Single-Cell Analysis Clarifies Pathological Heterogeneity in Tenosynovial Giant Cell Tumor and Identifies Biomarkers for Predicting Disease RecurrenceXie, Chen, Wu
et alAdv Sci (Weinh) (2025)
Abstract: Diffuse-type tenosynovial giant cell tumor (D-TGCT) and localized-type tenosynovial giant cell tumor (L-TGCT) share common genomic aberrations and histopathological features, but the former has a more aggressive nature and a higher recurrence rate, leading to worse prognoses for patients. In this study, single-cell RNA sequencing (scRNA-seq) on human D-TGCT and L-TGCT lesions is conducted to discover transcriptional differences. A unique cluster of tumor cells in D-TGCT is identified that regulated differentiation of CD34+ fibroblasts into MMP3+ fibroblasts or APOE+ fibroblasts via COL6A3 - (ITGAV + ITGB8) interaction. The APOE+ fibroblasts further activated IL-1B+CCL20+ macrophages through the CXCL12/CXCR4 axis. IL-1B+CCL20+ macrophages and MMP3+ fibroblasts participated in local aggression of D-TGCT. Two effective biomarkers, ROR1 and PRKD1 are also identified and validated, to predict disease recurrence. This study not only clarified the underlying mechanisms of aggressive behavior in D-TGCT but also provided a theoretical basis and potential targets for intervention into and treatment of this disease.© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.
Unveiling circulating targets in pancreatic cancer: Insights from proteogenomic evidence and clinical cohortsFeng, Chen, Li
et aliScience (2025) 28 (3), 111693
Abstract: Pancreatic cancer (PC), characterized by the absence of effective biomarkers and therapies, remains highly fatal. Data regarding the correlations between PC risk and individual plasma proteome known for minimally invasive biomarkers are scarce. Here, we analyzed 1,345 human plasma proteins using proteome-wide association studies, identifying 78 proteins significantly associated with PC risk. Of these, four proteins (ROR1, FN1, APOA5, and ABO) showed the most substantial causal link to PC, confirmed through Mendelian randomization and colocalization analyses. Data from two clinical cohorts further demonstrated that FN1 and ABO were notably overexpressed in both blood and tumor samples from PC patients, compared to healthy controls or para-tumor tissues. Additionally, elevated FN1 and ABO levels correlated with shorter median survival in patients. Multiple drugs targeting FN1 or ROR1 are available or in clinical trials. These findings suggest that plasma protein FN1 associated with PC holds potential as both prognostic biomarkers and therapeutic targets.© 2025 The Authors. Published by Elsevier Inc.
Downregulation of RORl via STAT3 and P300 Promotes P38 Pathway- Dependent Lens Epithelial Cells Apoptosis in Age-Related CataractZhang, Hu, Su
et alBiochem Genet (2025)
Abstract: Lens Epithelial Cells (LECs) apoptosis is a critical driving factor of age-related cataract (ARC), but the specific molecular mechanisms remain undefined. Herein, a novel target of ROR1 regulation was identified, the mechanism was elucidated by which ROR1 and its associated pathway proteins influence hydrogen peroxide (H2O2)-induced apoptosis of LECs in ARC. We found decreased ROR1 expression in human cataract lens capsules compared to normal ones, the trend was also observed in young and old mice. Experiments including CCK8, Hoechst 33,342 staining, and Western blot analysis confirmed that reduced ROR1 levels were linked to H2O2-induced apoptosis in HLEB3 cells. To investigate its effects on cell viability and apoptosis, we created a ROR1 interference plasmid and an overexpression plasmid. The overexpression of ROR1 effectively inhibited H2O2-induced apoptosis of HLEB3 cells while ROR1 knockdown lowered the viability and increased the apoptosis of HLEB3 cells. Additionally, increased P38 phosphorylation was identified as a contributor to lens epithelial cell apoptosis and ARC, with ROR1 influencing this through the phosphorylation of the P38. Similarly, the relationships between P300 and STAT3, upstream of ROR1, in apoptosis of LECs and ARC were explored, and it was found that P300 and STAT3 were negatively correlated with apoptosis of LECs and ARC. In addition, the double luciferase report showed that P300 and STAT3 synergistically up-regulated the expression of ROR1. Overall, this study demonstrates that the STAT3/ROR1/P38 pathway mitigates apoptosis of LECs in ARC progression, offering a novel strategy for ARC prevention and treatment in clinical settings.© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Updates on the Biological Heterogeneity of Mantle Cell LymphomaIp, Kabat, Fogel
et alCancers (Basel) (2025) 17 (4)
Abstract: Advancements in mantle cell lymphoma (MCL) have illuminated the disease's molecular diversity, leading to a wide variation in the outcomes observed in MCL. Current prognostic risk scores are continuously revised to incorporate new updates in the mechanistic or biologic understanding of MCL. Nevertheless, key high-risk features of MCL associated with rapid disease progression and poor survival, such as TP53 mutations, complex karyotypes, and blastoid or pleomorphic morphologies, remain absent from available prognostic tools. The greater accessibility of genomic technologies, such as next-generation sequencing (NGS), has enabled clinicians to identify specific genetic alterations that serve as prognostic signals and disease monitoring parameters, cultivating accurate risk profiling that is illustrative of MCL heterogeneity. Through an increased understanding of distinct MCL behaviors, novel therapies that mechanistically target disease biology, including Bruton's tyrosine kinase inhibitors, BCL-2 inhibitors, ROR1 inhibitors, and bispecific T-cell engagers, have broadened the treatment armamentarium for relapsed/refractory MCL cases. These interventions, in addition to chemoimmunotherapy and autologous stem cell transplantation mainstays, confer the individualization of treatment and improved survival outcomes. Further exploration of the considerable biological heterogeneity of MCL can enhance knowledge, management, and the treatment of this rare lymphoma subtype.
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