J Clin Invest
· 2026 Jun · PMID 42222891
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Alveolar type 2 cells (AT2s) are critical to lung regeneration, and the absence of large-scale methods to expand AT2s has hindered regenerative medicine efforts. We report a microcarrier-based, large-scale expansion meth...Alveolar type 2 cells (AT2s) are critical to lung regeneration, and the absence of large-scale methods to expand AT2s has hindered regenerative medicine efforts. We report a microcarrier-based, large-scale expansion method that was used to generate hundreds of billions of human AT2s. Through our process, expanded AT2s largely retained their phenotype. Furthermore, we showed that culture medium, substrate composition, and stiffness are all critical to the maintenance of AT2s. Finally, we showed that expanded AT2s can differentiate into alveolar type 1-like cells, both in vitro and in a decellularized porcine lung, demonstrating the utility of these cells for lung tissue engineering.
Li F, Shinomiya H, Kuramoto Y
… +21 more, Kanaoka K, Sakahashi Y, Ishihara Y, Kioka H, Ide S, Yamaguchi-Kabata Y, Tadaka S, Motoike IN, Kinoshita K, Ohneda K, Sakurai H, Okumura T, Miyashita Y, Jojima K, Kato H, Matsuoka K, Tanabe K, Nishimura S, Takashima S, Asano Y, Sakata Y
J Clin Invest
· 2026 Jun · PMID 42222889
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Dilated cardiomyopathy (DCM) is a genetically heterogeneous disorder, characterized by ventricular dilatation and impaired systolic function, leading to heart failure and sudden cardiac death. Despite advances in genomic...Dilated cardiomyopathy (DCM) is a genetically heterogeneous disorder, characterized by ventricular dilatation and impaired systolic function, leading to heart failure and sudden cardiac death. Despite advances in genomic technologies, the genetic cause of DCM remains unidentified in more than half of the cases. Here, we performed an integrative analysis of genomic and transcriptomic data from patient-derived cardiac tissue to identify causative variants in genetically undiagnosed DCM. This approach enabled us to identify a homozygous splice-site variant (c.243+6T>A) in the sarcoglycan gene SGCB, which results in exon 2 skipping. This variant was significantly enriched in patients with DCM compared with the general population, with consistent genotype-phenotype correlations observed across multiple families. Protein-level analysis of cardiac tissue from homozygous individuals revealed loss of β-sarcoglycan, the protein product of SGCB, and destabilization of the sarcoglycan complex. Although SGCB has been previously associated with limb-girdle muscular dystrophy, these homozygous individuals showed no biochemical or clinical signs of skeletal muscle involvement, indicating an absence of myopathy. Compared with variant-negative patients with DCM, homozygous individuals also had a higher risk of early-onset adverse cardiac events. Together, these findings identify c.243+6T>A in SGCB as a cause of isolated DCM associated with unfavorable clinical outcomes.
Ma Y, Zhao C, Guo J
… +11 more, Fu Y, Wang W, Zhang J, Zhao K, Meng X, Yuan Z, Gao C, Jia M, Qin Y, Song H, Zhao W
J Clin Invest
· 2026 Jun · PMID 42222888
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The cyclic dinucleotide 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP) serves as a central immunotransmitter that propagates stimulator of interferon gene-dependent (STING-dependent) innate immu...The cyclic dinucleotide 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP) serves as a central immunotransmitter that propagates stimulator of interferon gene-dependent (STING-dependent) innate immunity across tissues; however, how microenvironmental metabolites regulate its spatiotemporal dynamics remains unknown. Here, we identified polyamines (spermine and spermidine) as critical rheostats controlling 2'3'-cGAMP functionality. Mechanistically, polyamines sequestered 2'3'-cGAMP into polymer-like aggregates, blocking intercellular propagation and suppressing intracellular STING activation by reducing ligand-receptor binding affinity. Deficiency of spermidine and spermine N1-acetyltransferase 1 (SAT1), the rate-limiting enzyme in polyamine catabolism, elevated polyamine levels to entrap extracellular 2'3'-cGAMP and inhibit STING activation. Synergistic administration of endogenous 2'3'-cGAMP with SAT1 stabilizer N1,N11-diethylnorspermine restored 2'3'-cGAMP bioavailability and STING signaling, facilitated type I interferon responses to reprogram immunologically suppressive tumors into immunologically active states and enhanced tumor clearance. Our study established polyamine-cGAMP interactions as a critical spatiotemporal regulatory mechanism for tissue-level immunity, providing a unified model for metabolite-mediated cyclic GMP-AMP synthase-STING (cGAS-STING) regulation across diseases.
Michels S, Chen C, Ruf WP
… +13 more, Garcia Garcia MM, Arnold FJ, Wu Z, Bennett CL, Shams D, Thompson LM, Walker AC, Dickson DW, Petrucelli L, Dorst J, Prudencio M, Li W, La Spada AR
J Clin Invest
· 2026 Jun · PMID 42222887
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The role of the epigenome in age-related neurodegenerative disorders remains understudied. Here, we analyzed circulating cell-free DNA (cfDNA) from blood to detect methylation changes as a liquid biopsy for Amyotrophic L...The role of the epigenome in age-related neurodegenerative disorders remains understudied. Here, we analyzed circulating cell-free DNA (cfDNA) from blood to detect methylation changes as a liquid biopsy for Amyotrophic Lateral Sclerosis (ALS). Our study included 20 patients with sporadic ALS, 10 patients with C9orf72-associated ALS, 10 asymptomatic carriers of the C9orf72 repeat expansion mutation, and 21 nondisease control individuals. Following targeted enzymatic methyl-sequencing (EM-seq) of approximately 4 million CpG sites, we detected numerous differentially methylated genes, including several implicated in ALS disease risk and pathogenesis. By integrating multiple epigenetic features, we delineated a distinct epigenetic signature, which achieved an average area under the curve (AUC) of 0.91 ± 0.10 upon receiver operator characteristic (ROC) analysis, which enabled detection of approximately 70% of patients with ALS with close to 100% specificity. Furthermore, we also identified a set of genes whose methylation status significantly correlated with clinical disease progression and cerebrospinal fluid (CSF) neurofilament levels. Our results reveal the potential of cfDNA-based biomarkers to accurately diagnose ALS and potentially predict disease progression.
J Clin Invest
· 2026 Jun · PMID 42222886
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The Western diet (WD) is a rich source of saturated fatty acids, especially palmitic acid (PA), which has been implicated in the pathogenesis of insulin resistance, oxidative stress, inflammation, diabetes, and multiorga...The Western diet (WD) is a rich source of saturated fatty acids, especially palmitic acid (PA), which has been implicated in the pathogenesis of insulin resistance, oxidative stress, inflammation, diabetes, and multiorgan dysfunction in obesity and diabetes. In this issue of the JCI, a study by Balasubramaniam et al. describes mechanisms linking a WD, PA, ferroptosis (iron-dependent cell death), and loss of colonic motility. Chronic PA exposure drove ferroptosis in murine in vitro systems and human myenteric ganglia. Mice fed a WD for 12 weeks developed enteropathy and loss of colonic motility, which was reversed by adeno-associated virus-mediated (AAV-mediated) overexpression of the transcription factor NFE2L2, preventing ferroptosis and restoring redox balance to enteric neurons. The study provides critical data establishing PA-induced ferroptosis as a mediator and potential therapeutic target in enteric nervous system disorders associated with obesity.
J Clin Invest
· 2026 Jun · PMID 42222885
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Identification of the genetic mutations underlying the ultrarare monogenic conditions STING-associated vasculopathy with onset in infancy (SAVI) and coatomer protein complex subunit alpha (COPA) syndrome revealed a role...Identification of the genetic mutations underlying the ultrarare monogenic conditions STING-associated vasculopathy with onset in infancy (SAVI) and coatomer protein complex subunit alpha (COPA) syndrome revealed a role for the stimulator of interferon genes (STING) immune pathway in the pathogenesis of interstitial lung disease (ILD) in these conditions. STING-focused therapeutics could be a potential avenue for the treatment of SAVI and COPA syndrome in the future, yet the relevance of STING to more common types of ILD is not clear. Here, we provide an overview of SAVI and COPA syndrome, the nature of ILD in these conditions, and current evidence regarding STING activity in their pathogenesis. We discuss data from studies of a variety of other ILDs and model systems and explore the potential role for STING in more common forms of ILD.
J Clin Invest
· 2026 Jun · PMID 42222884
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Liver fibrosis is a common pathological outcome of chronic liver disease and is driven by inflammatory responses. However, the early signals that initiate the inflammatory cascade remain poorly understood. Emerging evide...Liver fibrosis is a common pathological outcome of chronic liver disease and is driven by inflammatory responses. However, the early signals that initiate the inflammatory cascade remain poorly understood. Emerging evidence suggests that liver sinusoidal endothelial cells (LSECs) are not merely passive bystanders, but active regulators during liver fibrosis. In this issue of the JCI, Gan et al. demonstrated in multiple preclinical models that BRD4/PML-mediated super-enhancer activation in LSECs drives proinflammatory angiocrine signaling, thereby initiating liver fibrosis. Thus, targeting this endothelial axis may offer a promising therapeutic strategy for the treatment of liver fibrosis.
Park DJ, Jones KM, Anderson JB
… +2 more, Finck AV, Miner JJ
J Clin Invest
· 2026 Jun · PMID 42222883
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Breakthroughs in rare genetic disease research elucidate the relationships among cytosolic DNA sensing, genome instability, and autoimmune disease phenotypes. Cytosolic self-DNA is a potent trigger of innate immunity, ac...Breakthroughs in rare genetic disease research elucidate the relationships among cytosolic DNA sensing, genome instability, and autoimmune disease phenotypes. Cytosolic self-DNA is a potent trigger of innate immunity, activating the DNA sensor cyclic GMP-AMP synthase (cGAS) and its downstream effector stimulator of interferon genes (STING). This pathway is negatively regulated by the DNA-degrading enzyme three-prime repair exonuclease 1 (TREX1); loss-of-function TREX1 variants lead to accumulation of cytosolic DNA, resulting in STING-mediated autoinflammation. Similarly, STING gain-of-function mutations cause STING-associated vasculopathy with onset in infancy, another disease characterized by multi-organ damage, disability, and premature death. The TREX1-cGAS-STING pathway has also been implicated in regulation of genome stability. Indeed, DNA damage lies at the heart of a separate TREX1-mediated disease, known as retinal vasculopathy with cerebral leukoencephalopathy, where the aberrant nuclear activity of mislocalized TREX1 damages genomic DNA, resulting in multi-organ degeneration syndrome with features of autoimmunity. Thus, monogenic autoimmune diseases and DNA damage syndromes sometimes overlap clinically, and the study of these diseases has created pathways for developing first-in-class small molecule therapeutics.
Wu W, Zhang P, Wang D
… +13 more, Wu X, Wu Q, Li D, Huang T, Wang R, Li H, Mi H, Taori S, Yuan F, Duan T, Chen Z, Yuan H, Rich JN
J Clin Invest
· 2026 Jun · PMID 42222882
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Cancers reprogram their metabolism to provide anabolic needs without driving excessive oxidative stress. Attention has focused on glucose metabolism, yet amino acid synthesis and degradation also promote tumor cell state...Cancers reprogram their metabolism to provide anabolic needs without driving excessive oxidative stress. Attention has focused on glucose metabolism, yet amino acid synthesis and degradation also promote tumor cell states and growth. Here, we assessed amino acids that maintain cancer stem cells in glioblastoma and found increased proline levels relative to differentiated tumor progeny through increased proline synthesis. Cancer stem cells preferentially expressed the signaling molecule FAM3C induced by the stem cell transcription factor SOX2 to drive expression of proline synthesis enzymes. FAM3C classically mediated cellular responses as a secreted protein but gained intracellular functions in cancer stem cells through binding the histone reader spindlin 1 (SPIN1), thereby preventing its lysosomal degradation, assisting its nuclear localization, and promoting epigenetic regulation of proline synthesis. Proline synthesis depleted ROS, and genetic targeting of FAM3C attenuated ROS scavenging, whereas SPIN1 OE restored ROS levels. Molecular docking identified tucatinib as a brain-penetrant pharmacologic disruptor of FAM3C-SPIN1 interactions, promoting SPIN1 degradation and reducing intracellular proline levels. Thus, cancer stem cells induced a favorable metabolic state through proline synthesis and ROS depletion, revealing potential therapeutic dependencies.
J Clin Invest
· 2026 Jun · PMID 42222881
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Cytosolic DNA sensing through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has emerged as a promising strategy to elicit antitumor immunity. However, clinical translation of STING ago...Cytosolic DNA sensing through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has emerged as a promising strategy to elicit antitumor immunity. However, clinical translation of STING agonists has been hindered by limited efficacy and dose-limiting inflammatory toxicity, highlighting that simply providing activating ligands is insufficient to achieve durable immune responses. In this issue of the Journal of Clinical Investigation, Liao et al. showed that intracellular aspartate availability critically shapes STING signaling responsiveness. Aspartate deficiency disrupted pyrimidine synthesis, induced mtDNA stress, and engaged a feed-forward Z-DNA binding protein 1 and receptor interacting serine/threonine kinase 1/3 axis. Rather than directly triggering immunity, this metabolic state primed DNA sensing and fueled downstream signaling, thereby enabling robust and sustained antitumor immune responses. Together, these findings position nucleotide metabolism as a key determinant of innate immune responsiveness and suggest that metabolic conditioning may enhance the efficacy of STING-targeted therapies.
Liao Y, Wang H, Liu H
… +11 more, Chen X, Sun R, Li X, Yang Z, Liu C, Wu W, He Z, Zhao Y, Mao Y, Ye D, Yang H
J Clin Invest
· 2026 Jun · PMID 42222880
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Metabolic signals critically shape innate immune responses. Through pharmacological screening of metabolic pathways, we identified aspartate metabolism as a key regulator of cyclic GMP-AMP synthase (cGAS)-stimulator of i...Metabolic signals critically shape innate immune responses. Through pharmacological screening of metabolic pathways, we identified aspartate metabolism as a key regulator of cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling. Genetically or aminooxyacetic acid-mediated (AOA-mediated) pharmacologically reducing aspartate levels markedly potentiated the cGAS-STING pathway, leading to stronger upregulation of type I interferons and interferon-stimulated genes. Mechanistically, disruption of de novo pyrimidine synthesis, a major downstream pathway of aspartate, induced mtDNA replication stress and increased mtDNA double-strand breaks, promoting mtDNA release into the cytosol. Cytosolic mtDNA synergized with cGAS-STING agonists to upregulate Z-DNA binding protein 1 (ZBP1), which recruits RIPK1/3 to sustain IRF3 phosphorylation, forming a positive feedback loop that amplifies innate immune signaling. In immunocompetent mouse models, AOA enhanced the antitumor efficacy of STING agonists, chemotherapy, or radiotherapy, whereas aspartate supplementation abrogated these effects. Consistently, aspartate levels negatively correlated with antitumor immunity in colorectal cancer patient samples. Together, our study identifies aspartate-pyrimidine metabolism as a critical metabolic checkpoint that licenses STING signaling by enabling mtDNA stress to cooperate with agonist stimulation, driving type I interferon-dependent ZBP1 induction and feed-forward amplification of STING signaling, thus offering a promising strategy to enhance antitumor immunity.
J Clin Invest
· 2026 Jul · PMID 42207844
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BACKGROUNDRight ventricular failure (RVF) is a major determinant of mortality in pulmonary arterial hypertension (PAH), and hepatic dysfunction predicts adverse outcomes. However, the cell-specific effects of PAH/RVF on...BACKGROUNDRight ventricular failure (RVF) is a major determinant of mortality in pulmonary arterial hypertension (PAH), and hepatic dysfunction predicts adverse outcomes. However, the cell-specific effects of PAH/RVF on the human liver remain poorly defined.METHODSWe performed single-nucleus RNA-seq (snRNA-seq) of autopsy-derived liver tissue from 5 patients with PAH and 4 healthy individuals (non-PAH) treated as controls and compared these findings with publicly available snRNA-seq datasets from nonalcoholic steatohepatitis (NASH) and Fontan-associated liver disease (FALD). Transcriptomic analyses were integrated with histologic assessment, mitochondrion-enriched proteomics, and correlations with clinical markers of PAH/RVF severity.RESULTSPAH livers showed cell-specific metabolic, inflammatory, and fibrotic remodeling distinct from NASH and FALD. PAH hepatocytes exhibited a hypoxia-adapted, Warburg-like metabolic phenotype with reduced fatty acid metabolism, gluconeogenesis, cytochrome P450 activity, and ketone metabolism. PAH endothelial cells demonstrated increased glycolytic pathway activity and altered adhesion/barrier signaling. PAH hepatic stellate cells (HSCs) displayed HIF-1 and PI3K/Akt pathway activation, increased IL-6 expression, and histologic evidence of perivascular fibrotic remodeling. PAH macrophages showed complement activation with reduced JAK/STAT signaling. HSC HIF-1 activity correlated with clinical markers of PAH/RVF severity.CONCLUSIONPAH induces a distinct metabolic and inflammatory hepatopathy characterized by hepatocyte metabolic reprogramming, HSC activation, macrophage complement signaling, and suppressed ketone metabolism. These findings support PAH-associated hepatopathy as a disease-specific end-organ phenotype linked to RVF severity.FUNDINGNIH grants F31 HL170585, R01 HL158795, and R01 HL162927.
Singh PN, Bachir EH, Howe JR
… +9 more, Bellizzi AM, Cejas P, Madha-Krause S, Epstein CB, Chan JA, Bernstein B, Kulke MH, Zhou Q, Shivdasani RA
J Clin Invest
· 2026 Jul · PMID 42166365
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Cancers reflect aberrant growth and differentiation of normal cell populations. Biological understanding of small intestine neuroendocrine tumors (SI-NETs) is hampered because their closest normal counterparts, enteroend...Cancers reflect aberrant growth and differentiation of normal cell populations. Biological understanding of small intestine neuroendocrine tumors (SI-NETs) is hampered because their closest normal counterparts, enteroendocrine cells (EECs), constitute tiny fractions of intestinal epithelium. Recent characterization of adult human EEC ontogeny from intestinal stem cells can help overcome that limitation. Transient expression of the transcription factor gene ASCL1 normally ensures proper timing and fidelity of well-differentiated EECs, which express NEUROD1. Here, we report that SI-NETs resembled mature enterochromaffin cells; however, individual tumor cells coexpressed stem/progenitor genes, harboring each differentiation state along the EEC trajectory except ASCL1+ precursors. We found that enhancers normally active, and others inactive, during EEC differentiation underlie aberrant SI-NET gene activity. SI-NETs uniformly expressed NEUROD1 but lacked ASCL1, owing to inaccessible chromatin and repressive H3K27me3 marking at the ASCL1 locus. Multiple cyclin-dependent kinase inhibitor (CDKi) genes were similarly silenced, other than CDKN1B, the only gene recurrently mutated in SI-NETs. Deletion of CDKN1B altered cell cycle kinetics during human EEC differentiation, and deletions of ASCL1 or CDKN1B activated certain genes that are expressed in SI-NETs but not in the normal EEC trajectory. We propose that a limited CDKi repertoire and absence of ASCL1-dependent constraints on EEC maturation together explain unique SI-NET characteristics.
Tanaka M, Kim NC, Draper I
… +8 more, Littel HR, Gunasekaran M, Turner J, Wells NM, Mujteba Q, Asakura Y, Kang PB, Asakura A
J Clin Invest
· 2026 Jul · PMID 42154534
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We previously identified a muscular dystrophy caused by biallelic variants in JAGGED2 (JAG2), whose protein product, JAG2, is a canonical NOTCH ligand. However, the disease mechanism remains unclear, particularly with re...We previously identified a muscular dystrophy caused by biallelic variants in JAGGED2 (JAG2), whose protein product, JAG2, is a canonical NOTCH ligand. However, the disease mechanism remains unclear, particularly with respect to muscle stem cell (muscle satellite cell/MuSC) function and muscle regeneration. We examined the consequences of JAG2 deficiency and modeled pathogenic JAG2 variants in vitro and in vivo, the latter in mouse and fly models and with particular attention to the MuSC-muscle endothelial cell (MuEC) niche. We found that both Jag2 deficiency and overexpression of pathogenic JAG2 variants impaired NOTCH signaling and myogenic self-renewal and differentiation. Hypomorphic Jag2 mutant (Jag2sm) mice displayed depleted MuSCs, corresponding with impaired muscle regeneration in those mice. Coculture experiments and the examination of cell type-specific Jag2 conditional knockout mice demonstrated that MuEC-specific Jag2 knockout resulted in reduced MuSC self-renewal, while MuSC-specific Jag2 knockout resulted in reduced myogenic differentiation. Human reference JAG2, but not human pathogenic variants of JAG2, rescued the deficiency of Serrate, the Drosophila ortholog of JAG2. Therefore, pathogenic variants in JAG2 impair muscle development and regeneration through disrupted cell-autonomous cis-inhibition and nonautonomous trans-activation involving NOTCH signaling dysfunction. Our findings indicate that optimizing JAG2-mediated NOTCH signaling is a potential therapeutic approach for JAG2-related muscular dystrophy.
Mu J, Maeda K, Iida T
… +18 more, Mii S, Esaki N, Shiraki Y, Mizutani Y, Nakamura M, Yamamura T, Sawada T, Ishikawa E, Murate K, Hirose T, Furukawa K, Oishi A, Suzuki H, Kishida T, Nakayama G, Fujishiro M, Kawashima H, Enomoto A
J Clin Invest
· 2026 Jul · PMID 42154532
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Dysfunctional intestinal fibrosis is an irreversible complication of Crohn's disease (CD). The complex heterogeneity of intestinal mesenchymal cells makes it difficult to understand the pathogenesis of intestinal fibrosi...Dysfunctional intestinal fibrosis is an irreversible complication of Crohn's disease (CD). The complex heterogeneity of intestinal mesenchymal cells makes it difficult to understand the pathogenesis of intestinal fibrosis. Previously, we identified Meflin as a marker of fibroblast subsets. This study aimed to explore the role of Meflin-positive fibroblasts in intestinal fibrogenesis and investigate the potential of pharmacological control of Meflin expression as a treatment for patients with CD. Our results indicated that Meflin expression was upregulated in fibroblasts at the early stage of fibrosis but was downregulated in established fibrosis in both patients with CD and 2 different mouse models, which are the chronic dextran sodium sulfate (DSS) model and an IL-10-deficient model that spontaneously develops intestinal inflammation. Meflin-deficient mice exacerbated intestinal fibrosis with dysregulated expression of noncanonical Wnt ligand WNT5A and its receptor ROR2. Pharmacologically induced Meflin expression through the administration of a synthetic retinoid reversed intestinal fibrosis in the DSS model and suppressed profibrotic protein secretion in fibroblasts isolated from patients with CD. Our findings indicate that Meflin-positive fibroblasts represent a functional subpopulation that suppresses intestinal fibrosis. Augmentation of Meflin expression shows antifibrotic effects and holds promise as a therapeutic approach for intestinal fibrosis in patients with CD.
Bandaru R, Fu H, Zheng H
… +17 more, Liang J, Wang L, Gulati S, Hinrichs BH, Teng M, Zhang B, Kocherginsky M, Lin DC, Hildeman DA, Worden FP, Old M, Dunlap NE, Kaczmar JM, Gillison ML, El-Gamal D, Wise Draper T, Liu Y
J Clin Invest
· 2026 Jul · PMID 42154530
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BACKGROUNDMinimally invasive biomarkers predicting the immunotherapy response in head and neck squamous cell carcinoma (HNSCC) remain an unmet clinical need.METHODSIn a prospective, multi-institutional phase II trial, we...BACKGROUNDMinimally invasive biomarkers predicting the immunotherapy response in head and neck squamous cell carcinoma (HNSCC) remain an unmet clinical need.METHODSIn a prospective, multi-institutional phase II trial, we performed whole-genome sequencing of 185 longitudinal plasma cell-free DNA (cfDNA) samples from 68 patients with locally advanced, surgically resectable HNSCC who received neoadjuvant and adjuvant pembrolizumab. We developed the regional motif diversity score (rMDS), a fragmentomic metric that quantifies the entropy of cfDNA 5'-end motifs across genomic regions.RESULTSUnsupervised analysis showed that rMDS robustly distinguished responders from nonresponders, outperforming established fragmentomic metrics and copy number alterations while remaining independent of technical confounders. Longitudinal rMDS changes localized to regions enriched for immune-, lectin-, and keratinization-related genes - hallmarks of squamous cell carcinoma - reflecting tumor-peripheral immunity interplay during treatment. The most dynamic regions clustered at telomere-proximal loci, suggesting a link between telomere biology and cfDNA fragmentation. An rMDS-based machine learning classifier achieved AUC 0.89-0.99 across validation settings, with the highest accuracy after treatment, outperforming PD-L1 expression and tumor fraction in matched samples. Predicted responders showed improved disease-free survival (log-rank P = 0.035; HR 2.67, 95% CI 1.03-6.92).CONCLUSIONrMDS represents a biologically meaningful and clinically actionable biomarker for the immunotherapy response in HNSCC, and merits integration into future risk assessment frameworks.TRIAL REGISTRATIONClinicalTrials.gov NCT02641093.FUNDINGNational Human Genome Research Institute (NHGRI), NIH grant R56HG012360; startup funds from Cincinnati Children's Hospital Medical Center, Northwestern University, and Robert H. Lurie Comprehensive Cancer Center; Science Olympiad Alumni Research Grant, Science Olympiad USA Foundation; Merck Sharp & Dohme Corp.
Lin Q, Luo J, Duan Z
… +14 more, Luo J, Zhang W, Xia Y, Zeng Y, Fang X, Liang J, Chen J, Lin Q, Quan Y, Hu R, Liu H, Liu Q, Li J, Gong C
J Clin Invest
· 2026 May · PMID 42138086
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Bone metastasis remains a major cause of morbidity in estrogen receptor-positive breast cancer, with RANKL inhibitor resistance emerging as a critical clinical challenge. Nearly 40% of patients develop progressive skelet...Bone metastasis remains a major cause of morbidity in estrogen receptor-positive breast cancer, with RANKL inhibitor resistance emerging as a critical clinical challenge. Nearly 40% of patients develop progressive skeletal lesions despite denosumab therapy, highlighting an urgent need to identify resistance mechanisms and alternative therapeutic strategies. We identified a RANKL-independent osteoclast activation pathway mediated by the CRKL/circCCDC50/NFATc1 axis. Mechanistically, CRKL promoted EIF4A3-dependent circCCDC50 biogenesis, which was packaged into large oncosomes and transferred to osteoclast precursors. Nuclear circCCDC50 recruited CARM1 to epigenetically activate NFATc1 transcription, establishing a self-reinforcing loop that sustained osteolysis despite RANKL blockade. Pharmacological inhibition of CARM1 (TP-064) effectively suppressed osteoclastogenesis and bone metastasis in denosumab-resistant models. These findings revealed a targetable resistance mechanism and provided a clinically actionable strategy to overcome microenvironment-driven metastasis through dual targeting of tumor and bone niches.
Teh SSK, Kotwal A, Bennett A
… +16 more, Halper-Stromberg E, Morsberger L, Zamani S, Shi Y, Skaist A, Zhu Q, Bowland K, Liang H, Hruban RH, Hung CF, Anders RA, Roberts NJ, Scharpf RB, Goldstein M, Zou YS, Eshleman JR
J Clin Invest
· 2026 May · PMID 42138085
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While radiation is an effective oncologic therapy, killing cancer by inducing DNA double-strand breaks (DSBs), it lacks specificity for neoplastic cells. We have previously adapted the CRISPR/Cas9 gene-editing technology...While radiation is an effective oncologic therapy, killing cancer by inducing DNA double-strand breaks (DSBs), it lacks specificity for neoplastic cells. We have previously adapted the CRISPR/Cas9 gene-editing technology as a cancer-specific treatment modality targeting somatic mutations in pancreatic cancer (PC). However, its tumoricidal potential remains unclear, especially in comparison with therapeutic doses of radiation. Here, we demonstrate that CRISPR/Cas9-induced DSBs are more cytotoxic in PCs than a comparable number of radiation-induced DSBs. We observed more than 90% tumor growth inhibition by targeting 9 sites with cancer-specific sgRNAs. Through both bioinformatics and cytogenetics analyses, we found that CRISPR/Cas9-induced DSBs triggered ongoing chromosomal rearrangements, with 87% of structural variants not directly produced from the initial CRISPR/Cas9-induced DSBs, and chromosomal instability peaking before cell death. By comparing the cytotoxicity of CRISPR/Cas9- and radiation-induced DSBs, we demonstrated that the number of DSBs required to achieve equitoxic effects was approximately 3 times higher for radiation than CRISPR/Cas9. Finally, we showed that PC cells that had survived CRISPR/Cas9 targeting retained susceptibility to subsequent CRISPR/Cas9-induced DSBs at different genomic sites with more than 87% growth inhibition. Together, our data support the therapeutic potential of CRISPR/Cas9 as an anticancer strategy.
J Clin Invest
· 2026 May · PMID 42138084
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Immune checkpoint inhibitors (ICIs) have improved patient outcomes substantially in non-small cell lung cancer (NSCLC). Despite considerable effort, our understanding of the features that predict for immunotherapy respon...Immune checkpoint inhibitors (ICIs) have improved patient outcomes substantially in non-small cell lung cancer (NSCLC). Despite considerable effort, our understanding of the features that predict for immunotherapy response and resistance in patients remains incomplete. In this issue of the JCI, Isomoto and colleagues utilized a multiplex IHC platform to profile the spatial organization of the lung cancer tumor immune microenvironment, enabling the identification of spatial immune features that correlate with immunotherapy efficacy. This study enhances our knowledge of the spatial organization of features impacting ICI efficacy by identifying a three-variable spatial composite - including CD73 upregulation in EGFR-mutant NSCLC - that substantially outperforms PD-L1 expression in predicting immunotherapy efficacy. Moreover, it establishes spatial proteomic profiling as a platform for generating therapeutic hypotheses that are actionable and mechanistic in NSCLC.
J Clin Invest
· 2026 May · PMID 42138083
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Anemia affects one-third of the population globally and is marked by impaired erythropoiesis that results in substantial mortality and morbidity. Over the past few decades, our understanding of the molecular mechanisms u...Anemia affects one-third of the population globally and is marked by impaired erythropoiesis that results in substantial mortality and morbidity. Over the past few decades, our understanding of the molecular mechanisms underlying anemia has progressed but translating that knowledge into effective targeted therapeutics remains challenging. Preclinical and clinical studies substantiate the efficacy of modulating erythropoietin-driven signaling pathways to stimulate erythropoiesis. Additional approaches include strategies to maintain iron homeostasis and control iron metabolism, using small molecules and oral supplements. New frontiers in molecular regulation of anemia include perturbation of regulatory genes and spliceosome proteins in erythroid cells, as well as mutation-specific therapeutic approaches. Finally, new evidence supporting the importance of neuronal signaling and mitochondrial dynamics in shaping erythropoiesis is pointing toward novel interventions. Here, we discuss the molecular and genetic factors underlying defective erythropoiesis and highlight current and emerging therapies, including molecular targets to overcome drug resistance.