Issue published August 15, 2025 Previous issue
- Volume 135, Issue 16
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On the cover: SOX2 regulates upper GI squamous epithelial identity
Jin et al. report the critical role of the transcription factor SOX2 in foregut squamous epithelial differentiation. Decreased expression of SOX2 is an initiating step in progression to Barrett’s esophagus. The cover art was produced using Adobe Photoshop based on an H&E image of Barrett’s esophagus adjacent to esophageal squamous epithelium. Image credit: Ramon Jin.
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Review Series
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Abstract
The genetic landscape of pancreatic ductal adenocarcinoma (PDAC) is well-established and dominated by four key genetic driver mutations. Mutational activation of the KRAS oncogene is the initiating genetic event, followed by genetic loss of function of the CDKN2A, TP53, and SMAD4 tumor suppressor genes. Disappointingly, this information has not been leveraged to develop clinically effective targeted therapies for PDAC treatment, where current standards of care remain cocktails of conventional cytotoxic drugs. Nearly all (~95%) PDAC harbors KRAS mutations, and experimental studies have validated the essential role of KRAS mutation in PDAC tumorigenic and metastatic growth. Identified in 1982 as the first gene shown to be aberrantly activated in human cancer, KRAS has been the focus of intensive drug discovery efforts. Widely considered “undruggable,” KRAS has been the elephant in the room for PDAC treatment. This perception was shattered recently with the approval of two KRAS inhibitors for the treatment of KRASG12C-mutant lung and colorectal cancer, fueling hope that KRAS inhibitors will lead to a breakthrough in PDAC therapy. In this Review, we summarize the key role of aberrant KRAS signaling in the biology of pancreatic cancer; provide an overview of past, current, and emerging anti-KRAS treatment strategies; and discuss current challenges that limit the clinical efficacy of directly targeting KRAS for pancreatic cancer treatment.
Authors
Kristina Drizyte-Miller, Taiwo Talabi, Ashwin Somasundaram, Adrienne D. Cox, Channing J. Der
×Abstract
Pancreatic cancer has a 5-year survival rate of approximately 13% and is projected to become the second-leading cause of cancer-related deaths by 2040. Despite advances in preclinical research, clinical translation remains challenging, and combination chemotherapy remains the standard of care. The intrinsic heterogeneity of pancreas cancer underscores the potential of precision medicine approaches to improve patient outcomes. However, clinical implementation faces substantial challenges, including patient performance status, metastatic disease at diagnosis, intrinsic drug resistance, and a highly complex tumor microenvironment. Emerging targeted therapies, such as RAS inhibitors, offer promise for personalized treatment. These developments have prompted precision medicine–focused clinical trials using molecular subtyping for patient stratification. Effective development of precision medicine therapies depends heavily on robust preclinical models capable of accurately recapitulating the complexities of the pancreatic tumor microenvironment. Two-dimensional, air-liquid interface, and patient-derived organoid cultures combined with in vivo genetically engineered mouse models and patient-derived xenografts represent valuable experimental systems. This Review critically examines the strengths and limitations of these experimental model systems. We highlight their relevance and utility for advancing precision medicine strategies in pancreas cancer.
Authors
Vasiliki Pantazopoulou, Casie S. Kubota, Satoshi Ogawa, Kevin Christian Montecillo Gulay, Xiaoxue Lin, Hyemin Song, Jonathan R. Weitz, Hervé Tiriac, Andrew M. Lowy, Dannielle D. Engle
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Commentaries
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Abstract
Platelet hyperreactivity, defined as enhanced sensitivity to activation in response to classical agonists, contributes to the increased risk of arterial thrombosis associated with chronic inflammatory diseases. In this issue of the JCI, Kong and colleagues used an unbiased proteomic approach to identify elevated SEC61B in platelets from patients with diabetes and from hyperglycemic mice. Typically, SEC61B participates in protein transport within the endoplasmic reticulum (ER), but it can also act as an ion channel that allows calcium to leak from ER to cytoplasm. The authors showed that elevated SEC61B expression caused increased calcium leak, elevated basal cytoplasmic calcium concentrations, and platelet hyperreactivity. In vitro and in vivo pharmacological interventions to alter calcium homeostasis through this pathway affected platelet reactivity. The results of this work are consistent with those of previous studies showing that platelets from patients with chronic diseases behaved differently than those from healthy participants. These findings identify potential disease-specific targets to prevent and treat arterial thrombosis.
Authors
Roy L. Silverstein
×Abstract
Leukocyte-associated Ig-like receptor 1 (LAIR1) is a collagen-binding inhibitory immune receptor that negatively regulates cellular activation. In this issue of the JCI, Tao et al. show that LAIR1-inhibitory signaling plays an important role in immunosuppressive M2-like tumor-associated macrophages (TAMs) in aggressive brain tumors. LAIR1 KO, antibody blockade, and an immunotherapy that incorporates a LAIR1-inhibitory module into a chimeric antigen receptor (CAR) all led to increased antitumor activity by CAR T cells, reduced M2-like TAMs, altered collagen networks, and increased survival rates in mouse tumor models. These findings demonstrate an innovative immunotherapeutic approach for cancer that leverages LAIR1 inhibition to combat multiple tumor immune evasion strategies.
Authors
Ezri P. Perrin, Hannah K. Dorando, Jacqueline E. Payton
Tanner O. Monroe Published August 15, 2025
Citation Information: J Clin Invest. 2025;135(16):e195921. https://doi.org/10.1172/JCI195921.
×Abstract
For many conditions, genotyping aids in clinical decision making. However, interpreting the clinical significance of genetic variants remains challenging, in part because a single risk variant does not always lead to disease, and variant carriers experience variable outcomes. One hypothesis underlying these phenomena, which are known as incomplete penetrance and variable expressivity, respectively, is that additional common genetic variation beyond the primary variant influences the presence and severity of disease. In this issue of JCI, Poeschla et al. present a compelling argument that common variants linked to telomere length act together with high-risk telomere biology disorder variants to scale outcomes. These data support a model in which many variants interact to shape cumulative risk.
Authors
Tanner O. Monroe
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Research Letters
Alireza Raissadati, … , Han Zhu, Sean M. Wu Published August 15, 2025
Citation Information: J Clin Invest. 2025;135(16):e188817. https://doi.org/10.1172/JCI188817.
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Authors
Alireza Raissadati, Xuanyu Zhou, Harrison Chou, Yuhsin Vivian Huang, Shaheen Khatua, Yin Sun, Anne Xu, Sharon Loa, Arturo Hernandez, Han Zhu, Sean M. Wu
Sadia Saeed, … , Philippe Froguel, Giles S.H. Yeo Published June 23, 2025
Citation Information: J Clin Invest. 2025;135(16):e191008. https://doi.org/10.1172/JCI191008.
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Authors
Sadia Saeed, Anna-Maria Siegert, Y.C. Loraine Tung, Roohia Khanam, Qasim M. Janjua, Jaida Manzoor, Mehdi Derhourhi, Bénédicte Toussaint, Brian Y.H. Lam, Sherine Awad Mahmoud, Emmanuel Vaillant, Emmanuel Buse Falay, Souhila Amanzougarene, Hina Ayesha, Waqas I. Khan, Nosheen Ramazan, Vladimir Saudek, Stephen O’Rahilly, Anthony P. Goldstone, Muhammad Arslan, Amélie Bonnefond, Philippe Froguel, Giles S.H. Yeo
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Authors
Caitlin M. Stewart, Sonya Parpart-Li, James R. White, Mitesh Patel, Oliver Artz, Michael B. Foote, Erika Gedvilaite, Michelle F. Lamendola-Essel, Drew Gerber, Rohini Bhattacharya, Justin M. Haseltine, Kety Huberman, Kelly L. Bolton, Ross L. Levine, Luis A. Diaz Jr.
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Research Articles
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Abstract
Mucopolysaccharidoses (MPS) are lysosomal storage diseases caused by defects in catabolism of glycosaminoglycans. MPS I, II, III, and VII, which are associated with lysosomal accumulation of heparan sulphate (HS), manifest with neurological deterioration and currently lack effective treatments. We report that neuraminidase 1 (NEU1) activity is drastically reduced in brain tissues of patients with neurological MPS and mouse models but not in neurological lysosomal disorders without HS storage. Accumulated HS disrupts the lysosomal multienzyme complex of NEU1 with cathepsin A, β-galactosidase (GLB1), and glucosamine-6-sulfate sulfatase (GALNS), leading to NEU1 deficiency and partial GLB1 and GALNS deficiencies in cortical tissues and induced pluripotent stem cell–derived (iPSC-derived) cortical neurons of patients with neurological MPS. Increased sialylation of N-linked glycans in brains of patients with MPS and mice implicated insufficient processing of sialylated glycans, except for polysialic acid. Correction of NEU1 activity in MPS IIIC mice by lentiviral (LV) gene transfer ameliorated previously identified hallmarks of the disease, including memory impairment, behavioral traits, and reduced levels of excitatory synapse markers VGLUT1 and PSD95. Overexpression of NEU1 also restored levels of VGLUT1/PSD95–positive puncta in cortical iPSC-derived MPS IIIA neurons. Our results demonstrate that HS-induced secondary NEU1 deficiency and aberrant sialylation of brain glycoproteins constitute what we believe is a novel pathological pathway in the neurological MPS spectrum crucially contributing to CNS pathology.
Authors
TianMeng Xu, Rachel Heon-Roberts, Travis Moore, Patricia Dubot, Xuefang Pan, Tianlin Guo, Christopher W. Cairo, Rebecca J. Holley, Brian Bigger, Thomas M. Durcan, Thierry Levade, Jerôme Ausseil, Bénédicte Amilhon, Alexei Gorelik, Bhushan Nagar, Shaukat Khan, Shunji Tomatsu, Luisa Sturiale, Angelo Palmigiano, Iris Röckle, Hauke Thiesler, Herbert Hildebrandt, Domenico Garozzo, Alexey V. Pshezhetsky
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A subgroup (~20%–30%) of castration-resistant prostate cancer (CRPC) aberrantly expresses a gastrointestinal (GI) transcriptome governed by 2 GI-lineage-restricted transcription factors, HNF1A and HNF4G. In this study, we found that expression of GI transcriptome in CRPC correlated with adverse clinical outcomes to androgen receptor (AR) signaling inhibitor treatment and shorter overall survival. Bromo- and extraterminal domain inhibitors (BETi) downregulated HNF1A, HNF4G, and the GI transcriptome in multiple CRPC models, including cell lines, patient-derived organoids, and patient-derived xenografts, whereas AR and the androgen-dependent transcriptome were largely spared. Accordingly, BETi selectively inhibited growth of GI transcriptome-positive preclinical models of prostate cancer. Mechanistically, BETi inhibited BRD4 binding at enhancers globally, including both AR and HNF4G bound enhancers, while gene expression was selectively perturbed. Restoration of HNF4G expression in the presence of BETi rescued target gene expression without rescuing BRD4 binding. This suggests that inhibition of master transcription factors expression underlies the selective transcriptional effects of BETi.
Authors
Shipra Shukla, Dan Li, Woo Hyun Cho, Dana M. Schoeps, Holly M. Nguyen, Jennifer L. Conner, Marjorie L. Roskes, Anisha Tehim, Gabriella Bayshtok, Mohini R. Pachai, Juan Yan, Nicholas A. Teri, Eric Campeau, Sarah Attwell, Patrick Trojer, Irina Ostrovnaya, Anuradha Gopalan, Ekta Khurana, Eva Corey, Ping Chi, Yu Chen
Alice Horisberger, … , James A. Lederer, Deepak A. Rao Published June 19, 2025
Citation Information: J Clin Invest. 2025;135(16):e181034. https://doi.org/10.1172/JCI181034.
×Abstract
Lupus nephritis (LN) is a frequent manifestation of systemic lupus erythematosus, and fewer than half of patients achieve complete renal response with standard immunosuppressants. Identifying noninvasive, blood-based immune alterations associated with renal injury could aid therapeutic decisions. Here, we used mass cytometry immunophenotyping of peripheral blood mononuclear cells in 145 patients with biopsy-proven LN and 40 healthy controls to evaluate the heterogeneity of immune activation and identify correlates of renal parameters. Unbiased analysis identified 3 immunologically distinct groups of patients that were associated with different patterns of histopathology, renal cell infiltrates, urine proteomic profiles, and treatment response at 1 year. Patients with enriched circulating granzyme B+ T cells showed more active disease and increased numbers of activated CD8+ T cells in the kidney, yet they had the highest likelihood of treatment response. A second group characterized by a high type I interferon signature had a lower likelihood of response to therapy, while a third group appeared immunologically inactive but with chronic renal injuries. The major immunologic axes of variation could be distilled down to 5 simple cytometric parameters that recapitulate several clinical associations, highlighting the potential for blood immunoprofiling to translate to clinically useful noninvasive metrics to assess immune-mediated disease in LN.
Authors
Alice Horisberger, Alec Griffith, Joshua Keegan, Arnon Arazi, John Pulford, Ekaterina Murzin, Kaitlyn Howard, Brandon Hancock, Andrea Fava, Takanori Sasaki, Tusharkanti Ghosh, Jun Inamo, Rebecca Beuschel, Ye Cao, Katie Preisinger, Maria Gutierrez-Arcelus, Thomas M. Eisenhaure, Joel Guthridge, Paul J. Hoover, Maria Dall’Era, David Wofsy, Diane L. Kamen, Kenneth C. Kalunian, Richard Furie, Michael Belmont, Peter Izmirly, Robert Clancy, David Hildeman, E. Steve Woodle, William Apruzzese, Maureen A. McMahon, Jennifer Grossman, Jennifer L. Barnas, Fernanda Payan-Schober, Mariko Ishimori, Michael Weisman, Matthias Kretzler, Celine C. Berthier, Jeffrey B. Hodgin, Dawit S. Demeke, Chaim Putterman, Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Network, Michael B. Brenner, Jennifer H. Anolik, Soumya Raychaudhuri, Nir Hacohen, Judith A. James, Anne Davidson, Michelle A. Petri, Jill P. Buyon, Betty Diamond, Fan Zhang, James A. Lederer, Deepak A. Rao
Soumya Poddar, … , Simone Filosto, Sattva S. Neelapu Published June 19, 2025
Citation Information: J Clin Invest. 2025;135(16):e181893. https://doi.org/10.1172/JCI181893.
×Abstract
BACKGROUND Axicabtagene ciloleucel (axi-cel), anti-CD19 chimeric antigen receptor (CAR) T cell therapy, demonstrated remarkable efficacy with manageable toxicity in relapsed/refractory indolent B cell lymphomas in the ZUMA-5 trial.METHODS Here, we report associations of product attributes, serum biomarkers, clinical features, and tumor characteristics with outcome in 124 patients with follicular lymphoma (FL).RESULTS In univariate and multivariate analyses, pretreatment inflammatory markers, including TNF-α and IL-12p40, as well as total metabolic tumor volume (TMTV), associated with disease progression. Conversely, T-naive–like product phenotype associated with improved outcome, particularly in patients with high TMTV. These covariates improved risk stratification when combined with the FL International Prognostic Index. Postinfusion, CAR T cell expansion associated with improved outcome, while serum inflammatory and immunomodulatory markers, including TNF-α, associated with disease progression and occurrence of high-grade cytokine release syndrome or neurologic events, presenting targets to improve the therapeutic index of axi-cel in FL. Tumor gene expression profiling revealed that both type I and II IFN signaling associated with disease progression and higher expression of T cell exhaustion markers, including TIM3 and LAG3. Pre- or posttreatment CD19 expression on tumor was not associated with outcome.CONCLUSION These findings offer insights into mechanisms of resistance and toxicity, risk stratification, and strategies for development of next generation CAR-T approaches.TRIAL REGISTRATION ClinicalTrials.gov NCT03105336.FUNDING Kite, a Gilead Company.
Authors
Soumya Poddar, Jiali Yan, Gayatri Tiwari, Darawan Rinchai, Justin Budka, Wangshu Zhang, Weixin Peng, Shruti Salunkhe, Madison Davis, Qinghua Song, Sara Beygi, Harry Miao, Mike Mattie, Rhine S. Shen, Caron A. Jacobson, Davide Bedognetti, Simone Filosto, Sattva S. Neelapu
Maria L. Allende, … , Cynthia J. Tifft, Richard L. Proia Published June 17, 2025
Citation Information: J Clin Invest. 2025;135(16):e183434. https://doi.org/10.1172/JCI183434.
×Abstract
Late-onset Tay-Sachs (LOTS) disease is a lysosomal storage disorder most commonly caused by a point mutation (c.805G>A) in the HEXA gene encoding the α subunit of the lysosomal enzyme β-hexosaminidase A. LOTS manifests as a range of gradually worsening neurological symptoms beginning in young adulthood. Here, we explored the efficacy of an adenine base editor (ABE) programmed with an sgRNA to correct the HEXA c.805G>A mutation. Base editing in fibroblasts from a patient with LOTS successfully converted the pathogenic HEXA c.805A to G and partially restored β-hexosaminidase activity, with minimal genome-wide off-target editing. We generated a LOTS mouse model in which the mice exhibited decreased β-hexosaminidase activity, accumulation of GM2 ganglioside in the brain, progressive neurological manifestations, and reduced lifespan. Treatment of LOTS mice with the neurotropic virus AAV-PHP.eB carrying the ABE and an sgRNA targeting the LOTS point mutation partially corrected the c.805G>A mutation in the CNS, significantly increased brain β-hexosaminidase activity, and substantially reduced GM2 ganglioside accumulation in the brain. Moreover, the therapy delayed symptom onset and significantly extended median lifespan. These findings highlight the potential of base editing as an effective treatment for LOTS and its broader applicability to other lysosomal storage disorders.
Authors
Maria L. Allende, Mari Kono, Y. Terry Lee, Samantha M. Olmsted, Vienna Huso, Jenna Y. Bakir, Florencia Pratto, Cuiling Li, Colleen Byrnes, Galina Tuymetova, Hongling Zhu, Cynthia J. Tifft, Richard L. Proia
×Abstract
The incretin peptides glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors coordinate β cell secretion that is proportional to nutrient intake. This effect permits consistent and restricted glucose excursions across a range of carbohydrate intake. The canonical signaling downstream of ligand-activated incretin receptors involves coupling to Gαs protein and generation of intracellular cAMP. However, recent reports have highlighted the importance of additional signaling nodes engaged by incretin receptors, including other G proteins and β-arrestin proteins. Here, the importance of Gαs signaling was tested in mice with conditional, postdevelopmental β cell deletion of Gnas (encoding Gαs) under physiological and pharmacological conditions. Deletion of Gαs/cAMP signaling induced immediate and profound hyperglycemia that responded minimally to incretin receptor agonists, a sulfonylurea, or bethanechol. While islet area and insulin content were not affected in Gnasβcell–/–, perifusion of isolated islets demonstrated impaired responses to glucose, incretins, acetylcholine, and IBMX In the absence of Gαs, incretin-stimulated insulin secretion was impaired but not absent, with some contribution from Gαq signaling. Collectively, these findings validate a central role for cAMP in mediating incretin signaling, but also demonstrate broad impairment of insulin secretion in the absence of Gαs that causes both fasting hyperglycemia and glucose intolerance.
Authors
Megan E. Capozzi, David Bouslov, Ashot Sargsyan, Michelle Y. Chan, Alex Chen, Sarah M. Gray, Katrina Viloria, Akshay Bareja, Jonathan D. Douros, Sophie L. Lewandowski, Jason C.L. Tong, Annie Hasib, Federica Cuozzo, Elizabeth C. Ross, Matthew W. Foster, Lee S. Weinstein, Mehboob A. Hussain, Matthew J. Merrins, Francis S. Willard, Mark O. Huising, Kyle W. Sloop, David J. Hodson, David A. D’Alessio, Jonathan E. Campbell
Haipeng Tao, … , W. Gregory Sawyer, Jianping Huang Published July 1, 2025
Citation Information: J Clin Invest. 2025;135(16):e184043. https://doi.org/10.1172/JCI184043.
×Abstract
Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment (TME) and dampen the immune response, negatively affecting patient survival. Therefore, targeting TAMs could address the limitations of current cancer treatments. However, drug development in this area remains limited. The leukocyte-associated Ig-like receptor 1 (LAIR1), also called CD305, is prominently expressed on the surface of TAMs. We have uncovered what we believe to be a previously unrecognized immunosuppressive LAIR1/factor XIII A/collagen IV pathway across various cancer types. Inhibition of LAIR1, either through knockout (Lair1–/–), antibody blockade (anti-Lair1 antibody), or a chimeric antigen receptor (CAR) design (3-in-1 CAR by combining tumor targeting, T cell trafficking, and remodeling of the immunosuppressive TME in 1 CAR construct) provided an enhanced antitumor response. LAIR1 inhibition enhanced peripheral and intratumoral CD8 memory T cell populations, induced a phenotypic shift of M2-like macrophages toward M1 macrophages, and normalized tumor collagen IV and structural components in the TME, facilitating effective tumor–T cell interactions and tumor suppression. Enhanced antitumor responses were observed when Lair1–/– or anti-Lair1 antibody was used alone or in combination with CAR T cells or when the 3-in-1 CAR T cells were used solely in tumor models resistant to chemotherapy–radiation–programmed cell death protein 1 (PD-1) blockade. These findings position LAIR1 inhibition as a promising strategy for cancer immunotherapies.
Authors
Haipeng Tao, Dongjiang Chen, Changlin Yang, Duy T. Nguyen, Georges Abboud, Ruixuan Liu, Tianyi Liu, Avirup Chakraborty, Alicia Y. Hou, Nicole A. Petit, Muhammad Abbas, Robert W. Davis, Janie Zhang, Christina Von Roemeling, Mohammed O. Gbadamosi, Linchun Jin, Tongjun Gu, Tuo Lin, Pengchen Wang, Alfonso Pepe, Diego Ivan Pedro, Hector R. Mendez-Gomez, Chao Xie, Aida Karachi, Frances Weidert, Dan Jin, Chenggang Wang, Kaytora Long-James, Elizabeth K. Molchan, Paul Castillo, John A. Ligon, Ashley P. Ghiaseddin, Elias J. Sayour, Maryam Rahman, Loic P. Deleyrolle, Betty Y.S. Kim, Duane A. Mitchell, W. Gregory Sawyer, Jianping Huang
Yvonne X. Kong, … , Mark Larance, Freda H. Passam Published August 15, 2025
Citation Information: J Clin Invest. 2025;135(16):e184597. https://doi.org/10.1172/JCI184597.
×Abstract
Platelet hyperreactivity increases the risk of cardiovascular thrombosis in diabetes and failure of antiplatelet drug therapies. Elevated basal and agonist-induced calcium flux is a fundamental cause of platelet hyperreactivity in diabetes; however, the mechanisms responsible for this remain largely unknown. Using a high-sensitivity, unbiased proteomic platform, we consistently detected over 2,400 intracellular proteins and identified proteins that were differentially released by platelets in type 2 diabetes. We identified that SEC61 translocon subunit β (SEC61B) was increased in platelets from humans and mice with hyperglycemia and in megakaryocytes from mice with hyperglycemia. SEC61 is known to act as an endoplasmic reticulum (ER) calcium leak channel in nucleated cells. Using HEK293 cells, we showed that SEC61B overexpression increased calcium flux into the cytosol and decreased protein synthesis. Concordantly, platelets in hyperglycemic mice mobilized more calcium and had decreased protein synthesis. Platelets in both humans and mice with hyperglycemia had increased ER stress. ER stress induced the expression of platelet SEC61B and increased cytosolic calcium. Inhibition of SEC61 with anisomycin decreased platelet calcium flux and inhibited platelet aggregation in vitro and in vivo. These studies demonstrate the existence of a mechanism whereby ER stress–induced upregulation of platelet SEC61B leads to increased cytosolic calcium, potentially contributing to platelet hyperreactivity in diabetes.
Authors
Yvonne X. Kong, Rajan Rehan, Cesar L. Moreno, Søren Madsen, Yunwei Zhang, Huiwen Zhao, Miao Qi, Callum B. Houlahan, Siân P. Cartland, Declan Robertshaw, Vincent Trang, Frederick Jun Liang Ong, Michael Liu, Edward Cheng, Imala Alwis, Alexander Dupuy, Michelle Cielesh, Kristen C. Cooke, Meg Potter, Jacqueline Stöckli, Grant Morahan, Maggie L. Kalev-Zylinska, Matthew T. Rondina, Sol Schulman, Jean Y. H. Yang, G. Gregory Neely, Simone M. Schoenwaelder, Shaun P. Jackson, David E. James, Mary M. Kavurma, Samantha L. Hocking, Stephen M. Twigg, James C. Weaver, Mark Larance, Freda H. Passam
×Abstract
Metachromatic leukodystrophy (MLD) is an autosomal recessive neurodegenerative disorder caused by mutations in the arylsulfatase A (ARSA) gene, resulting in lower sulfatase activity and the toxic accumulation of sulfatides in the central and peripheral nervous system. Children account for 70% of cases and become progressively disabled, with death occurring within 10 years of disease onset. Gene therapy approaches to restore ARSA expression via adeno-associated virus (AAV) vectors have been promising but hampered by limited brain biodistribution. We report the development of an engineered capsid, AAV.GMU01, demonstrating superior biodistribution and transgene expression in the central nervous system of nonhuman primates (NHPs). Next, we show that AAV.GMU01-ARSA–treated MLD mice exhibit persistent, normal levels of sulfatase activity and a concomitant reduction in toxic sulfatides. Treated mice also show a reduction in MLD-associated pathology and auditory dysfunction. Lastly, we demonstrate that treatment with AAV.GMU01-ARSA in NHPs is well tolerated and results in potentially therapeutic ARSA expression in the brain. In summary, we propose AAV.GMU01-ARSA–mediated gene replacement as a clinically viable approach to achieve broad and therapeutic levels of ARSA.
Authors
Shyam Ramachandran, Jeffery Ardinger, Jie Bu, MiAngela Ramos, Lilu Guo, Dhiman Ghosh, Mahmud Hossain, Shih-Ching Chou, Yao Chen, Erik Wischhof, Swathi Ayloo, Roger Trullo, Yuxia Luo, Jessica M. Hogestyn, Daniel M. DuBreuil, Emily Crosier, Johanna G. Flyer-Adams, Amy M. Richards, Michael Tsabar, Giorgio Gaglia, Shelley Nass, Bindu Nambiar, Denise Woodcock, Catherine O’Riordan, Qi Tang, Bradford Elmer, Bailin Zhang, Martin Goulet, Christian Mueller
Lei Cao, … , Cheng Zhang, Meng Zhang Published June 17, 2025
Citation Information: J Clin Invest. 2025;135(16):e186509. https://doi.org/10.1172/JCI186509.
×Abstract
Atherosclerosis arises from disrupted cholesterol metabolism, notably impaired macrophage cholesterol efflux leading to foam cell formation. Through single-cell and bulk RNA-Seq, we identified Listerin E3 ubiquitin protein ligase 1 (Listerin) as a regulator of macrophage cholesterol metabolism. Listerin expression increased during atherosclerosis progression in humans and rodents. Its deficiency suppressed cholesterol efflux, promoted foam cell formation, and exacerbated plaque features (macrophage infiltration, lipid deposition, necrotic cores) in macrophage-specific KO mice. Conversely, Listerin overexpression attenuated these atherosclerotic manifestations. Mechanistically, Listerin stabilizes ABCA1, a key cholesterol efflux mediator, by catalyzing K63-linked polyubiquitination at residues K1884/K1957, countering ESCRT-mediated lysosomal degradation of ABCA1 induced by oxidized LDL (oxLDL). ABCA1 agonist erythrodiol restored cholesterol efflux in Listerin-deficient macrophages, while KO of ABCA1 abolished Listerin’s effects in Tsuchiya human monocytic leukemia line (THP-1) cells. This study establishes Listerin as a protective factor in atherosclerosis via posttranslational stabilization of ABCA1, offering a potential therapeutic strategy targeting ABCA1 ubiquitination to enhance cholesterol efflux.
Authors
Lei Cao, Jie Zhang, Liwen Yu, Wei Yang, Wenqian Qi, Ruiqing Ren, Yapeng Liu, Yonghao Hou, Yu Cao, Qian Li, Xiaohong Wang, Zhengguo Zhang, Bo Li, Wenhai Sui, Yun Zhang, Chengjiang Gao, Cheng Zhang, Meng Zhang
×Abstract
Tumor gene alterations can serve as predictive biomarkers for therapy response. The nucleotide excision repair (NER) helicase ERCC2 carries heterozygous missense mutations in approximately 10% of bladder tumors, and these may predict sensitivity to cisplatin treatment. To explore the clinical actionability of ERCC2 mutations, we assembled a multinational cohort of 2,012 individuals with bladder cancer and applied the highly quantitative CRISPR-Select assay to functionally profile recurrent ERCC2 mutations. We also developed a single-allele editing version of CRISPR-Select to assess heterozygous missense variants in their native context. From the cohort, 506 ERCC2 mutations were identified, with 93% being heterozygous missense variants. CRISPR-Select pinpointed deleterious, cisplatin-sensitizing mutations, particularly within the conserved helicase domains. Importantly, single-allele editing revealed that heterozygous helicase-domain mutations markedly increased cisplatin sensitivity. Integration with clinical data confirmed that these mutations were associated with improved response to platinum-based neoadjuvant chemotherapy. Comparison with computational algorithms showed substantial discrepancies, highlighting the importance of precision functional assays for interpreting mutation effects in clinically relevant contexts. Our results demonstrate that CRISPR-Select provides a robust platform to advance biomarker-driven therapy in bladder cancer and supports its potential integration into precision oncology workflows.
Authors
Judit Börcsök, Diyavarshini Gopaul, Daphne Devesa-Serrano, Clémence Mooser, Nicolas Jonsson, Matteo Cagiada, Dag R. Stormoen, Maya N. Ataya, Brendan J. Guercio, Hristos Z. Kaimakliotis, Gopa Iyer, Kresten Lindorff-Larsen, Lars Dyrskjøt, Kent W. Mouw, Zoltan Szallasi, Claus S. Sørensen
Dae-Seok Kim, … , Chao Li, Philipp E. Scherer Published June 17, 2025
Citation Information: J Clin Invest. 2025;135(16):e187202. https://doi.org/10.1172/JCI187202.
×Abstract
Proinflammatory signaling in adipocytes is essential for healthy adipose expansion, remodeling, and tissue integrity. We investigated the effects of targeting inflammation in either adipocytes or mammary gland epithelial cells, in the context of mammary tumor development, by locally expressing the antiinflammatory adenoviral RIDα/β protein complex in a cell type–specific manner. Suppression of adipocyte inflammation (RIDad mice) in a mammary tumor model driven by MMTV-PyMT (PyMT-RIDad mice) led to an elevated number of tumor-associated macrophages and upregulation of immunoregulatory molecules in the mammary fat pad. This was accompanied by metabolic dysfunction and abnormal mammary gland development. Importantly, this phenotype correlated with accelerated mammary tumor onset, enhanced growth, and lung metastasis. Tumors in PyMT-RIDad mice exhibited upregulated CD36 expression, suggesting enhanced fatty acid uptake. Conversely, suppression of inflammation in mammary gland epithelial cells by RIDα/β expression (RIDMMTV mice) decelerated mammary tumor growth without affecting tumor onset or macrophage accumulation. These findings highlight the differential impact on tumor development exerted through the suppression of inflammatory signals in different cell types in the microenvironment. Our results underscore the role of the suppression of adipocyte inflammation leading to a tumor-friendly microenvironment, promoting mammary cancer progression. This study sheds light on the complex interplay between inflammation, specifically driven by the adipocyte, in breast cancer pathogenesis.
Authors
Dae-Seok Kim, Toshiharu Onodera, Jan-Bernd Funcke, Kyounghee Min, Qingzhang Zhu, Qian Lin, Shiuhwei Chen, Chanmin Joung, Min Kim, R. Max Wynn, Joselin Velasco, Charlotte Lee, Megan Virostek, Chao Li, Philipp E. Scherer
Jheng-Syuan Shao, … , Yao-Ming Chang, Ya-Jen Chang Published July 17, 2025
Citation Information: J Clin Invest. 2025;135(16):e187372. https://doi.org/10.1172/JCI187372.
×Abstract
Group 3 innate lymphoid cells (ILC3s) have emerged as an important player in the pathogenesis of neutrophilic asthma. However, the regulatory mechanism supporting ILC3 responses in the lung remains largely unclear. Here, we demonstrated that stem cell factor (SCF) expression is significantly increased and positively correlated with IL-17A and MPO expression in asthmatic patients. Notably, we identified ILC3 as a major IL-17A–producing responder to SCF in the lung. In mice, SCF synergized with IL-1β/IL-23 to enhance pulmonary ILC3 activation and neutrophilic inflammation. Mechanistically, SCF promoted ILC3 proliferation and cytokine production. Transcriptomic analysis revealed that SCF treatment upregulated the genes related to proliferation and Th17 differentiation, associated with increased AKT and STAT3 signaling. In contrast, deficiency of SCF receptor c-Kit reduced ILC3 proliferation and IL-17A production, resulting in the amelioration of airway hyperreactivity (AHR) and neutrophilic inflammation in mouse neutrophilic asthma model. Furthermore, genetic deletion of SCF in fibroblasts revealed fibroblasts as the primary source of SCF for ILC3 activation in the lung. Moreover, administration of imatinib, a c-Kit inhibitor, alleviated LPS, air pollution or ovalbumin/LPS-induced AHR and neutrophilic inflammation. Our findings elucidated a positive modulatory role of SCF/c-Kit signaling in ILC3 responses during neutrophilic inflammation, offering a potential therapeutic target for neutrophilic asthma.
Authors
Jheng-Syuan Shao, Alan Chuan-Ying Lai, Wei-Chang Huang, Ko-Chien Wu, Po-Yu Chi, Yao-Ming Chang, Ya-Jen Chang
×Abstract
Despite effective antiretroviral therapy, transcriptionally competent HIV-1 reservoirs remain and contribute to persistent immune activation in people living with HIV (PWH). HIV-1–infected macrophages are important mediators of chronic innate immune activation, though the mechanisms remain unclear. We previously reported that nuclear export and cytoplasmic expression of HIV-1 intron-containing RNA (icRNA) activates mitochondrial antiviral signaling (MAVS) protein–mediated type I IFN responses in macrophages. In this study, we demonstrate an essential role of melanoma differentiation–associated protein 5 (MDA5) in sensing HIV-1 icRNA and promoting MAVS-dependent interferon regulatory factor 5 (IRF5) activation in macrophages. Suppression of MDA5 but not retinoic acid–inducible gene I expression nor disruption of the endosomal TLR pathway abrogated HIV-1 icRNA-induced type I IFN responses and IP-10 expression in macrophages. Furthermore, induction of IP-10 in macrophages upon HIV-1 icRNA sensing by MDA5 was dependent on IRF5. Additionally, monocytes and monocyte-derived macrophages (MDMs) from older (>50 years) individuals exhibited constitutively higher levels of IRF5 expression compared with younger (<35 years) individuals, and HIV-1 icRNA-induced IP-10 expression was significantly enhanced in older macrophages, which was attenuated upon ablation of IRF5 expression, suggesting that IRF5 functions as a major mediator of proinflammatory response downstream of MDA5-dependent HIV-1 icRNA sensing, dysregulation of which might contribute to chronic inflammation in older PWH.
Authors
Sita Ramaswamy, Hisashi Akiyama, Jacob Berrigan, Andrés A. Quiñones-Molina, Alex J. Olson, Yunhan Chen, YanMei Liang, Andrew J. Henderson, Archana Asundi, Manish Sagar, Suryaram Gummuluru
×Abstract
The mechanisms of neutrophilic and mixed neutrophilic-eosinophilic asthma are poorly understood. We found that extracellular DNA and nucleosomes (Nucs) were elevated in the airways of patients with neutrophilic-eosinophilic asthma and correlated with bronchoalveolar lavage neutrophils. Bronchial tissue from neutrophilic-eosinophilic asthma had more DNA sensor–positive cells. Intranasally administered DNA did not induce airway hyperreactivity (AHR) or any pathology but induced AHR and neutrophilic-eosinophilic inflammation when coadministered with the allergen Alternaria (Alt). Nuc alone induced antiinflammatory/defensive genes, whereas the Nuc-Alt combination increased levels of TNF-α and innate cytokines. The Alt-Nuc phenotype was abolished in Cgas–/–, ALR–/–, Sting–/–, LysMCre:Stingfl/fl, IL7RCre:Rorαfl/fl, and Tnfr2–/– mice. Alt, unexpectedly, played an essential role in the Nuc-induced phenotype. It abrogated Nuc induction of antiinflammatory genes, facilitated Nuc uptake, induced type 2 innate lymphoid cells, which, in the presence of Nuc, produced high levels of TNF-α, and promoted neutrophilic infiltration. We established a paradigm whereby allergens inhibit the antiinflammatory effects of DNA/Nuc and facilitate STING-TNF-α–driven neutrophilic-eosinophilic inflammation in asthma.
Authors
Anand Sripada, Divya Verma, Rangati Varma, Kapil Sirohi, Carolyn Kwiat, Mohini Pathria, Mukesh Verma, Anita Sahu, Vamsi Guntur, Laurie Manka, Brian Vestal, Camille Moore, Richard J. Martin, Magdalena M. Gorska, John Cambier, Andrew Getahun, Rafeul Alam
×Abstract
Anxiety disorders pose a substantial threat to global mental health, with chronic stress identified as a major etiologic factor. Over the past few decades, extensive studies have revealed that chronic stress induces anxiety states through a distributed neuronal network of interconnected brain structures. However, the precise circuit mechanisms underlying the transition from chronic stress to anxiety remain incompletely understood. Employing the chronic social defeat stress (CSDS) paradigm in mice, we uncovered a critical role of the parasubthalamic nucleus (PSTh) in both the induction and expression of anxiety-like behavior. The anxiogenic effect was mediated by an excitatory trisynaptic circuitry involving the lateral parabrachial nucleus (LPB), PSTh, and bed nucleus of the stria terminalis (BNST). Furthermore, CSDS downregulated Kv4.3 channels in glutamatergic neurons of the PSTh. Reexpression of these channels dampened neuronal overexcitability and alleviated anxiety-like behavior in stressed animals. In parallel with the well-known anxiety network centered on the amygdala, here we identify a noncanonical LPB-PSTh-BNST pathway in the transformation of stress into anxiety. These findings suggest that the PSTh may serve as a potential therapeutic target for anxiety-related disorders.
Authors
Na Liu, Jun Wang, Huan Wang, Bin Gao, Zheng Lin, Tian-Le Xu, Shumin Duan, Han Xu
×Abstract
Influenza-associated bacterial superinfections in the lung lead to increased morbidity and mortality. Nearly all people have preexisting memory to influenza virus, which can protect against subsequent infection in the lung. This study explored the role B cells play in protection against bacterial (Staphylococcus aureus or Klebsiella pneumoniae) superinfection with previous heterotypic influenza memory. B cell deficiency resulted in an increased inflammatory lung environment and lung tissue injury during superinfection. Loss of B cells increased populations of memory CD8+ T cells in the lung, and these CD8+ T cells were transcriptionally and functionally distinct from those of WT mice. Use of antibody-deficient mouse models showed that this phenotype was specifically due to loss of antibody production from B cells. Passive immunization with influenza antibody serum in B cell–deficient mice rescued the CD8+ T cell phenotype. CD8+ T cell depletion and lethal superinfection challenge experiments showed that the cytotoxic memory CD8+ T cells from B cell–deficient mice protect against superinfection bacterial burden and mortality. These findings provide insight into the importance of B cells for regulating immune responses against infection.
Authors
Leigh M. Miller, Alexis M. Duray, Ellyse M. Cipolla, Flavia Rago, Brooke P. Dresden, Kristen L. Parenteau, Abhigya Gupta, John F. Alcorn
Ramon U. Jin, … , Hui Zhang, Jason C. Mills Published June 30, 2025
Citation Information: J Clin Invest. 2025;135(16):e190374. https://doi.org/10.1172/JCI190374.
×Abstract
Esophageal adenocarcinoma is increasingly prevalent and is thought to arise from Barrett’s esophagus (BE), a metaplastic condition in which chronic acid and bile reflux transforms the esophageal squamous epithelium into a gastric-intestinal glandular mucosa. The molecular determinants driving this metaplasia are poorly understood. We developed a human BE organoid biobank that recapitulates BE’s molecular heterogeneity. Bulk and single-cell transcriptomics, supported by patient tissue analysis, revealed that BE differentiation reflects a balance between SOX2 (foregut/esophageal) and CDX2 (hindgut/intestinal) transcription factors. Using squamous-specific inducible Sox2-KO (Krt5CreER/+ Sox2Δ/Δ ROSA26tdTomato/+) mice, we observed increased basal proliferation, reduced squamous differentiation, and expanded metaplastic glands at the squamocolumnar junction, some tracing back to Krt5-expressing cells. CUT&RUN analysis showed SOX2 bound and promoted differentiation-associated targets (e.g., Krt13) and repressed proliferation-associated targets (e.g., Mki67). Thus, SOX2 is critical for foregut squamous epithelial differentiation, and its decreased expression is likely an initiating step in progression to BE and then to esophageal adenocarcinoma.
Authors
Ramon U. Jin, Yuanwei Xu, T. Mamie Lih, Yang-Zhe Huang, Toni M. Nittolo, Blake E. Sells, Olivia M. Dres, Jean S. Wang, Qing K. Li, Hui Zhang, Jason C. Mills
Subhransu S. Sahoo, … , Ram S. Mani, Diego H. Castrillon Published August 15, 2025
Citation Information: J Clin Invest. 2025;135(16):e190989. https://doi.org/10.1172/JCI190989.
×Abstract
Functional inactivation of tumor suppressor genes drives cancer initiation, progression, and treatment responses. Most tumor suppressor genes are inactivated through 1 of 2 well-characterized mechanisms: DNA-level mutations, such as point mutations or deletions, and promoter DNA hypermethylation. Here, we report a distinct third mechanism of tumor suppressor inactivation based on alterations to the histone rather than DNA code. We demonstrated that PAX2 is an endometrial tumor suppressor recurrently inactivated by a distinct epigenetic reprogramming event in more than 80% of human endometrial cancers. Integrative transcriptomic, epigenomic, 3D genomic, and machine learning analyses showed that PAX2 transcriptional downregulation is associated with replacement of open/active chromatin features (H3K27ac/H3K4me3) with inaccessible/repressive chromatin features (H3K27me3) in a framework dictated by 3D genome organization. The spread of the repressive H3K27me3 signal resembled a pearl necklace, with its length modulated by cohesin loops, thereby preventing transcriptional dysregulation of neighboring genes. This mechanism, involving the loss of a promoter-proximal superenhancer, was shown to underlie transcriptional silencing of PAX2 in human endometrial cancers. Mouse and human preclinical models established PAX2 as a potent endometrial tumor suppressor. Functionally, PAX2 loss promoted endometrial carcinogenesis by rewiring the transcriptional landscape via global enhancer reprogramming. The discovery that most endometrial cancers originate from a recurring epigenetic alteration carries profound implications for their diagnosis and treatment.
Authors
Subhransu S. Sahoo, Susmita G. Ramanand, Ileana C. Cuevas, Yunpeng Gao, Sora Lee, Ahmed Abbas, Xunzhi Zhang, Ashwani Kumar, Prasad Koduru, Sambit Roy, Russell R. Broaddus, Victoria L. Bae-Jump, Andrew B. Gladden, Jayanthi Lea, Elena Lucas, Chao Xing, Akio Kobayashi, Ram S. Mani, Diego H. Castrillon
Michael Poeschla, … , Sharon A. Savage, Vijay G. Sankaran Published June 3, 2025
Citation Information: J Clin Invest. 2025;135(16):e191107. https://doi.org/10.1172/JCI191107.
×Abstract
BACKGROUND Telomere biology disorders (TBDs) exhibit incomplete penetrance and variable expressivity, even among individuals harboring the same pathogenic variant. We assessed whether common genetic variants associated with telomere length combine with large-effect variants to impact penetrance and expressivity in TBDs.METHODS We constructed polygenic scores (PGS) for telomere length in the UK Biobank to quantify common variant burden and assessed the PGS distribution across patient cohorts and biobanks to determine whether individuals with severe TBD presentations have increased polygenic burden causing short telomeres. We also characterized rare TBD variant carriers in the UK Biobank.RESULTS Individuals with TBDs in cohorts enriched for severe pediatric presentations have polygenic scores predictive of short telomeres. In the UK Biobank, we identified carriers of pathogenic TBD variants who were enriched for adult-onset manifestations of TBDs. Unlike individuals in disease cohorts, the PGS of adult carriers did not show a common variant burden for shorter telomeres, consistent with the absence of childhood-onset disease. Notably, TBD variant carriers were enriched for idiopathic pulmonary fibrosis diagnoses and telomere length PGS stratified pulmonary fibrosis risk. Finally, common variants affecting telomere length were enriched in enhancers regulating known TBD genes.CONCLUSION Common genetic variants combined with large-effect causal variants to impact clinical manifestations in rare TBDs. These findings offer a framework for understanding phenotypic variability in other presumed monogenic disorders.FUNDING This work was supported by NIH grants R01DK103794, R01HL146500, R01CA265726, R01CA292941, and the Howard Hughes Medical Institute.
Authors
Michael Poeschla, Uma P. Arora, Amanda Walne, Lisa J. McReynolds, Marena R. Niewisch, Neelam Giri, Logan P. Zeigler, Alexander Gusev, Mitchell J. Machiela, Hemanth Tummala, Sharon A. Savage, Vijay G. Sankaran
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Abstract
Calciphylaxis is a rare but life-threatening disorder characterized by ectopic calcification affecting the subcutaneous tissues and blood vessels of the skin. Once diagnosed, survival rates are less than a year and yet despite the severity of the condition, the pathobiology of calciphylaxis is ill understood. Here, we create animal models of calciphylaxis that recapitulate many characteristics of the human phenotype. We demonstrate that cutaneous calcification is preceded by inflammatory cell infiltration. We show that increased local skin inflammation, regardless of the inciting cause, in the presence of hypercalcemia and hyperphosphatemia contributes to cutaneous ectopic calcification. Genetically modified rodents lacking immune activation of T and B cells or NK cells are resistant to developing cutaneous calcification. Consistent with this, administration of the immunosuppressive cyclophosphamide rescued calcific deposits as did T cell suppression with cyclosporine. We demonstrate IL17 is upregulated in calcific skin and neutrophils are the predominant cell types expressing IL 17 and tissue alkaline phosphatase that is necessary for ectopic calcification. Targeting IL17 with a monoclonal antibody or using a myeloperoxidase inhibitor to blunt neutrophil activation notably attenuated calcific deposits in vivo. Taken together, these observations provide fresh insight into the role of the immune system and the IL17/neutrophil axis in mediating ectopic calcification in rodent models of calciphylaxis.
Authors
Bo Tao, Edward Z. Cao, James Hyun, Sivakumar Ramadoss, Juan F. Alvarez, Lianjiu Su, Qihao Sun, Zhihao Liu, Linlin Zhang, Alejandro Espinoza, Yiqian Gu, Feiyang Ma, Shen Li, Matteo Pellegrini, Arjun Deb
Abstract
Genome editing has shown the potential to treat genetic hearing loss. However, current editing therapies for genetic hearing loss have shown efficacy only in hearing rescue. In this study, we evaluated a rescue strategy using AAV2-mediated delivery of SaCas9/sgRNA in the mature inner ear of the P2rx2V61L/+ mouse model of DFNA41, a dominant, delayed-onset, and progressive hearing loss in humans. We demonstrate that local injection in adult mice results in efficient and specific editing that abolishes the mutation without notable off-target effects or AAV genome integration. Editing effectively restores long-term auditory and vestibular function. Editing further protects P2rx2V61L/+ mice from hypersensitivity to noise-induced hearing loss (NIHL), a phenotype also observed in DFNA41 patients. Intervention at a juvenile stage broadens the frequency range rescued, highlighting the importance of early intervention. An effective and specific gRNA for the human P2RX2 V60L mutation has been identified. Our study establishes the feasibility of editing to treat DFNA41 caused by P2RX2 V60L mutation in humans and opens an avenue for using editing to rescue hearing and vestibular function while mitigating noise-induced hearing loss.
Authors
Wei Wei, Wenliang Zhu, Stewart Silver, Ariel M. Armstrong, Fletcher S. Robbins, Arun Prabhu Rameshbabu, Katherina Walz, Yizhou Quan, Wan Du, Yehree Kim, Artur A. Indzhykulian, Yilai Shu, Xue-Zhong Liu, Zheng-Yi Chen
Abstract
Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have transformed the treatment landscape for hormone receptor-positive (HR+) breast cancer. However, their long-term efficacy is limited by acquired resistance, and CDK4/6i monotherapy remains ineffective in triple-negative breast cancer (TNBC). Here, we demonstrate that dual inhibition of CDK4/6 and CDK7 is a promising strategy to overcome therapeutic resistance in both HR+ and TNBC models. Kinetic analyses reveal that CDK7 inhibitors (CDK7i) primarily impair RNA polymerase II-mediated transcription rather than directly targeting cell-cycle CDKs. This transcriptional suppression attenuates E2F-driven transcriptional amplification, a key mechanism for developing CDK4/6i resistance following the degradation of the retinoblastoma protein. Consequently, combining CDK7i at minimal effective concentrations with CDK4/6i potently inhibits the growth of drug-resistant tumors. Furthermore, dual CDK4/6 and CDK7 inhibition stimulates immune-related signaling and cytokine production in cancer cells, promoting anti-tumor immune responses within the tumor microenvironment. These findings provide mechanistic insights into CDK inhibition and support the therapeutic potential of combining CDK7i with CDK4/6i for breast cancer treatment.
Authors
Sungsoo Kim, Eugene Son, Ha-Ram Park, Minah Kim, Hee Won Yang
Abstract
Toll like receptor (TLR) 7 and 9, endosomal sensors for RNA and DNA, are key mediators of autoreactivity. Although generally considered homologous, they paradoxically have opposing effects on lupus: TLR7 exacerbates disease while TLR9 protects from disease. How they mediate opposing effects in autoimmunity remains undetermined. We hypothesized that differences in signaling qualities of the Toll-Interleukin 1 Receptor (TIR) domains of TLR7 and TLR9 could be responsible for their opposing effects. To test this, we introduced the TIR domain of TLR9 into the endogenous TLR7 locus and the TLR7 TIR domain into the endogenous TLR9 locus of mice, creating chimeric molecules termed TLR779 and TLR997. Lupus-prone MRL/lpr mice carrying Tlr779 had greatly ameliorated disease while MRL/lpr mice carrying Tlr997 had markedly exacerbated disease compared to respective TlrWT mice. These experiments establish that TLR7 and TLR9 TIR domains have divergent properties and control disease quality, thus explaining the longstanding “TLR paradox.”
Authors
Claire Leibler, Kayla B. Thomas, Coralie Josensi, Russell C. Levack, Shuchi Smita, Shinu John, Daniel J. Wikenheiser, Sheldon Bastacky, Sebastien Gingras, Kevin M. Nickerson, Mark J. Shlomchik
Abstract
Despite the potential of targeted epigenetic therapies, most cancers do not respond to current epigenetic drugs. The Polycomb repressive complex EZH2 inhibitor tazemetostat was recently approved for the treatment of SMARCB1-deficient epithelioid sarcomas, based on the functional antagonism between PRC2 and SMARCB1. Through the analysis of tazemetostat-treated patient tumors, we recently defined key principles of their response and resistance to EZH2 epigenetic therapy. Here, using transcriptomic inference from SMARCB1-deficient tumor cells, we nominated the DNA damage repair kinase ATR as a target for rational EZH2 combination epigenetic therapy. We showed that EZH2 inhibition promotes DNA damage in epithelioid and rhabdoid tumor cells, at least in part via its induction of piggyBac transposable element derived 5 (PGBD5). We leveraged this collateral synthetic lethal dependency to target PGBD5-dependent DNA damage by inhibition of ATR, but not CHK1, using the ATR inhibitor elimusertib. Consequently, combined EZH2 and ATR inhibition improved therapeutic responses in diverse patient-derived epithelioid and rhabdoid tumors in vivo. This advances a combination epigenetic therapy based on EZH2-PGBD5 synthetic lethal dependency suitable for immediate translation to clinical trials for patients.
Authors
Yaniv Kazansky, Helen S. Mueller, Daniel Cameron, Phillip Demarest, Nadia Zaffaroni, Noemi Arrighetti, Valentina Zuco, Prabhjot S. Mundi, Yasumichi Kuwahara, Romel Somwar, Rui Qu, Andrea Califano, Elisa de Stanchina, Filemon S. Dela Cruz, Andrew L. Kung, Mrinal M. Gounder, Alex Kentsis
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Series edited by Ben Z. Stanger
Pancreatic Cancer
Series edited by Ben Z. Stanger
Pancreatic ductal adenocarcinoma (PDAC) has among the poorest prognosis and highest refractory rates of all tumor types. The reviews in this series, by Dr. Ben Z. Stanger, bring together experts across multiple disciplines to explore what makes PDAC and other pancreatic cancers so distinctively challenging and provide an update on recent multipronged approaches aimed at improving early diagnosis and treatment.
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Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)