Issue published July 1, 2025 Previous issue
- Volume 135, Issue 13
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On the cover: Targeting of MTAP synergizes with PARP inhibitors in triple-negative breast cancer
Zeng et al. report that deficiency in methylthioadenosine phosphorylase (MTAP), a key enzyme in the methionine salvage pathway, sensitizes triple-negative breast cancer to PARP inhibition by reducing s-adenosylmethionine (SAM) and impairing DNA damage repair. The cover art depicts-triple negative breast cancer cells being targeted by a combination of small molecule inhibitors of PARP (green) and MTAP (blue). Image credit: Xiangyu Zeng.
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Review Series
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Abstract
Metabolic dysfunction–associated steatotic liver disease (MASLD) is the most common pediatric liver disease, affecting approximately 10% of children. Its prevalence is rising at an alarming rate, with cases increasingly identified even in early childhood. While MASLD shares key features across the lifespan, its earlier onset reflects developmental vulnerabilities and unique mechanistic drivers. Perinatal influences, including maternal obesity, gestational diabetes, and early-life nutritional exposures, play a central role by disrupting metabolic programming, driving mitochondrial dysfunction, and inducing epigenetic modifications. These early stressors interact with genetic predispositions, such as PNPLA3 and TM6SF2 variants, to amplify susceptibility and shape disease severity. Pediatric MASLD also exhibits distinct histological features, particularly predominant periportal (zone 1) steatosis, inflammation, and fibrosis, which contrast with the centrilobular or pericentral (zone 3) patterns often seen in adults. These findings provide insight into spatial heterogeneity, developmental pathophysiology, and unique disease progression trajectories in children. Addressing MASLD in children requires pediatric-specific approaches to diagnosis, risk stratification, and intervention. By integrating epidemiological trends, mechanistic insights, and translational advances, this Review highlights opportunities for targeted therapies and prevention strategies aimed at mitigating early-life drivers of MASLD, reducing disease burden, and improving long-term outcomes.
Authors
Jeffrey B. Schwimmer, Sudha B. Biddinger, Samar H. Ibrahim
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Metabolic dysfunction–associated steatohepatitis (MASH), the progressive inflammatory form of MASLD, is now a leading cause of chronic liver disease worldwide. Driven by obesity and type 2 diabetes, MASH significantly increases the risk of cirrhosis, hepatocellular carcinoma, and liver failure. While public health interventions remain essential, therapeutic strategies targeting metabolic dysfunction, inflammation, and fibrosis are urgently needed. This Review focuses on pharmacological treatments in advanced development, including incretin-based therapies (GLP-1, dual, and triple agonists), metabolic modulators (PPAR, FGF21, and THR-β agonists), and novel agents such as fatty acid synthase inhibitors. Current regulatory approval is based on histological end points, with increasing interest in noninvasive biomarkers and personalized treatment approaches. Recent trials with agents such as semaglutide, tirzepatide, survodutide, lanifibranor, pegozafermin, and resmetirom demonstrate substantial promise in resolving MASH and improving fibrosis, but unresolved issues remain regarding treatment duration, response heterogeneity, and long-term adherence. Genetic variants (e.g., PNPLA3 polymorphisms) and emerging molecular biomarkers may enhance stratification, while artificial intelligence is beginning to shape trial design and drug development. As the field moves toward combination therapies and precision medicine, the definition of therapeutic success will likely evolve to reflect both histological improvement and patient-reported outcomes. This Review provides a timely synthesis of the landscape, challenges, and future directions in MASH therapeutics.
Authors
Philip N. Newsome, Rohit Loomba
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Reviews
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Abstract
Endometriosis is an estrogen-dependent chronic inflammatory syndrome characterized by viable endometrial tissue outside the uterine cavity and associated with pain and infertility. Endometriosis, as tissue or a pathological process, is dynamic in that its establishment and progression require repeated episodes of retrograde travel of shed endometrial tissue, which implants in the lower abdominal cavity following ovulatory cycles and survives. Estrogen-rich follicular fluid released onto peritoneal surfaces during ovulation may also support endometriotic implants. DNA evidence indicates that endometriosis originates from eutopic endometrial tissue, which may reach the abdominal cavity in a retrograde manner primarily via the uterine tubes. Unlike uterine bleeding associated with non-ovulatory circumstances, retrograde menstruation following an ovulation maximizes shedding of epithelial cells localized to deep invaginations of the basalis portion of the endometrium, which likely carry somatic cancer-driver mutations such as KRAS. The attached endometrial stromal cells are mostly mutation free but display epigenetic defects including overexpression of aromatase and estrogen receptor-β and downregulation of progesterone receptor, causing estrogen excess and progesterone resistance. These tissue clones may form implants in involuting ovarian corpus luteum cysts and peritoneal surfaces and induce tissue remodeling and fibrosis, manifested as deep-infiltrating endometriosis. The first-line treatment for chronic pelvic pain associated with endometriosis is suppression of ovulation, with the goal of relieving pain. Infertility is often managed using in vitro fertilization, which improves the embryo quality and alters endometrial development.
Authors
Serdar E. Bulun
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Cancer care is being transformed by therapies leveraging T lymphocytes to attack tumor cells. In parallel, recent basic discoveries have converged into a framework of lymphocyte-dependent immunity as a regenerative process that is sometimes outstripped by high-level engagement. In a stem cell–like fashion, selected T cells must balance mutually opposing demands of differentiation and self-renewal. Activating versus inhibitory signals to T cells instruct opposing cell metabolism, linked to alternative cell fates that arise in sibling cells through lopsided information transfer. Emerging studies indicate that durable immunotherapy response may be limited by the abundance of self-renewing T cells. Leveraging of basic discoveries of regenerative signaling to bolster sustained, stem-like output of freshly differentiated T cells is offering new strategies to overcome cancer immunotherapy resistance. Lymphocyte regeneration may also sustain harmful autoimmune attack. Undercutting the self-renewal of pathogenic clones may thus emerge as a therapeutic strategy for autoimmune diseases.
Authors
Steven L. Reiner
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Commentaries
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Abstract
Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, presents a clinical challenge in developing effective treatment options. In this issue of the JCI, Zeng et al. demonstrate a provocative and promising therapeutic strategy for TNBC by leveraging the metabolic vulnerabilities presented by methylthioadenosine phosphorylase (MTAP) deletion to genotoxic stress inducers, such as poly (ADP-ribose) polymerase inhibitors (PARPi). They found that combining MTAP deletion or inhibition with PARPi was highly effective in brain metastatic TNBC where the methionine-limited environment further enhanced this combination. This approach underscores the importance of targeting metabolic vulnerabilities in the development of personalized cancer therapies.
Authors
Samyuktha Suresh, James M. Ford
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Recent studies have highlighted a possible role for gut microbiota in modulating Alzheimer’s disease pathology, particularly through the actions of gut-derived metabolites and their influence on the immune system. In this issue of the JCI, Chandra et al. reveal that circulating levels of the gut microbiota–derived metabolite propionate affected amyloid burden and glial activation in a mouse model of Aβ amyloidosis. The study also identifies a mechanism for the therapeutic benefit of propionate supplementation, showing that propionate lowered peripheral IL-17 and suppressed Th17 cell activity. These results support the idea of therapeutic targeting of the gut/brain/immune axis, particularly via modulation of Th17 responses, and suggest translational strategies involving microbiome-based or immunological interventions for dementia prevention and treatment.
Authors
Wade K. Self, David M. Holtzman
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Research Articles
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Abstract
Coinhibitory receptors function as central modulators of the immune response to resolve T effector activation and/or to sustain immune homeostasis. Here, using humanized SCID mice, we found that neuropilin–2 (NRP2) is inducible on late effector and exhausted subsets of human CD4+ T cells and that it is coexpressed with established coinhibitory molecules including PD-1, CTLA4, TIGIT, LAG3, and TIM3. In murine models, we also found that NRP2 is expressed on effector memory CD4+ T cells with an exhausted phenotype and that it functions as a key coinhibitory molecule. Knockout (KO) of NRP2 resulted in hyperactive CD4+ T cell responses and enhanced inflammation in delayed-type hypersensitivity and transplantation models. After cardiac transplantation, allograft rejection and graft failure were accelerated in global as well as CD4+ T cell–specific KO recipients, and enhanced alloimmunity was dependent on NRP2 expression on CD4+ T effectors but not on CD4+Foxp3+ Tregs. Also, KO Tregs were found to be as efficient as WT cells in the suppression of effector responses in vitro and in vivo. These collective findings identify NRP2 as a potentially novel coinhibitory receptor and demonstrate that its expression on CD4+ T effector cells is of great functional importance in immunity.
Authors
Johannes Wedel, Nora Kochupurakkal, Sek Won Kong, Sayantan Bose, Ji-Won Lee, Madeline Maslyar, Bayan Alsairafi, Kayla MacLeod, Kaifeng Liu, Hengcheng Zhang, Masaki Komatsu, Hironao Nakayama, Diane R. Bielenberg, David M. Briscoe
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Lymphocyte activation gene 3 (LAG3) is a coinhibitory receptor expressed by various immune cells. Although the immunomodulatory potential of LAG3 is being explored in cancer and autoimmunity, there is no information on its role after organ transplantation. Our study investigated the functions of LAG3 in a mouse model of renal allograft rejection. LAG3–/– recipients rapidly rejected MHC-mismatched renal allografts that were spontaneously accepted by WT recipients, with graft histology characteristic of antibody-mediated rejection. Depletion of recipient B cells but not CD8+ T cells significantly extended kidney allograft survival in LAG3–/– recipients. Treatment of WT recipients with an antagonistic LAG3 antibody enhanced anti-donor immune responses and induced kidney damage associated with chronic rejection. The studies of conditional LAG3–/– recipients and mixed bone marrow chimeras demonstrated that LAG3 expression on either T or B cells is sufficient to regulate anti-donor humoral immunity but not to induce acute allograft rejection. The numbers and proinflammatory functions of graft-infiltrating NK cells were markedly increased in LAG3–/– recipients, suggesting that LAG3 also regulates the effector stage of antibody-mediated rejection. These findings identified LAG3 as a regulator of immune responses to kidney allografts and a potential therapeutic target for antibody-mediated rejection prevention and treatment.
Authors
Michael Nicosia, Ran Fan, Juyeun Lee, Gabriella All, Victoria Gorbacheva, José I. Valenzuela, Yosuke Yamamoto, Ashley Beavers, Nina Dvorina, William M. Baldwin III, Eduardo Chuluyan, Motoo Araki, Brian T. Gaudette, Robert L. Fairchild, Booki Min, Anna Valujskikh
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Germinal center (GC) B cells are pivotal in establishing a robust humoral immune response and long-term serological immunity while maintaining antibody self-tolerance. GC B cells rely on autophagy for antigen presentation and homeostatic maintenance. However, these functions, primarily associated with the light zone, cannot explain the spatiotemporal autophagy upregulation in the dark zone of GCs. Here, combining imaging, molecular, and genomic approaches, we defined a functional mechanism controlling chromatin accessibility in GC B cells during their dark zone transition. This mechanism links autophagy and nuclear lamin B1 dynamics with their downstream effects, including somatic hypermutation and antibody affinity maturation. Moreover, the autophagy–lamin B1 axis is highly active in the aberrant ectopic GCs in the salivary glands of Sjögren’s disease, defining its role in autoimmunity.
Authors
Marta C. Sallan, Filip Filipsky, Christina H. Shi, Elena Pontarini, Manuela Terranova-Barberio, Gordon Beattie, Andrew Clear, Michele Bombardieri, Kevin Y. Yip, Dinis Pedro Calado, Mark S. Cragg, Sonya James, Mathew Carter, Jessica Okosun, John G. Gribben, Tanya Klymenko, Andrejs Braun
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Complement activation is a relevant driver in the pathomechanisms of vasculitis. The involved proteins in the interaction between endothelia, complement, and platelets in these conditions are only partially understood. Thrombospondin-1 (TSP-1), found in platelet α-granules and released from activated endothelial cells, interacts with factor H (FH) and vWF. However, to our knowledge, direct regulatory interaction with the complement cascade has not yet been described. Our study shows that TSP-1 is a potent, FH-independent inhibitor of the alternative complement pathway. TSP-1 binds to complement proteins and inhibits cleavage of C3 and C5 and the formation of the membrane attack complex. We validated complement-regulatory function in blood samples from patients with primary complement defects. The physiological relevance of TSP-1 was demonstrated in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) by significantly enhanced TSP-1 staining in glomerular lesions and increased complement activity and NETosis after TSP-1 deficiency in an in vitro and in vivo model of AAV. The complement-inhibiting function of TSP-1 represents an important mechanism in the interaction of endothelia and complement. In particular, the interplay between released TSP-1 and the complement system locally, especially on surfaces, influences the balance between complement activation and inhibition and may be relevant in various vascular diseases.
Authors
Swagata Konwar, Sophie Schroda, Manuel Rogg, Jessika Kleindienst, Eva L. Decker, Martin Pohl, Barbara Zieger, Jens Panse, Hong Wang, Robert Grosse, Christoph Schell, Sabine Vidal, Xiaobo Liu, Christian Gorzelanny, Todor Tschongov, Karsten Häffner
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Accumulating evidence implicates the gut microbiome (GMB) in the pathogenesis and progression of Alzheimer’s disease (AD). We recently showed that the GMB regulates reactive astrocytosis and Aβ plaque accumulation in a male APPPS1-21 AD mouse model. Yet, the mechanism(s) by which GMB perturbation alters reactive astrocytosis in a manner that reduces Aβ deposition remain unknown. Here, we performed metabolomics on plasma from mice treated with antibiotics (ABX) and identified a significant increase in plasma propionate, a gut-derived short-chain fatty acid, only in male mice. Administration of sodium propionate reduced reactive astrocytosis and Aβ plaques in APPPS1-21 mice, phenocopying the ABX-induced phenotype. Astrocyte-specific RNA-Seq on ABX- and propionate-treated mice showed reduced expression of proinflammatory and increased expression of neurotrophic genes. Next, we performed flow cytometry experiments, in which we found that ABX and propionate decreased peripheral RAR-related orphan receptor-γ+ (Rorγt+) CD4+ (Th17) cells and IL-17 secretion, which positively correlated with reactive astrocytosis. Last, using an IL-17 mAb to deplete IL-17, we found that propionate reduced reactive astrocytosis and Aβ plaques in an IL-17–dependent manner. Together, these results suggest that gut-derived propionate regulates reactive astrocytosis and Aβ amyloidosis by decreasing peripheral Th17 cells and IL-17 release. Thus, propionate treatment or strategies boosting propionate production may represent novel therapeutic strategies for the treatment of AD.
Authors
Sidhanth Chandra, Jelena Popovic, Naveen K. Singhal, Elyse A. Watkins, Hemraj B. Dodiya, Ian Q. Weigle, Miranda A. Salvo, Abhirami Ramakrishnan, Zhangying Chen, Thomas Watson, Aashutosh Shetti, Natalie Piehl, Xiaoqiong Zhang, Leah Cuddy, Katherine R. Sadleir, Steven J. Schwulst, Murali Prakriya, David Gate, Sangram S. Sisodia, Robert Vassar
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The activated JAK2/STAT pathway is characteristic of myeloproliferative neoplasms (MPNs). The pleckstrin 2 (PLEK2) signalosome is downstream of the JAK2/STAT5 pathway and plays an important role in MPN development. The detailed molecular composition of this signalosome is unclear. Here, we reveal peptidylprolyl isomerase-like 2 (PPIL2) as a critical component of the complex in regulating human and murine erythropoiesis. PPIL2 was a direct target of STAT5 and was upregulated in patients with MPN and in a Jak2V617F MPN mouse model. Mechanistically, PPIL2 interacted with and catalyzed p53 polyubiquitination and proteasome-mediated degradation to promote cell growth. Ppil2 deficiency, or inhibition by cyclosporin A, led to a marked upregulation of p53 in vivo and ameliorated myeloproliferative phenotypes in Jak2V617F mice. Cyclosporin A also markedly reduced JAK2-mutated erythroid and myeloid proliferation in an induced pluripotent stem cell–derived human bone marrow organoid model. Our findings reveal PPIL2 as a critical component of the PLEK2 signalosome in driving MPN pathogenesis through negative regulation of p53, thus providing a target and opportunity for drug repurposing using cyclosporin A to treat MPNs.
Authors
Pan Wang, Xu Han, Kehan Ren, Ermin Li, Honghao Bi, Inci Aydemir, Madina Sukhanova, Yijie Liu, Jing Yang, Peng Ji
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Phenylketonuria (PKU), an inborn error of phenylalanine (Phe) metabolism, is a common cause of intellectual disability. However, the mechanisms by which elevated Phe levels cause cognitive impairment remain unclear. Here, we show that submillimolar Phe perturbs synaptic plasticity through the hyperactivation of GluN2B-containing NMDARs. PahEnu2 PKU model mice exhibited submillimolar and supramillimolar concentrations of Phe in the cerebrospinal fluid (CSF) and serum, respectively. l-Phe produced concentration-dependent bidirectional effects on NMDA-induced currents, without affecting synaptic NMDA receptors (NMDARs) in hippocampal CA1 neurons. l-Phe-induced hyperactivation of extrasynaptic GluN2B resulted in activity-dependent downregulation of AMPA receptors during burst or sustained synaptic activity. Administration of l-Phe in mice decreased neural activity and impaired memory, which were blocked by pretreatment with GluN2B inhibitors. Furthermore, pharmacological and virus-mediated suppression of GluN2B reversed the impaired learning in PahEnu2 mice. Collectively, these results suggest the concentration of Phe in the CSF of patients with PKU perturbs extrasynaptic NMDARs and synaptic plasticity and that suppression of GluN2B may have the potential to improve cognitive function in patients with PKU.
Authors
Woo Seok Song, Young Sook Kim, Young-Soo Bae, Sang Ho Yoon, Jae Min Lim, Myoung-Hwan Kim
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In preclinical mouse models of triple-negative breast cancer (TNBC), we show that a combination of chemotherapy with cisplatin (CDDP) and eribulin (Eri) was additive from an immunological point of view and was accompanied by the induction of an intratumoral immune and inflammatory response favored by the immunogenic cell death induced by CDDP, as well as by the vascular and tumor stromal remodeling induced by each chemotherapy. Unexpectedly, despite the favorable immune context created by this immunomodulatory chemotherapy combination, our models remained refractory to the addition of anti–PD-L1 immunotherapy. These surprising observations led us to discover that CDDP chemotherapy was simultaneously responsible for the production of TGF-β by several populations of cells present in tumors, which favored the emergence of different subpopulations of immune cells and cancer-associated fibroblasts characterized by immunosuppressive properties. Accordingly, co-treatment with anti–TGF-β restored the immunological synergy between this immunogenic doublet of chemotherapy and anti–PD-L1 in a CD8-dependent manner. Translational studies revealed the unfavorable prognostic effect of the TGF-β pathway on the immune response in human TNBC, as well as the ability of CDDP to induce this cytokine also in human TNBC cell lines, thus highlighting the clinical relevance of targeting TGF-β in the context of human TNBC treated with chemoimmunotherapy.
Authors
Laura Kalfeist, Fanny Ledys, Stacy Petit, Cyriane Poirrier, Samia Kada Mohammed, Loïck Galland, Valentin Derangère, Alis Ilie, David Rageot, Romain Aucagne, Pierre-Simon Bellaye, Caroline Truntzer, Marion Thibaudin, Mickaël Rialland, François Ghiringhelli, Emeric Limagne, Sylvain Ladoire
×Abstract
Sustaining the strong rhythmic interactions between cellular adaptations and environmental cues has been posited as essential for preserving the physiological and behavioral alignment of an organism to the proper phase of the daily light/dark (LD) cycle. Here, we demonstrate that mitochondria and synaptic input organization of suprachiasmatic (SCN) vasoactive intestinal peptide–expressing (VIP-expressing) neurons showed circadian rhythmicity. Perturbed mitochondrial dynamics achieved by conditional ablation of the fusogenic protein mitofusin 2 (Mfn2) in VIP neurons caused disrupted circadian oscillation in mitochondria and synapses in SCN VIP neurons, leading to desynchronization of entrainment to the LD cycle in Mfn2-deficient mice that resulted in an advanced phase angle of their locomotor activity onset, alterations in core body temperature, and sleep-wake amount and architecture. Our data provide direct evidence of circadian SCN clock machinery dependence on high-performance, Mfn2-regulated mitochondrial dynamics in VIP neurons for maintaining the coherence in daily biological rhythms of the mammalian organism.
Authors
Milan Stoiljkovic, Jae Eun Song, Hee-kyung Hong, Heiko Endle, Luis Varela, Jonatas Catarino, Xiao-Bing Gao, Zong-Wu Liu, Peter Sotonyi, Sabrina Diano, Jonathan Cedernaes, Joseph Bass, Tamas L. Horvath
×Abstract
Chagas disease, caused by Trypanosoma cruzi, is endemic to Latin America and is characterized by chronic inflammation of cardiac tissues due to parasite persistence. Hypoxia within infected tissues may trigger the stabilization of HIF-1 and be linked to ATP release. Extracellular ATP exhibits microbicidal effects but is scavenged by CD39 and CD73 ectonucleotidases, which ultimately generate adenosine (ADO), a potent immunosuppressor. Here, we comprehensively study the importance of HIF-1 stabilization and the CD39/CD73/ADO axis, on CD4+ T cells with the cytotoxic phenotype, in facilitating the persistence of T. cruzi. Myocardial infection induces prominent areas of hypoxia, which is concomitant with HIF-1α stabilization in T cells and linked to early expansion of CD39+CD73+CD4+ T cell infiltrating population. Functional assays further demonstrate that HIF-1 stabilization and CD73 activity are associated with impaired CD4+ T cell cytotoxic potential. RNA-Seq analysis reveals that HIF-1 and purinergic signaling pathways are overrepresented in cardiac tissues of patients with end-stage Chagas disease. The findings highlight a major effect of purinergic signaling on CD4+ T cells with potential cytotoxic capacity in the setting of T. cruzi infection and have translational implications for therapy.
Authors
Gastón Bergero, Yanina L. Mazzocco, Sebastian Del Rosso, Ruining Liu, Zoé M. Cejas Gallardo, Simon C. Robson, Martin Rottenberg, Maria P. Aoki
×Abstract
Stem-like T cells selectively contribute to autoimmunity, but the activities that promote their pathogenicity are incompletely understood. Here, we identify the transcription coregulator OCA-B as a driver of the pathogenic maturation of stem-like CD4+ T cells to promote autoimmune demyelination. Using 2 human multiple sclerosis (MS) datasets, we show that POU2AF1, the gene encoding OCA-B, is elevated in CD4+ T cells from patients with MS. We show that T cell–intrinsic OCA-B loss protects mice from experimental autoimmune encephalomyelitis (EAE) while preserving responses to viral CNS infection. In EAE models driven by antigen re-encounter, OCA-B deletion nearly eliminates CNS infiltration, proinflammatory cytokine production, and clinical disease. OCA-B–expressing CD4+ T cells of mice primed with autoantigen express an encephalitogenic gene program and preferentially confer disease. In a relapsing-remitting EAE model, OCA-B loss protects mice specifically at relapse. During remission, OCA-B promotes the expression of Tcf7, Slamf6, and Sell in proliferating CNS T cell populations. At relapse time points, OCA-B loss results in both the accumulation of an immunomodulatory CD4+ T cell population expressing Ccr9 and Bach2, and loss of proinflammatory gene expression from Th17 cells. These results identify OCA-B as a driver of pathogenic CD4+ T cells.
Authors
Erik P. Hughes, Amber R. Syage, Elnaz Mirzaei Mehrabad, Thomas E. Lane, Benjamin T. Spike, Dean Tantin
×Abstract
Triple-negative breast cancer (TNBC) represents the most malignant subtype of breast cancer. The clinical application of PARP inhibitors (PARPi) is limited by the low frequency of BRCA1/2 mutations in TNBC. Here, we identified that MTAP deletion sensitized genotoxic agents in our clinical cohort of metastatic TNBC. Further study demonstrated that MTAP deficiency or inhibition rendered TNBC susceptibility to chemotherapeutic agents, particularly PARPi. Mechanistically, targeting MTAP that synergized with PARPi by disrupting the METTL16-MAT2A axis involved in methionine metabolism and depleting in vivo s-adenosylmethionine (SAM) levels. Exhausted SAM in turn impaired PARPi-induced DNA damage repair through attenuation of MRE11 recruitment and end resection by diminishing MRE11 methylation. Notably, brain metastatic TNBC markedly benefited from a lower dose of PARPi and MTAP deficiency/inhibition synergy due to the inherently limited methionine environment in the brain. Collectively, our findings revealed a feed-forward loop between methionine metabolism and DNA repair through SAM, highlighting a therapeutic strategy of PARPi combined with MTAP deficiency/inhibition for TNBC.
Authors
Xiangyu Zeng, Fei Zhao, Xinyi Tu, Yong Zhang, Wen Yang, Jing Hou, Qi Jiang, Shouhai Zhu, Zheming Wu, Yalan Hao, Lingxin Zhang, Richard M. Weinshilboum, Kaixiong Tao, Liewei Wang, Zhenkun Lou
×Abstract
Alcohol-associated liver disease represents a significant global health challenge, with gut microbial dysbiosis and bacterial translocation playing a critical role in its pathogenesis. Patients with alcohol-associated hepatitis had increased fecal abundance of mammalian viruses, including retroviruses. This study investigated the role of endogenous retroviruses (ERVs) in the development of alcohol-associated liver disease. Transcriptomic analysis of duodenal and liver biopsies revealed increased expression of several human ERVs, including HERV-K and HERV-H, in patients with alcohol-associated liver disease compared with individuals acting as controls. Chronic-binge ethanol feeding markedly induced ERV abundance in intestinal epithelial cells but not the livers of mice. Ethanol increased ERV expression and activated the Z-DNA binding protein 1 (Zbp1)–mixed lineage kinase domain-like pseudokinase (Mlkl) signaling pathways to induce necroptosis in intestinal epithelial cells. Antiretroviral treatment reduced ethanol-induced intestinal ERV expression, stabilized the gut barrier, and decreased liver disease in microbiota-humanized mice. Furthermore, mice with an intestine-specific deletion of Zbp1 were protected against bacterial translocation and ethanol-induced steatohepatitis. These findings indicate that ethanol exploits this pathway by inducing ERVs and promoting innate immune responses, which results in the death of intestinal epithelial cells, gut barrier dysfunction, and liver disease. Targeting the ERV/Zbp1 pathway may offer new therapies for patients with alcohol-associated liver disease.
Authors
Noemí Cabré, Marcos F. Fondevila, Wenchao Wei, Tomoo Yamazaki, Fernanda Raya Tonetti, Alvaro Eguileor, Ricard Garcia-Carbonell, Abraham S. Meijnikman, Yukiko Miyamoto, Susan Mayo, Yanhan Wang, Xinlian Zhang, Thorsten Trimbuch, Seija Lehnardt, Lars Eckmann, Derrick E. Fouts, Cristina Llorente, Hidekazu Tsukamoto, Peter Stärkel, Bernd Schnabl
×Abstract
The ATP6V0A4 gene encodes the a4 subunit of vacuolar H+-ATPase (V-ATPase), which mediates hydrogen ion transport across the membrane. Previous studies have suggested that mutations in ATP6V0A4 consistently result in a loss of function, impairing the hydrogen ion transport efficacy of V-ATPase and leading to distal renal tubular acidosis and sensorineural hearing loss. Here, we identified a 32-year-old male patient and his father, both of whom harbored a heterozygous ATP6V0A4 p.V512L mutation and exhibited hypochloremic metabolic alkalosis, acidic urine, and hypokalemia. Through a series of protein structural analyses and functional experiments, the V512L mutation was confirmed as a gain-of-function mutation in the ATP6V0A4 gene. V512-a4 increased a4 subunit expression abundance by enhancing V512L-a4 stability and reducing its degradation, which in turn potentiated the capacity of V-ATPase to acidify the tubular lumen, leading to acidic urine and metabolic alkalosis. Through mutant V512L-a4 subunit structure-based virtual and experimental screening, we identified F351 (C25H26FN3O2S), a small-molecule inhibitor specifically targeting the V512L-a4 mutant. In conclusion, we identified a gain-of-function mutation in the ATP6V0A4 gene, broadening its phenotypic and mutational spectrum, and we provide valuable insights into potential therapeutic approaches for diseases associated with ATP6V0A4 mutations.
Authors
Si-qi Peng, Qian-qian Wu, Wan-yi Wang, Yi-Lin Zhang, Rui-ning Zhou, Jun Liao, Jin-xuan Wei, Yan Yang, Wen Shi, Jun-lan Yang, Xiao-xu Wang, Zhi-yuan Wei, Jia-xuan Sun, Lu Huang, Hong Fan, Hui Cai, Cheng-kun Wang, Xin-hua Li, Ting-song Li, Bi-cheng Liu, Xiao-liang Zhang, Bin Wang
×Abstract
Neurofibromatosis type 1 (NF1) is a genetic disorder caused by mutations of the NF1 tumor suppressor gene resulting in the loss of function of neurofibromin, a GTPase-activating protein (GAP) for Ras. While the malignant manifestations of NF1 are associated with loss of heterozygosity of the residual WT allele, the nonmalignant neurodevelopmental sequelae, including autism spectrum disorder (ASD) and/or attention deficit hyperactivity disorder (ADHD) are prevalent morbidities that occur in the setting of neurofibromin haploinsufficiency. We reasoned that augmenting endogenous levels of WT neurofibromin could serve as a potential therapeutic strategy to correct the neurodevelopmental manifestations of NF1. Here, we used a combination of genetic screening and genetically engineered murine models to identify a role for the F-box protein FBXW11 as a regulator of neurofibromin degradation. Disruption of Fbxw11, through germline mutation or targeted genetic manipulation in the nucleus accumbens, increased neurofibromin levels, suppressed Ras-dependent ERK phosphorylation, and corrected social learning deficits and impulsive behaviors in male Nf1+/– mice. Our results demonstrate that preventing the degradation of neurofibromin is a feasible and effective approach to ameliorate the neurodevelopmental phenotypes in a haploinsufficient disease model.
Authors
Su Jung Park, Jodi L. Lukkes, Ka-Kui Chan, Hayley P. Drozd, Callie B. Burgin, Shaomin Qian, Morgan McKenzie Sullivan, Cesar Gabriel Guevara, Nolen Cunningham, Stephanie Arenas, Makenna A. Collins, Jacob Zucker, JinHee Won, Abbi Smith, Li Jiang, Dana K. Mitchell, Steven D. Rhodes, Steven P. Angus, D. Wade Clapp
×Abstract
Anemia is the primary clinical manifestation of myelodysplastic syndromes (MDSs), but the molecular pathogenesis of ineffective erythropoiesis remains incompletely understood. Luspatercept, an activin receptor 2B (ACVRIIB-Fc) ligand trap, has been approved to treat anemia; however, its molecular mechanism of action is unclear. We found that activin receptor 2B (ACVR2B), its ligand growth and differentiation factor 11 (GDF11), and an effector, SMAD2, are upregulated in samples of patients with MDS. GDF11 inhibited human erythropoiesis in vitro and caused anemia in zebrafish, effects that were abrogated by luspatercept. Upon GDF11 stimulation of human erythroid progenitors, SMAD2 binding occurred in the erythroid regulatory regions, including at the GATA1 intron. Intronic SMAD2-binding led to skipping of exon 2 of GATA1, resulting in a shorter, hypomorphic isoform (GATA1s). CRISPR deletion of the SMAD2-binding intronic region decreased GATA1s production upon GDF11 stimulation. Expression of GATA1s in a mouse model led to anemia, rescued by a murine ActRIIB-Fc (RAP-536). Finally, RNA-Seq analysis of samples from the phase 3 MEDALIST trial revealed that responders to luspatercept had a higher proportion of GATA1s compared with nonresponders. Moreover, the increase in RBCs after treatment was linked to a relative decrease in GATA1s isoforms. Our study indicates that GDF11-mediated SMAD2 activation results in an increase in functionally impaired GATA1 isoforms, consequently contributing to anemia and influencing responses to luspatercept in MDS.
Authors
Srinivas Aluri, Te Ling, Ellen Fraint, Samarpana Chakraborty, Kevin Zhang, Aarif Ahsan, Leah Kravets, Gowri Poigaialwar, Rongbao Zhao, Kith Pradhan, Anitria Cotton, Kimo Bachiashvili, Jung-In Yang, Anjali Budhathoki, Beamon Agarwal, Shanisha Gordon Mitchell, Milagros Carbajal, Srabani Sahu, Jacqueline Boultwood, Andrea Pellagatti, Ulrich Steidl, Amittha Wickrema, Satish Nandakumar, Aditi Shastri, Rajasekhar N.V.S. Suragani, Teresa V. Bowman, John D. Crispino, Sadanand Vodala, Amit Verma
×Abstract
BACKGROUND Treatment of tubo-ovarian high-grade serous carcinoma (HGSC) includes cytoreductive surgery, platinum-based chemotherapy, and often poly(ADP-ribose) polymerase (PARP) inhibitors. While homologous recombination (HR) deficiency is a well-established predictor of therapy sensitivity, over 50% of HR-proficient HGSCs also exhibit sensitivity. Currently, there are no biomarkers to identify which HR-proficient HGSCs will be sensitive to standard-of-care therapy. Replication stress may serve as a key determinant of response.METHODS We evaluated phospho–RPA2-T21 (p-RPA2) foci via immunofluorescence as a biomarker of replication stress in formalin-fixed, paraffin-embedded HGSC samples collected at diagnosis from patients treated with platinum chemotherapy (discovery cohort, n = 31; validation cohort, n = 244) or PARP inhibitors (n = 63). Recurrent HGSCs (n = 38) were also analyzed. p-RPA2 score was calculated using automated imaging analysis.RESULTS Samples were defined as p-RPA2-high if more than 16% of cells had ≥2 p-RPA2 foci on automated analysis. In the discovery cohort, HR-proficient, p-RPA2-high HGSCs demonstrated significantly higher rates of a chemotherapy response score of 3 to platinum chemotherapy than HR-proficient, p-RPA2-low HGSCs. In the validation cohort, patients with HR-proficient, p-RPA2-high HGSCs had significantly longer survival after platinum treatment than those with HR-proficient, p-RPA2-low HGSCs. Additionally, the p-RPA2 assay effectively predicted survival outcomes in patients treated with PARP inhibitors and in recurrent HGSC samples.CONCLUSION Our study underscores the importance of considering replication stress markers, such as p-RPA2, alongside HR status in therapeutic planning. This approach has the potential to increase the number of patients receiving effective therapy while reducing unnecessary toxicity.FUNDING The Reproductive Scientist Development Program, GOG Foundation, Pilot Translational and Clinical Studies function of the Washington University Institute of Clinical and Translational Sciences, the Foundation for Barnes-Jewish Hospital, Washington University School of Medicine Dean’s Scholar Program, The Cancer Biology Pathway Training Grant (5T32CA113275-17), The Lucy, Anarcha, and Betsey (L.A.B.) Award from the Department of Obstetrics and Gynecology at Washington University School of Medicine, and Veterans Affairs Office of Research and Development (I01BX006020).
Authors
Angela Schab, Amanda Compadre, Rebecca Drexler, Megan Loeb, Kevin Rodriguez, Joshua Brill, Shariska Harrington, Carmen Sandoval, Brooke Sanders, Lindsay Kuroki, Carolyn McCourt, Andrea R. Hagemann, Premal Thaker, David Mutch, Matthew Powell, Violeta Serra, Ian S. Hagemann, Ann E. Walts, Beth Y. Karlan, Sandra Orsulic, Katherine C. Fuh, Lulu Sun, Priyanka Verma, Elena Lomonosova, Peinan Zhao, Dineo Khabele, Mary M. Mullen
×Abstract
Synovial sarcoma is an aggressive soft-tissue cancer driven by the chimeric SS18::SSX fusion oncoprotein, which disrupts chromatin remodeling by combining two antagonistic transcriptional regulators. SS18 participates in BAF complexes that open chromatin, while the SSX genes are cancer-testis antigens that interface with chromatin decorated with monoubiquitinated histone H2A placed by polycomb repressive complex activity. Because KDM2B brings polycomb repressive complex to unmethylated CpG islands, it is plausible that methylation directly determines the distribution of SS18::SSX to target loci. Given that synovial sarcoma is also characterized by a peculiarly low DNA hypomethylation profile, we hypothesized that further disturbance of DNA methylation would have a negative impact on synovial sarcoma growth. DNMT1 disruption by CRISPR/Cas9 targeting or pharmacological inhibition with cytidine analogs 5-aza-2′-deoxycytidine (decitabine) and 5-azacytidine led to decreased genome-wide methylation, redistribution of SS18::SSX, and altered gene expression profiles, most prominently including upregulation of tumor suppressor genes, immune-related genes, and mesenchymal differentiation-related genes. These drugs suppressed growth of synovial sarcoma cell lines and drove cytoreduction in mouse genetic models. DNMT1 inhibitors, already approved for treating myelodysplastic syndromes, warrant further clinical investigation for synovial sarcoma as repurposed, targeted treatments exploiting a vulnerability in the intrinsic biology of this cancer.
Authors
Nobuhiko Hasegawa, Nezha S. Benabdallah, Kyllie Smith-Fry, Li Li, Sarah McCollum, Jinxiu Li, Caelen A. Jones, Lena Wagner, Vineet Dalal, Viola Golde, Anastasija Pejkovska, Lara Carroll, Malay Haldar, Seth M. Pollack, Scott W. Lowe, Torsten O. Nielsen, Ana Banito, Kevin B. Jones
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Abstract
The role of type 1 conventional dendritic cells (cDC1) in tolerance induction to solid organ allografts is unknown and important for strategies that seek to prolong allograft viability. Using a murine model deficient in cDC1s, we report cDC1s are required for donor antigen and costimulation blockade (DST + CoB) tolerance induction and survival of cardiac allografts. cDC1 deficiency led to decreases in CD4+CD25+FoxP3+ T cells within both allograft and spleen tissue of transplant recipients and this was found to be antigen specific. Donor antigen stimulation induced TGF-β1 expression both in vivo cDC1 and in vitro Flt3L derived cDC1. Genetic deletion of Tgfβ1 in cDC1s prevented induction of antigen specific CD4+CD25+FoxP3+ T cells and was associated with cardiac allograft rejection. In parallel, single-cell RNA sequencing and metabolic analysis revealed upregulation of cDC1 mitochondrial metabolic signatures after in vivo exposure to DST + CoB. Genetic inactivation of cDC1 mitochondrial metabolism reduced expression of cDC1 TGF-β1, decreased antigen specific T regulatory cell populations, and impaired allograft tolerance. Taken together, our findings newly implicate cDC1s in strategies to preserve solid organ allografts and also implicate mitochondrial metabolism of cDC1s as a molecular mechanism to enhance the generation of antigen-specific CD4+CD25+FoxP3+ T cells through TGF-β1.
Authors
Samantha L Schroth, Lei Zhang, Rebecca T.L. Jones, Kristofor Glinton, Nikita L. Mani, Hiroyasu Inui, Jesse T. Davidson, Samuel E. Weinberg, Navdeep Chandel, Maria-Luisa Alegre, Edward B. Thorp
Abstract
Chronic inflammatory diseases, like rheumatoid arthritis (RA) have been described to cause central nervous system (CNS) activation. Less is known about environmental factors that enable the CNS to suppress peripheral inflammation in RA. Here, we identified gut microbiota-derived histamine as such factor. We show that low levels of histamine activate the enteric nervous system, increase inhibitory neurotransmitter concentrations in the spinal cord and restore homeostatic microglia, thereby reducing inflammation in the joints. Selective histamine 3 receptor (H3R) signaling in the intestine is critical for this effect, as systemic and intrathecal application did not show effects. Microglia depletion or pharmacological silencing of local nerve fibers impaired oral H3R agonist-induced pro-resolving effects on arthritis. Moreover, therapeutic supplementation of the short-chain fatty acid (SCFA) propionate identified one way to expand local intestinal histamine concentrations in mice and humans. Thus, we define a gut-CNS-joint axis pathway where microbiota-derived histamine initiates the resolution of arthritis via the CNS.
Authors
Kerstin Dürholz, Leona Ehnes, Mathias Linnerbauer, Eva Schmid, Heike Danzer, Michael Hinzpeter-Schmidt, Lena Lößlein, Lena Amend, Michael Frech, Vugar Azizov, Fabian Schälter, Arne Gessner, Sébastien Lucas, Till-Robin Lesker, R. Verena Taudte, Jörg Hofmann, Felix Beyer, Hadar Bootz-Maoz, Yasmin Reich, Hadar Romano, Daniele Mauro, Ruth Beckervordersandforth, Maja Skov Kragsnaes, Torkell Ellingsen, Wei Xiang, Aiden Haghikia, Cezmi A. Akdis, Francesco Ciccia, Tobias Bäuerle, Kerstin Sarter, Till Strowig, Nissan Yissachar, Georg Schett, Veit Rothhammer, Mario M. Zaiss
Abstract
Few effective therapeutic options exist following progression on immune checkpoint blockade (ICB) for melanoma. Here we utilize a platform incorporating transcriptomic profiling, high-throughput drug screening (HTDS) and murine models to demonstrate the pre-clinical efficacy of several combinatorial regimens against ICB-resistant melanoma. Transcriptomic analysis of ICB-resistant melanomas demonstrated activation of several targetable pathways. HTDS targeting these pathways identified several effective combinations in ICB-resistant patient-derived xenograft models. The combination of cobimetinib and regorafenib (termed Cobi+Reg) emerged as a particularly promising regimen, with efficacy against distinct molecular melanoma subtypes and following progression on ICB in immunocompetent models. Transcriptomic and spatial analysis of Cobi+Reg-treated tumors demonstrated upregulation of antigen presentation machinery, with concomitantly increased activated T cell infiltration. Combining Cobi+Reg with ICB was superior to either modality in vivo. This analytical platform exploits the biology of ICB-resistant melanoma to identify therapeutic vulnerabilities, resulting in the identification of drug combinations that form the basis for rational clinical trial design in the setting of advanced melanoma resistant to ICB.
Authors
Imran Khan, Aida Rodriguez-Brotons, Anukana Bhattacharjee, Vladimir Bezrookove, Altaf Dar, David De Semir, Mehdi Nosrati, Ryan Ice, Liliana Soroceanu, Stanley P. Leong, Kevin B. Kim, Yihui Shi, James E. Cleaver, James R. Miller, Pierre-Yves Desprez, John M. Kirkwood, Marcus Bosenberg, Nathan Salomonis, Sean McAllister, Mohammed Kashani-Sabet
Abstract
Somatic mutations that increase clone fitness or resist disease are positively selected, but the impact of these mutations on organismal health remains unclear. We previously showed that Tbx3 deletion increases hepatocyte fitness within fatty livers. Here, we detected TBX3 somatic mutations in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). In mice, Tbx3 deletion protected against, whereas Tbx3 overexpression exacerbated MASLD. Tbx3 deletion reduced lipid overload by accelerating VLDL secretion. Choline deficient diets, which block VLDL secretion, abrogated this protective effect. TBX3 transcriptionally suppressed the conventional secretory pathway and cholesterol biosynthesis. Hdlbp is a direct target of TBX3 that is responsible for the altered VLDL secretion. In contrast to wild-type TBX3, the TBX3 I155S and A280S mutations found in patients failed to suppress VLDL secretion. In conclusion, TBX3 mutant clones expand during MASLD through increased lipid disposal, demonstrating that clonal fitness can benefit the liver at the cost of hyperlipidemia.
Authors
Gregory Mannino, Gabriella Quinn, Min Zhu, Zixi Wang, Xun Wang, Boyuan Li, Meng-Hsiung Hsieh, Thomas Mathews, Lauren Zacharias, Wen Gu, Purva Gopal, Natalia Brzozowska, Peter Campbell, Matt Hoare, Glen Liszczak, Hao Zhu
Abstract
Downregulation of antigen presentation and lack of immune infiltration are defining features of small cell lung cancer (SCLC) limiting response to immune checkpoint blockade (ICB). While a high MHC Class I, immune-inflamed subset benefits from ICB, underlying mechanisms of immune response in SCLC have yet to be elucidated. Here we show that in the landmark IMpower133 clinical trial high, but not low, NOTCH1 expression is significantly associated with longer survival with the addition of ICB to chemotherapy among ~80% of SCLC patients with neuroendocrine-enriched tumors (ASCL1-enriched, HR 0.39, P = 0.0012; NEUROD1-enriched, HR 0.44, P = 0.024). Overexpression or pharmacologic activation of NOTCH1 in ASCL1 and NEUROD1 SCLC cell lines dramatically upregulates MHC Class I through epigenetic reactivation of STING. In syngeneic mouse models, Notch1 activation reprograms SCLC tumors from immune-excluded to immune-inflamed, facilitating durable, complete responses with ICB combined with a STING agonist. STING1 expression is significantly enriched in high compared to low NOTCH1 expressing tumors in IMpower133 thereby validating our proposed mechanism. Our data reveal a previously undiscovered role for NOTCH1 as a critical driver of SCLC immunogenicity and a potential predictive biomarker for ICB in SCLC. NOTCH1 activation may be a therapeutic strategy to unleash anti-tumor immune responses in SCLC and other neuroendocrine cancers in which NOTCH1 is typically suppressed.
Authors
Yoo Sun Kim, Barzin Y. Nabet, Briana N. Cortez, Nai-Yun Sun, Robin Sebastian, Christophe E. Redon, Anagh Ray, Liang Liu, Afeez A. Ishola, Sarah Loew, Anjali Dhall, Sivasish Sindiri, Velimir Gayevskiy, Min-Jung Lee, Shraddha Rastogi, Nahoko Sato, Noemi Kedei, Thorkell Andresson, Sudipto Das, Suresh Kumar, Alan E. Bers, Hongliang Zhang, Alberto Chiappori, Priyanka Gopal, Mohamed E. Abazeed, Haobin Chen, Mirit I. Aladjem, Yves Pommier, Moises J. Velez, David S. Shames, Nitin Roper
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Series edited by Claudia Kemper
Complement Biology and Therapeutics
Series edited by Claudia Kemper
The complement system executes an evolutionarily ancient innate immune response with important roles in many human diseases, including a variety of conditions involving the kidney, autoimmune disorders, age-related macular degeneration, and more. This series of reviews, curated by Dr. Claudia Kemper, highlights the latest discoveries in complement biology and examines ongoing efforts to target complement therapeutically. From the relatively newly uncovered functions of intracellular complement (complosome) to the complexities involved in using animal models of complementopathies, these reviews convey the challenges of studying complement and developing complement-targeted therapeutics as well as call attention to recent findings that supply momentum to the field.
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ISSN: 0021-9738 (print), 1558-8238 (online)