. Nanoparticle-based circulating plasma proteomics studies have reported varying number of proteins (ca 2000-7000), but it remains unclear whethe...Circulating blood proteomics enables minimally invasive biomarker discovery. Nanoparticle-based circulating plasma proteomics studies have reported varying number of proteins (ca 2000-7000), but it remains unclear whether a higher protein number is more informative. Here, we first develop OmniProt-a silica-nanoparticle workflow optimized through a systematic evaluation of nanoparticle types and protein corona formation parameters. Next, we present an Astral spectral library for 10,109 protein groups. Using the Astral with 60 sample-per-day throughput, OmniProt identifies ca 3000 to 6000 protein groups from human plasma. Platelet/erythrocyte/coagulation-related contamination artificially inflates protein identifications and compromises quantification accuracy in nanoparticle-enriched samples. Through controlled contamination experiments, we identified biomarkers for platelet/erythrocyte/coagulation-related contamination in nanoparticle-based plasma proteomics. We developed open-access software Baize for contamination assessment. We validated the pipeline in 193 patients with CT-indistinct benign nodules or early-stage lung cancers, flagging five contaminated samples. This study reveals that contamination alters protein identification/quantification in nanoparticle-based plasma proteomics and presents Baize software to evaluate it.
Weidele K, Werno C, Treitschke S
… +18 more, Botteron C, Hoffmann M, Scheitler S, Wöhrl L, Czyz Z, Feliciello G, Weber F, Ravikumar Varadarajan A, Warfsmann J, Materna-Reichelt S, Katzer M, Schreieder L, Mohammadi P, Hosseini H, Honarnejad K, Haferkamp S, Werner-Klein M, Klein CA
EMBO Mol Med
· 2026 Jan · PMID 41350774
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Relapse in melanoma after targeted or immune therapy necessitates the rapid identification of effective alternatives. To address this gap, we investigated whether the timely generation of preclinical models for functiona...Relapse in melanoma after targeted or immune therapy necessitates the rapid identification of effective alternatives. To address this gap, we investigated whether the timely generation of preclinical models for functional drug testing could reveal additional therapeutic options. Our study focused on: (i) the feasibility of generating in vivo and in vitro models from melanoma lymph node (LN)-derived disseminated cancer cells (DCCs) before relapse, (ii) the implementation of preclinical models to identify therapeutic alternatives, and (iii) the ability to detect patients who could benefit from early functional in vitro drug testing. Successful model generation was significantly associated with DCC quantity, LN origin, and mortality risk. All patient-derived xenograft models were available before patient death and, in 82% of cases, before relapse. Proof-of-concept in vitro drug screening using 315 anti-cancer drugs identified additional candidates, and coculture of DCCs and LN cells revealed specific T-cell activation and responses to immunotherapy. Our data establish a process for selecting melanoma patients at high risk of progression, enabling the timely generation of patient-derived models to support functionally guided treatment decisions at relapse.
Hao S, Xie G, Li D
… +18 more, Su K, Sheng F, Chen L, Gu Y, Jin H, Xu Y, Chen R, Qin Z, Xu D, Xu P, Zhou L, Kong N, Ding H, Chen Z, Liu S, Ji B, Yao K, Fu Q
EMBO Mol Med
· 2026 Jan · PMID 41326717
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The biomechanical signature is directly correlated with the progression of disease in multiple soft tissues. However, their variations and roles, particularly during the initiation period of the disease, remain unclear....The biomechanical signature is directly correlated with the progression of disease in multiple soft tissues. However, their variations and roles, particularly during the initiation period of the disease, remain unclear. Here, we report that PM2.5 exposure induces corneal biomechanical cues alterations prior to corneal injury, as evidenced by increased corneal hysteresis in humans, thickened corneal thickness in rats, and enhanced tensile stress and cortical stiffness in HCECs. Specifically, intracellular PAI-2 is identified as a crucial mediator of the biomechanical responses in HCECs. It modulates PM2.5-induced autophagy and inflammation through a PAI-2/myosin II/F-actin/YAP-positive feedback loop, which ultimately drives HCEC injury. Furthermore, extracellular secretory PAI-2 levels in tears reflect PM2.5-related corneal damage in real time, making it a specific biomarker for the early diagnosis when combined with biomechanical cues. Early intervention for PM2.5-induced ocular damage could be achieved by developing an LNP-siPAI-2 ocular local delivery system targeting intracellular PAI-2. Overall, we propose that biomechanical cues in conjunction with specific biomarkers may serve as targets for the early diagnosis and intervention of soft tissue diseases.
Srour S, Brown FK, Sheffield JW
… +7 more, ElGhazaly M, O'Connor D, Gibani MM, Darton TC, Pollard AJ, Collins MO, Humphreys D
EMBO Mol Med
· 2026 Jan · PMID 41326716
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Salmonella Typhi secretes typhoid toxin that activates cellular DNA damage responses (DDR) during acute typhoid fever. Human infection challenge studies revealed that the toxin suppresses bacteraemia via unknown mechanis...Salmonella Typhi secretes typhoid toxin that activates cellular DNA damage responses (DDR) during acute typhoid fever. Human infection challenge studies revealed that the toxin suppresses bacteraemia via unknown mechanisms. Using quantitative proteomic analysis on the plasma of bacteraemic participants, we demonstrate that wild-type toxigenic Salmonella induced secretion of lysozyme (LYZ) and apolipoprotein C3 (APOC3). Recombinant typhoid toxin or Salmonella infection recapitulated LYZ and APOC3 secretion in cultured cells, which involved ATM/ATR-dependent DDRs and confirmed observations in typhoid fever. LYZ caused spheroplast formation, inhibited the Salmonella type 3 secretion system, and intracellular infections. LYZ expression was regulated by p53 in a cell type-specific manner and driven by mitochondrial oxidative stress that caused nuclear DDRs and p53-mediated senescence responses. Addition of LYZ inhibited oxidative DNA damage and resulting senescence responses caused by typhoid toxin. Our findings may indicate that toxin-induced DDRs elicit antimicrobial responses, which suppress Salmonella bacteraemia during typhoid fever.
Mattsson-Carlgren N, Karlsson L, Tang W
… +9 more, Blennow K, Zetterberg H, Bateman RJ, Schindler SE, Barthelemy N, Palmqvist S, Stomrud E, Janelidze S, Hansson O
EMBO Mol Med
· 2026 Jan · PMID 41326715
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Brain amyloid-β (Aβ) pathology is a core feature of Alzheimer disease (AD) and can be quantified using positron emission tomography (PET). Cerebrospinal fluid (CSF) and plasma biomarkers detect abnormal Aβ, but it is unc...Brain amyloid-β (Aβ) pathology is a core feature of Alzheimer disease (AD) and can be quantified using positron emission tomography (PET). Cerebrospinal fluid (CSF) and plasma biomarkers detect abnormal Aβ, but it is unclear to what degree they can predict quantitative Aβ-PET. We explored plasma and CSF biomarkers in relation to Aβ-PET in the BioFINDER-2 study (N = 1053), and the BioFINDER-1 study (N = 238). We developed a machine learning pipeline to predict Aβ-PET using CSF and plasma measures. The best models achieved R = 0.79. Plasma P-tau217 and CSF Aβ42/Aβ40 contributed the most. CSF Aβ42/Aβ40 contributed most to identify Aβ-positivity, while continuous Aβ-PET load within the positive range was best predicted by plasma P-tau217. Models using only plasma measures approached performance of CSF models. Altered metabolism of soluble Aβ may be highly associated with presence of Aβ plaques, while soluble P-tau217 levels may continue to change during build-up of Aβ pathology.
EMBO Mol Med
· 2026 Jan · PMID 41326714
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Recent advancements in artificial intelligence (AI) have revolutionized the application of electrocardiography (ECG) in cardiovascular diagnostics. This review highlights the transformative impact of AI on traditional EC...Recent advancements in artificial intelligence (AI) have revolutionized the application of electrocardiography (ECG) in cardiovascular diagnostics. This review highlights the transformative impact of AI on traditional ECG analysis, detailing how deep learning algorithms are overcoming the limitations of human interpretation and conventional diagnostic criteria. Historically, ECG interpretation has relied on well-established, physiologically-based criteria. The advancement of AI-ECG is marked by its capacity to process complex high-dimensional data directly from raw signals, revealing patterns often missed by conventional methods. Notably, AI models have identified signs of asymptomatic low ejection fraction and paroxysmal atrial fibrillation during normal sinus rhythm, enabling earlier clinical intervention. In addition to improved diagnostic utility, AI-ECG offers promising applications in risk stratification and community screening. Several randomized controlled trials (RCTs) have shown that integrating AI into clinical workflows not only reduces critical intervention times but also identifies patients at elevated risk of adverse outcomes. Future directions involve integrating additional clinical data sources, improving model interpretability through explainable AI, and developing unified platforms to manage outputs from multiple models.
Catafal-Tardos E, Dachicourt L, Baglioni MV
… +6 more, Fares da Silva MGF, Secci D, Donia M, Kverneland AH, Svane IM, Bekiaris V
EMBO Mol Med
· 2026 Jan · PMID 41310392
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Gamma delta (γδ) T cells are innate-like lymphocytes with potent anti-tumor properties. Herein, we show that immune checkpoint receptors (ICRs) display differential expression and regulation by the JAK-STAT pathway in Vδ...Gamma delta (γδ) T cells are innate-like lymphocytes with potent anti-tumor properties. Herein, we show that immune checkpoint receptors (ICRs) display differential expression and regulation by the JAK-STAT pathway in Vδ1 and Vδ2 cells and identify constitutive (e.g. TIGIT, PD-1) and inducible (e.g. TIM-3, LAG-3, CTLA-4) ICRs. In melanoma, all γδ T cell subsets downregulated AP-1 transcription factors, but Vδ1 cells specifically expressed high levels of ICR, TOX and inhibitory killer Ig-like receptor (KIR) transcripts, reminiscent of exhaustion. However, patient-derived cells were functionally competent, although induction of LAG-3 and CTLA-4 was impaired. During anti-PD-1 monotherapy, Vδ1 cells specifically bound high levels of therapeutic antibody but only in patients who responded to treatment, revealing a potential new prognostic marker for evaluating the efficacy of IC blockade (ICB) therapy. Finally, expression of KIR genes in Vδ1 cells was downregulated in response to successful ICB therapy. Collectively, our data indicate an intricate relationship between ICRs and γδ T cells and reveal novel approaches by which these cells can be harnessed in order to discern or improve cancer immunotherapy.
Shi M, Ye Y, Hu L
… +9 more, Yan Y, Jiang S, Wang P, Li F, Ai M, Huang J, Yang L, Huang K, Liang M
EMBO Mol Med
· 2026 Jan · PMID 41299101
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Obesity is a major global health challenge, and promoting the browning of white adipose tissue (WAT) represents a promising therapeutic strategy. However, pharmacological approaches to induce adipose thermogenesis remain...Obesity is a major global health challenge, and promoting the browning of white adipose tissue (WAT) represents a promising therapeutic strategy. However, pharmacological approaches to induce adipose thermogenesis remain limited. Through a Connectivity Map-based screen, we identified isomeranzin (ISM) as a potent small-molecule activator of WAT browning. ISM enhances thermogenesis in adipocytes by activating the AMP-activated protein kinase (AMPK) pathway. Integrated limited proteolysis-mass spectrometry, cellular thermal shift assays, and molecular docking identified guanine nucleotide-binding protein G(s) alpha subunit (Gnas) as the direct binding target of ISM. Mechanistic studies further revealed that ISM induces WAT browning through the Gnas-dependent activation of cAMP-AMPK signaling cascade. These findings elucidate the molecular mechanism underlying ISM activity and highlight its potential as a lead compound for enhancing energy expenditure and combating obesity.
EMBO Mol Med
· 2026 Jan · PMID 41272322
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Vascular malformations (VMs) are congenital disorders characterized by structurally abnormal blood and lymphatic vessels. Advances in genetics have revealed that most sporadic VMs result from post-zygotic variants in gen...Vascular malformations (VMs) are congenital disorders characterized by structurally abnormal blood and lymphatic vessels. Advances in genetics have revealed that most sporadic VMs result from post-zygotic variants in genes involved in key endothelial signaling pathways, including the phosphoinositide-3-kinase (PI3K) and the mitogen-associated proliferation kinase (MAPK) pathways. As these variants are shared with cancer, genetics now have theragnostic impact by helping predict relevant targeted therapies. mTOR and PI3Kα inhibitors such as sirolimus and alpelisib have shown promising efficacy in slow-flow VMs, while reports have suggested that MAPK inhibitors such as trametinib may improve arteriovenous malformations. Despite these advances, several challenges remain, including obtaining accurate genetic diagnosis, enhancing treatment efficacy while mitigating drug-related toxicities, and personalizing multimodal treatment strategies. Emerging approaches such as mutant-selective inhibitors, proteolysis-targeting chimeras, and gene therapy hold promises for improving treatment specificity and minimizing adverse effects. This review provides an overview of the genetic bases of VMs, recent advances in targeted therapies, and future directions in the field, highlighting the ongoing evolution of precision medicine for VMs.
Manivannan M, Jehanno C, Kloc M
… +17 more, Gomez Miragaya J, Diepenbruck M, Volkmann K, Coissieux MM, Palafox M, Rouchon A, Kramer N, Schmidt A, Blum Y, Hamelin B, Schuster H, Heidinger M, Muenst S, Vetter M, Kurzeder C, Weber WP, Bentires-Alj M
EMBO Mol Med
· 2026 Jan · PMID 41261233
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Estrogen Receptor alpha (ER)-positive, HER2-negative breast cancers are less aggressive than other subtypes and show good patient clinical outcome because they are likely to respond to endocrine therapies. Unfortunately,...Estrogen Receptor alpha (ER)-positive, HER2-negative breast cancers are less aggressive than other subtypes and show good patient clinical outcome because they are likely to respond to endocrine therapies. Unfortunately, therapy-resistant metastases may develop and start an inexorable downhill course. ESR1 mutations leading to resistance to endocrine therapy are prevalent in 20-55% of patients with ER+ metastatic breast cancer. Here, we found that glucocorticoid receptor (GR) activation by dexamethasone in ESR1 mutant metastases-bearing mice decreases liver metastases and prolongs survival. Transcriptomic and proteomic profiling revealed that GR activation not only downregulates estrogen response signature but also induces dramatic loss of ER itself. ChIP-Seq analyses show that prolonged dexamethasone treatment almost completely abrogates ER chromatin binding and that GR binds a subset of ER-related genes, including ESR1. Finally, the GR activity signature predicts a good outcome in patients with ER+ breast cancer. In summary, we show that dexamethasone inhibits ER+ metastatic growth by depleting ER, and hence could be tested for treating patients with ER+ metastatic breast cancer, particularly those suffering from refractory ESR1 mutant metastases.
Middleton G, Mahamud FO, Storer ISR
… +15 more, Williams-Gunn A, Wostear F, Abdolrasouli A, Barclay E, Bradford A, Steward O, Schelenz S, McColl J, Lézé B, van Rhijn N, da Silva Dantas A, Furukawa T, Warren D, Waller ZAE, Bidula S
EMBO Mol Med
· 2025 Dec · PMID 41249737
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Fungi are estimated to cause the death of almost 4 million people annually, and we urgently need new drug targets to overcome antifungal resistance. We found that four-stranded nucleic acid structures called G-quadruplex...Fungi are estimated to cause the death of almost 4 million people annually, and we urgently need new drug targets to overcome antifungal resistance. We found that four-stranded nucleic acid structures called G-quadruplexes (G4s) could form within the critical priority fungal pathogen Aspergillus fumigatus. Sequences with the potential to form G4s could be found in genes involved in fungal growth, virulence, and drug resistance. This included cyp51A, which encodes the target of azoles. Notably, we observed the formation of both canonical and unusual acid-stabilised G4s in these sequences. We found that PhenDC3 (a G4-stabilising ligand) could refold DNA into antiparallel G4 structures in cyp51A that were associated with decreased transcription. PhenDC3 also had potent fungistatic activity, prevented germination, synergised with the antifungal amphotericin B in vitro and in vivo, and displayed low genotoxicity and cytotoxicity towards human cells. Interestingly, PhenDC3 had greater antifungal activity towards the pan-azole-resistant A. fumigatus TR34/L98H isolate, and another G4-stabiliser, pyridostatin, killed multi-drug-resistant Candida auris. Taken together, G4s represent a promising target for the development of antifungals with novel mechanisms of action.
Gizaw NY, Kolari K, Kallio P
… +2 more, Alitalo K, Kivelä R
EMBO Mol Med
· 2025 Dec · PMID 41249736
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Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma, with poor outcomes in high-risk and relapsed patients. Here, we identify de novo cholesterol biosynthesis as a critical metabolic vulnerability in...Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma, with poor outcomes in high-risk and relapsed patients. Here, we identify de novo cholesterol biosynthesis as a critical metabolic vulnerability in RMS. The transcription factor PROX1, previously implicated in RMS growth, acts as an upstream regulator of cholesterol biosynthesis, promoting expression of key pathway genes. Inhibition of cholesterol biosynthesis, either genetically or pharmacologically, impaired RMS cell proliferation, caused a broad halt of cell cycle progression, and activated ER stress-mediated apoptosis through the PERK-ATF4-CHOP axis. Notably, RMS cells could not be rescued by exogenous LDL cholesterol, indicating a unique reliance on endogenous cholesterol production, whereas normal cells, including myoblasts and astrocytes, largely relied on extracellular cholesterol uptake. Clinical and single-cell RNA-seq analyses further revealed that high expression of cholesterol biosynthesis genes correlate with poor survival and enrichment of cell cycle-related gene signatures across RMS subtypes. Together, these findings mechanistically link cholesterol biosynthesis to proliferative signaling and ER stress response in RMS and highlight this pathway as a promising, non-redundant therapeutic target.