Commentary
Abstract
The TMPRSS2:ERG gene fusion is a truncal oncogenic event in a large subset of prostate cancers, yet its clinical relevance has remained unclear. In this issue of the JCI, Köcher et al. have demonstrated that ERG overexpression in human prostate cancer cells rewired DNA double-strand break repair toward a poly(ADP-ribose) polymerase 1–dependent (PARP1-dependent) alternative end-joining pathway without disrupting canonical repair. This repair bias created a conditional dependency on PARP1 that was exposed by radiotherapy, rendering ERG-positive tumors selectively sensitive to PARP inhibition–mediated radiosensitization. The tumor-selective cytotoxic effect of combined PARP1 inhibition and irradiation was corroborated in human-derived prostate cancer organoids. These findings establish ERG as a predictive biomarker for precision radiotherapy and highlight a tumor-selective strategy to enhance radiotherapeutic efficacy in prostate cancer.
Authors
Xiaoju Wang, Arul M. Chinnaiyan
Abstract
For over a decade, sepsis phenotyping has identified hyperinflammatory and hypoinflammatory subphenotypes using host biomarkers and clinical variables, without factoring in contributions from infectious insults across patients. In this issue, Chanderraj and colleagues challenge this host-centric paradigm by demonstrating that pathogen characteristics independently contribute to sepsis subphenotypes. They reported that Enterobacterales infections, particularly Escherichia coli, strongly associated with hyperinflammatory subphenotypes, independent of illness severity. Bacterial burden, anatomic barrier breach, and circulating pathogen-associated molecular patterns influence phenotypic classification, with implications extending to culture-negative sepsis. Animal models supported causality, while reanalysis of an observational cohort and a clinical trial revealed that lactate clearance’s prognostic value and therapeutic effects of endotoxin removal with polymyxin B hemoadsorption vary by subphenotype and pathogen. These findings lay groundwork for integrative host-pathogen phenotyping; for precision medicine in critical illness, we must know not only who is sick, but what made them sick, and how the two interact.
Authors
Georgios D. Kitsios, Rebecca M. Baron
Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that constitute a major cause of mortality in individuals with neurofibromatosis type 1 (NF-1) and exhibit highly variable responses to radiotherapy. In this issue of the JCI, Zhu and colleagues integrated functional genomics, single-cell transcriptomics, and analysis of human tumors to show that type I IFN signaling shapes both tumor-intrinsic radiation sensitivity of MPNSTs and local recruitment and activation of T cells. Their findings establish IFN signaling as a central coordinator of the radiotherapy response in MPNSTs and suggest that incorporating targeted immunomodulation strategies may improve radiotherapy outcomes. The work also has direct implications for the role of the immune system and IFN signaling radiation–based treatment of soft tissue sarcomas beyond those involved in NF-1.
Authors
Sean P. Pitroda, Ralph R. Weichselbaum
Abstract
Organized adaptive immunity can emerge in the CNS under specific inflammatory and stromal conditions. The study by Yang et al. in this issue of the JCI reports that experimental ischemic stroke induced germinal center–like B cell follicles through microglial MIF–CD74/CXCR4 signaling and in situ B cell proliferation, promoting chronic neuroinflammation. These findings align with a growing body of evidence that the brain and meninges can support ectopic lymphoid structures in multiple sclerosis, during aging, and in certain gliomas. This Commentary integrates these observations to highlight shared principles, disease-specific outcomes, and unresolved questions regarding the identity and function of lymphoid aggregates in the CNS.
Authors
Catalina Lee-Chang
Safeguarding lymphatic identity: cooperative Erg and Fli1 activity in lymphatic vascular homeostasis
Abstract
Although transcriptional programs driving lymphatic endothelial cell (LEC) specification are being increasingly characterized, far less is known about the postnatal mechanisms that preserve lymphatic vessel identity and function. In this issue of the JCI, Yang et al. show that the E26 transformation-specific (ETS) transcription factors ETS-related gene (Erg) and Friend leukemia integration 1 (Fli1) cooperatively maintain adult LEC homeostasis by sustaining transcriptionally distinct LEC populations, vascular integrity, immune-vascular interactions, and repression of proinflammatory and prothrombotic gene programs. These findings extend the known roles of Erg and Fli1 beyond the blood endothelium and provide mechanistic insight into human lymphatic disease associated with Erg haploinsufficiency.
Authors
Kelly de Korodi, Tatiana V. Petrova
Abstract
Immunotherapy has shown limited efficacy in glioblastoma (GBM), reflecting profound immune evasion and an immunosuppressive microenvironment. In this Commentary, we highlight recent work by Zhang and colleagues identifying the transcription factor OLIG2 as a central mediator of immune evasion in GBM. Though OLIG2 has an established role in promoting GBM progression through its effects on glioma stem-like cells (GSCs), Zhang et al. demonstrated a further role for OLIG2 in suppressing antitumor immunity: in human GSCs and GSCs from mouse models of GBM, OLIG2 expression epigenetically repressed the interferon-responsive chemokine CXCL10, thereby limiting cytotoxic T cell infiltration. These findings provide a mechanistic explanation for immune resistance in GBM and support targeting tumor-intrinsic chromatin programs to enhance responses to immunotherapy.
Authors
Raymond Sun, Chao Gao, Rongze Olivia Lu
Abstract
Chronic stress triggers a range of physiological responses that could dysregulate the immune system and metabolic processes, thereby increasing susceptibility to various diseases. In this issue of the JCI, Wu et al. identified a metabolic bridge between chronic stress and liver cancer progression. Chronic stress–induced glucocorticoids promoted aminopeptidase N (ANPEP) expression and subsequent reprogramming of amino acid metabolism, leading to increased liver cancer growth and metastasis. ANPEP facilitated stabilization of the cystine-glutamate transporter system Xc– and increased l-cystine influx, thereby enhancing cellular antioxidant capacity to prevent ferroptosis. Silencing ANPEP in combination with sorafenib treatment showed a synergistic inhibitory effect on liver cancer progression. These findings uncover ANPEP as a valuable target for therapeutic interventions to treat patients with liver cancer experiencing chronic stress.
Authors
Maowu Luo, Weibo Luo
Abstract
Germline variants in the gene encoding succinate dehydrogenase subunit B (SDHB) occur in around 10% of all patients with pheochromocytomas and paragangliomas (PPGLs). Diagnosis of these variants has profound implications not only for the patient but also their first-degree relatives in terms of risk for PPGLs and other SDHB-associated tumors (renal cell cancer and gastrointestinal stromal tumors). Appropriate surveillance of SDHB variant carriers is associated with reduced mortality from these cancers. Curation of disease-causing (pathogenic) variants from benign variants is therefore crucial; however, this task is often difficult for missense variants when their impact on biological function is unclear. In this issue of the JCI, Lee et al. have described a newly developed cellular complementation assay for SDHB function that may assist variant curation in clinical practice and thereby improve outcomes for patients inheriting these cancer-risk variants.
Authors
Roderick Clifton-Bligh
Abstract
Comparative biology approaches have produced foundational discoveries in the mechanisms underlying thrombosis and hemostasis. In this issue of the JCI, work by Dahlgren and colleagues continues in this tradition using an approach that integrated a multispecies investigation of conserved function with genomic exploration and discovery. Dahlgren et al. describe the identification of pathogenic variants in the ER-associated degradation pathway protein SEL1L in a rare platelet disorder affecting horses. After establishing a conserved role for SEL1L in zebrafish, mouse, and human platelet function, the study found evidence for SEL1L variants in association with bleeding phenotypes in human GWAS. Altogether, the findings elucidate a previously unrecognized component of platelet function, laying the groundwork for mechanistic explanation of a subset of human bleeding phenotypes and providing a powerful endorsement of integrative, collaborative research.
Authors
Caitlin D. Schneider, James P. Luyendyk
Abstract
Checkpoint inhibitor–associated autoimmune diabetes (CIADM) is a life-altering and potentially life-threatening complication of immune checkpoint inhibitor (ICI) treatment in patients with cancer. Risk factors and predictors of this complication remain largely unknown. In this issue of the JCI, Wu et al. examined serum and PBMCs from 14 ICI-treated patients who developed CIADM and 28 matched controls. They identified several variables that were present prior to ICI treatment, including reduced pancreatic volume, islet autoantibodies, and biomarkers indicating immune cell activation, that together are highly predictive of development of CIADM. These findings could have profound clinical implications including treatment decisions, monitoring, and potential future prevention strategies.
Authors
Kevan C. Herold, Ana Luisa Perdigoto
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ISSN: 0021-9738 (print), 1558-8238 (online)