J. Pathol. [JOURNAL]
Sun
200 papers
Tumor Invasive Border Index (TIBI) in colorectal cancer: linking infiltrative morphology to molecular insights.
Kehusmaa A, Härkönen J, Li H … +27 more , Sirniö P, Äijälä VK, Karjalainen H, Kastinen M, Tapiainen VV, Mantere T, Pohjanen VM, Elomaa H, Sirkiä O, Pasquier N, Ahtiainen M, Helminen O, Wirta EV, Mattila TT, Lindgren O, Savela J, Rintala J, Meriläinen S, Saarnio J, Rautio T, Seppälä TT, Böhm J, Mecklin JP, Mäkinen MJ, Tuomisto A, Ivaska J, Väyrynen JP
J Pathol · 2026 Jun · PMID 42312545 · Publisher ↗
Tumor border configuration influences colorectal cancer (CRC) prognosis, yet its molecular determinants remain unclear and existing assessment criteria have faced challenges with reproducibility. We introduce the Tumor I...
Tumor border configuration influences colorectal cancer (CRC) prognosis, yet its molecular determinants remain unclear and existing assessment criteria have faced challenges with reproducibility. We introduce the Tumor Invasive Border Index (TIBI), a novel and reproducible method that quantifies the proportion of tumor stroma and adipose tissue within a hotspot at the deepest point of invasion. TIBI was evaluated in two CRC cohorts (n = 1,100 and n = 776) and analyzed in relation to tumor and patient features. Molecular correlates of an infiltrative growth pattern were explored in The Cancer Genome Atlas (TCGA) CRC cohorts (n = 350), with key features validated independently. High TIBI, indicating an infiltrative border, was associated with advanced disease, tumor budding, lymphovascular invasion, and an immune microenvironment characterized by lower M1-like macrophage and granulocyte densities. High TIBI independently predicted higher CRC-specific mortality, with multivariable hazard ratios of 1.52 (95% CI 1.07-2.17) in cohort 1 and 2.45 (95% CI 1.37-4.37) in cohort 2. Molecular analysis revealed associations with mismatch repair proficiency, TP53 and KRAS mutations, MYC signaling downregulation, and epithelial-mesenchymal transition upregulation. L1CAM and DSG3 were among the genes showing high expression in infiltrative tumors. As experimental validation, we identified a CRC cell line with high expression of L1CAM and DSG3 and demonstrated that silencing them reduced invasion in vitro. A TIBI-associated gene signature also predicted infiltrative growth and adverse outcome in the TCGA gastric cancer cohort. These findings highlight molecular characteristics of tumor border configuration and establish TIBI as a clinically relevant tumor biomarker. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Lipodystrophy and adipose tissue recovery are mediated by the Wnt/lipogenesis axis during skin fibrosis.
Madhavan SR, Moore P, Varshney R … +8 more , Montegut M, Ma Q, Klatt K, Parameswaran R, Ertugral EG, Kothapalli CR, Rudolph MC, Atit RP
J Pathol · 2026 Jun · PMID 42299858 · Publisher ↗
Acquired lipodystrophy in the dermal white adipose tissue (DWAT) is an early phenotype of skin fibrosis, followed by the accumulation of extracellular matrix (ECM). Lipodystrophy syndromes are estimated to affect 1 in 20...
Acquired lipodystrophy in the dermal white adipose tissue (DWAT) is an early phenotype of skin fibrosis, followed by the accumulation of extracellular matrix (ECM). Lipodystrophy syndromes are estimated to affect 1 in 20,000 people and are associated with metabolic comorbidities. Recently, we showed that fibrosis-associated lipodystrophy depended on sustained Wnt signaling, although the mechanism remains unclear. Transcriptomic profiling of mature dermal adipocytes in vivo revealed that Wnt activation downregulated the de novo lipogenesis (DNL) axis enzymes within 48 h. We further found that expression of fatty acid synthase (FASN), a key DNL enzyme, depends on sustained Wnt activation in vitro and in vivo. In a bleomycin model, and in human systemic sclerosis (< 1 year disease duration) and keloids, FASN was significantly downregulated. Notably, inhibition of FASN in mice during reversal of Wnt-induced fibrosis impaired the recovery of DWAT lipid content and ECM architecture. Collectively, these findings demonstrate that acquired lipodystrophy in skin fibrosis is mediated by a previously unrecognized role of the Wnt-DNL axis. These findings underscore the importance of this pathway in lipodystrophy and fibrosis and highlight its potential as a therapeutic target in skin fibrosis. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Optical mapping reveals a higher level of large-scale structural variants in a family with paternally transmitted myotonic dystrophy and independent Parkinson's disease.
Hasan MM, Craddock J, Gong T … +7 more , Lyons RJ, Stevanovski I, Chintalaphani SR, Deveson IW, Jaratlerdsiri W, Kumar KR, Hayes VM
J Pathol · 2026 Jun · PMID 42261605 · Publisher ↗
Myotonic dystrophy type 1 (DM1) is a clinically challenging multisystem neuromuscular hereditary disorder, with generational increase in severity and earlier age at onset. It is caused by an unstable cytosine-thymine-gua...
Myotonic dystrophy type 1 (DM1) is a clinically challenging multisystem neuromuscular hereditary disorder, with generational increase in severity and earlier age at onset. It is caused by an unstable cytosine-thymine-guanine repeat expansion at the DMPK locus, accompanied by associated genetic and epigenetic modifications. While somatic mosaicism and meiotic instability are well established, to the best of our knowledge, no study has performed a genome-wide interrogation for global inherited instability. Performing whole-genome optical mapping, with sequence base-resolved structural variant verification, we examine global inherited genomic instability in an atypical paternally transmitted DM1 family presenting with a range of neurological manifestations, including early-onset Parkinson's disease (PD). While the juvenile-onset DM1 proband presented with a 10-fold repeat expansion with associated hypermethylation, her partially hypermethylated asymptomatic protomutation father transmitted a 1.8-fold contracted allele in the younger premutation sibling. Adult-onset symptomatic DM1 and PD phenotypic paternal aunts showed significant genome-wide copy number alteration, including PD-associated chr19 aneuploidy loss, with additional losses on chr16, 17, and 22. In the absence of potentially pathogenic de novo or maternally inherited structural variants, the proband presented with large paternally inherited aberrations impacting gene candidates CASC15, CBFA2T3, GPHN, H3F3A, SDK1, and SPAG16, with advanced global hypomethylation. Here we suggest that inherited genomic instability may contribute to phenotypic variability, including multi-neurological presentations and single-generation repeat expansion or contraction. By providing a landscape of inherited large structural variants, this single-family study expands knowledge of this broad and growing class of diseases. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
FTO-mediated m6A modification of protein disulfide-isomerase activates VEGFA-VEGFR2 to suppress programmed cell death in osteosarcoma.
Wang J, Hao Y, He M … +1 more , Zhou W
J Pathol · 2026 Jun · PMID 42246398 · Publisher ↗
Osteosarcoma (OS) is a primary bone malignancy, and its progression can be hindered by inducing programmed cell death (PCD). Protein disulfide-isomerase (PDI) regulates cancer cell death; however, its functional role in...
Osteosarcoma (OS) is a primary bone malignancy, and its progression can be hindered by inducing programmed cell death (PCD). Protein disulfide-isomerase (PDI) regulates cancer cell death; however, its functional role in OS remains unclear. P4HB expression was assessed in tumor tissues and cells from patients with OS using RT-qPCR. The effects of P4HB on OS cell lines were evaluated. Western blotting was used to assess the impact of P4HB on various forms of PCD (apoptosis, ferroptosis, and pyroptosis). Bioinformatics analysis identified the upstream and downstream mechanisms of P4HB in OS progression. A xenograft tumorigenesis study was performed to elucidate the role and mechanism of P4HB in OS progression. Elevated P4HB expression was observed in OS tissue samples and cell lines. Downregulation of P4HB suppressed OS cell growth, migration, and invasiveness and induced PCD. Functional enrichment analysis and experimental validation revealed that PDI upregulated vascular endothelial growth factor A (VEGFA) vascular endothelial growth factor receptor 2 (VEGFR2) signaling. Methylation analysis showed that the m6A demethylase fat mass and obesity-associated protein (FTO) decreased P4HB m6A levels and enhanced VEGFA-VEGFR2 signaling in OS cells. Moreover, FTO overexpression enhanced the proliferative, migratory, and invasive capabilities of OS cells and decreased PCD. Finally, FTO knockdown inhibited tumor growth and lung metastasis of OS by decreasing the activity of the PDI/VEGFA-VEGFR2 signaling axis. Mechanistically, FTO-mediated m6A modification of P4HB regulates PCD in OS through activation of this axis. © 2026 The Pathological Society of Great Britain and Ireland.
Dopamine inhibits retinal pathological neovascularization in the oxygen-induced retinopathy mouse model.
Wang Q, Shi J, Ouyang S … +17 more , Zhang T, Yang H, Zhu J, Wang L, Lv Y, Dong S, Chen R, Ling X, Jiao S, Dong M, Yan W, Yang J, Yan B, Chen J, Qu J, Zhao F, Zhou X
J Pathol · 2026 Jun · PMID 42237060 · Publisher ↗
Pathological neovascularization is the leading cause of childhood blindness in retinopathy of prematurity (ROP). Anti-vascular endothelial growth factor agents are commonly used to treat this condition, yet their variabl...
Pathological neovascularization is the leading cause of childhood blindness in retinopathy of prematurity (ROP). Anti-vascular endothelial growth factor agents are commonly used to treat this condition, yet their variable efficacy and off-target effects demand alternative strategies. Here, we investigated the relationship between retinal dopamine (DA) dynamics and pathological angiogenesis in the oxygen-induced retinopathy (OIR) mouse model mimicking ROP pathogenesis. We determined the individual effects of apomorphine (APO), a non-selective DA receptor agonist, and selective agonists or antagonists of dopamine D1 receptor (Drd1) and dopamine D2 receptor (Drd2), on pathological neovascularization. Integrating single-cell RNA sequencing with Müller cell-specific Drd2 knockout OIR mice, we identified that Drd2-mediated signaling in Müller cells orchestrates hypoxia-inducible factor alpha and vascular endothelial growth factor A biosynthesis in Müller cells during the hypoxic-ischemic phase of OIR. Collectively, OIR-induced dopaminergic deficiency and impaired Drd2 activity in Müller cells synergistically exacerbate pathological angiogenesis. © 2026 The Pathological Society of Great Britain and Ireland.
Aberrant alternative splicing of purinergic receptor P2RX4 prevents sensitivity towards combinatorial treatment in colorectal and pancreatic cancer.
Steup C, Dosch J, Dietz-Fricke C … +10 more , Khosraviseftejani S, Engel E, Valk AF, Menger D, Welker P, Wild PJ, Kennel KB, Kantlehner M, Ziegler PK, Greten FR
J Pathol · 2026 Jun · PMID 42231750 · Publisher ↗
Recently, we suggested the combination of chemotherapy and P2RX4 inhibition as a promising novel therapeutic approach for P2RX4-expressing epithelial tumors to prevent paracrine resistance. Here, we aimed to assess wheth...
Recently, we suggested the combination of chemotherapy and P2RX4 inhibition as a promising novel therapeutic approach for P2RX4-expressing epithelial tumors to prevent paracrine resistance. Here, we aimed to assess whether determining P2RX4 expression status in colorectal and pancreatic cancer patients would allow stratification of potentially responsive patients. Therefore, P2RX4 expression levels were determined by RNA sequencing and immunohistochemistry. Subcellular localization of P2RX4 isoforms was analyzed in HeLa cells and patient-derived tumor organoids. In contrast to its RNA expression profile, P2RX4 protein levels exhibited differential regulation in human colorectal and pancreatic cancer epithelia due to alternative splicing. Interpatient heterogeneity was greater in colorectal cancer than in pancreatic cancer. Notably, these variations in expression did not correlate with overall patient survival. Alternative P2RX4 transcripts gave rise to functionally distinct protein isoforms that differed in subcellular localization and total protein abundance. Only the correctly spliced, canonical P2RX4 isoform was localized to the plasma membrane and was capable of mediating downstream signaling. Accordingly, P2RX4 inhibition in combination with chemotherapy was effective exclusively in patient-derived tumor organoids expressing the canonical P2RX4 transcript. In summary, immunohistochemical, but not transcriptomic, assessment of P2RX4 expression enabled the prediction of sensitivity to combinatorial treatment and facilitated the identification of patients who may benefit from P2RX4 inhibition during chemotherapy. Given the lower degree of heterogeneity observed in pancreatic cancer, this tumor entity may represent a promising candidate for early-phase clinical evaluation of chemotherapy combined with P2RX4 inhibition. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
CLEC14A correlates with neutrophil infiltration in hepatocellular carcinoma and mediates neutrophil recruitment across liver endothelial cells.
O'Rourke JM, Kavanagh D, O'Keeffe A … +22 more , Savoye K, Yang K, Patten DA, Willoughby CE, Llovet JM, Neag G, Reeves HL, Hewett PW, Kalia N, Shah T, Ma YT, Hunter K, Flint J, McMurray JL, Cain O, Spill F, Mann DA, Naylor AJ, Heath V, Weston CJ, Bicknell R, Shetty S
J Pathol · 2026 Jun · PMID 42223241 · Publisher ↗
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally, and cases are predicted to rise dramatically over the next few years. Overcoming the immune microenvironment in HCC remains a challenge...
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally, and cases are predicted to rise dramatically over the next few years. Overcoming the immune microenvironment in HCC remains a challenge, and innate immune populations such as tumour-associated neutrophils can potentially impair the success of immunotherapy. Elucidating the mechanisms of neutrophil recruitment across liver endothelium could lead to new approaches to boost the efficacy of immunotherapy. CLEC14A is an endothelium-specific receptor regulating sprouting angiogenesis, upregulated in low shear environments. We found CLEC14A to be highly expressed in both HCC vessels and on vasculature during acute liver injury, leading us to hypothesise that CLEC14A may regulate neutrophil recruitment to the liver and HCC. We found that CLEC14A positively correlated with a neutrophil signature and infiltration in public datasets and surgically resected tissue from HCC. Spatial transcriptomics (ST) of CLEC14A- and CLEC14A-expressing tumours confirmed upregulation of myeloperoxidase in CLEC14A tumours and correlation with other shear-dependent markers but a negative correlation with vascular endothelial growth factor A. To build on our correlation studies, we explored the role of CLEC14A in neutrophil recruitment across liver endothelium. We undertook in vitro recruitment studies with flow-based human liver endothelial assays and in vivo models of neutrophil recruitment. Using siRNA knockdown of CLEC14A and specific blocking antibodies to CLEC14A, we found that CLEC14A knockdown blocked the firm adhesion of neutrophils to liver endothelium, but this was independent of its interaction with its known ligand MMRN2. Finally, we confirmed that Clec14a deficiency led to a significant reduction in neutrophil recruitment across the sinusoids in an ischaemia-reperfusion liver injury model. We unveil a link between the angiogenic receptor CLEC14A and neutrophil recruitment. Targeting of CLEC14A on tumour endothelium is potentially a new approach to regulating neutrophil infiltration in HCC. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Targeting fibrosis in the treatment of lower urinary tract dysfunction.
Limkar AR, Vrba SM, Ricke EA … +4 more , Fabry Z, Lee MS, McVary KT, Ricke WA
J Pathol · 2026 May · PMID 42200686 · Publisher ↗
Benign prostatic hyperplasia (BPH) is a widely prevalent age-associated disease that is the main contributor to lower urinary tract dysfunction (LUTD) in aging men. Although prostate fibrosis has been recognized as a con...
Benign prostatic hyperplasia (BPH) is a widely prevalent age-associated disease that is the main contributor to lower urinary tract dysfunction (LUTD) in aging men. Although prostate fibrosis has been recognized as a contributor to BPH pathophysiology, there are not any clinically available therapeutics that target this aspect of disease progression. In this study, we evaluated the antifibrotic potential of thalidomide using both in vitro and in vivo models of BPH/LUTD. Using benign human prostate stromal cells stimulated with transforming growth factor β-1 (TGFβ1) followed by targeted transcriptomic profiling and assessment of canonical TGFβ signaling, we demonstrate that thalidomide attenuates expression of profibrotic genes, including extracellular matrix components. In aged male mice with LUTD, thalidomide administration led to a reduction in prostate collagen deposition and decreased organization of collagen fiber alignment. Functionally, thalidomide treatment improved LUTD in aged male mice, while prostate mass, androgen receptor expression and downstream signaling targets, and proliferative index remained unchanged, suggesting that the observed therapeutic effects are primarily mediated by antifibrotic mechanisms. Our findings highlight thalidomide's potential to modulate prostatic fibrosis and improve voiding function and support further investigation into the role of antifibrotic therapies as novel treatments for BPH/LUTD. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Histiocytosis development and clinical variation through the lens of genomics.
Kemps PG, van Halteren AG, van Wezel T … +1 more , Hogendoorn PC
J Pathol · 2026 May · PMID 42200684 · Publisher ↗
Histiocytic neoplasms are rare haematologic diseases characterised by clonal expansions of cells with a monocyte, macrophage or dendritic cell phenotype. Their clinical manifestations are diverse, ranging from indolent l...
Histiocytic neoplasms are rare haematologic diseases characterised by clonal expansions of cells with a monocyte, macrophage or dendritic cell phenotype. Their clinical manifestations are diverse, ranging from indolent lesions to aggressive systemic disease. Over recent decades, advances in genomic profiling have transformed the biological understanding of these conditions. The discovery of recurrent oncogenic mutations has reframed histiocytoses from primary inflammatory disorders to myeloid neoplasms, with a notable dependence on aberrant mitogen-activated protein kinase (MAPK) signalling. Novel genetic drivers continue to be uncovered, with many alterations correlating with distinct clinical and pathological phenotypes. Parallel studies have refined the understanding of disease ontogeny, demonstrating that diverse histiocytoses originate from haematopoietic stem/progenitor cells. In Langerhans cell histiocytosis, the differentiation stage of the mutated precursor cell is considered an important - but not the sole - determinant of disease extent and severity. Additional evidence suggests that specific clinical manifestations, such as neurodegenerative disease, may result from somatic mosaicism affecting tissue-resident macrophages derived from yolk sac progenitors. Collectively, these findings refine histiocytosis diagnosis, risk stratification, disease monitoring and treatment, with robust activity of kinase inhibitors in patients with severe or refractory disease. In this review, we synthesise recent genomic insights into histiocytosis development and variation, while addressing remaining questions and future directions. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Lymph node stromal topology as a hidden regulator of breast cancer outcome: commentary on reticular network analysis.
Vethencourt A, Salgado R, Gonzalez-Suarez E
J Pathol · 2026 May · PMID 42200492 · Publisher ↗
The axillary lymph node remains a cornerstone of breast cancer staging and therapeutic decision-making, yet it is still largely interpreted through a static anatomical framework. Emerging evidence challenges this paradig...
The axillary lymph node remains a cornerstone of breast cancer staging and therapeutic decision-making, yet it is still largely interpreted through a static anatomical framework. Emerging evidence challenges this paradigm, positioning tumor-draining lymph nodes as dynamic immunological ecosystems that actively regulate tumor progression and host response. In this context, Llewellyn et al introduce a quantitative framework to characterize fibroblastic reticular cell network topology and link nodal architecture to clinical outcomes. By quantifying features such as lacunarity, branching, and alignment in a breast cancer cohort, the authors show that fibroblastic reticular cell network organization is associated with prognosis in a context-dependent manner. While this approach represents a significant conceptual and methodological advance, its biological interpretation remains limited by the absence of functional validation and integrated immune profiling. Accumulating evidence indicates that lymph node microenvironments undergo profound immune reprogramming, highlighting the close interdependence between stromal topology and immune composition. These findings suggest that structural features alone may reflect distinct underlying biological states. Integrating spatial metrics with immune characterization may refine current staging systems, improve risk stratification, and ultimately inform future evolution of staging classifications by incorporating functional and spatial dimensions of nodal involvement. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Disrupted endocannabinoid signaling contributes to systemic inflammation in acute pancreatitis.
Goncalves-Romeu P, Cárdenas-Jaen K, de-Madaria E … +5 more , Hernández JM, Fluvià L, Torres-Ribas L, Closa D, Guillamat-Prats R
J Pathol · 2026 May · PMID 42153289 · Publisher ↗
Acute pancreatitis (AP) is an inflammatory disease that can lead to systemic complications in severe cases. The endocannabinoid system has emerged as a potential modulator of inflammation in AP. We investigated the role...
Acute pancreatitis (AP) is an inflammatory disease that can lead to systemic complications in severe cases. The endocannabinoid system has emerged as a potential modulator of inflammation in AP. We investigated the role of the endocannabinoid 2-arachidonoylglycerol (2-AG) and the cannabinoid receptors CB1 and CB2 during AP. A severity-dependent decrease in circulating 2-AG was found both in patients and a murine AP model. Restoring 2-AG - by avoiding its degradation via monoacylglycerol lipase inhibitor or direct 2-AG administration - reduced local and systemic inflammation, modulated peritoneal macrophage polarization, and mitigated lung injury. Notably, endocannabinoid system effects were consistent across sexes. Both cannabinoid receptors were involved in disease pathophysiology. Genetic Cnr1 knockout and pharmacological CB2 blockade showed distinct and complementary roles of both receptors in regulating inflammation, immune infiltration, and pulmonary damage. These findings highlight a protective role for 2-AG and highlight the endocannabinoid system - and cannabinoid receptors in particular - as a promising therapeutic target to modulate inflammation and reduce systemic complications in acute pancreatitis. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Testican-1-MMP axis in tumour extracellular matrix (ECM) remodelling: interaction dynamics analysis and an in silico perspective.
Youssefi S, Saleki K, Kadam P … +4 more , Mazloomi A, Mukherjee A, Dekker LV, Nateri AS
J Pathol · 2026 May · PMID 42141259 · Publisher ↗
The extracellular matrix (ECM) plays a pivotal role in facilitating tumour development, invasiveness, metastasis, and immunoevasive processes through dynamic ECM remodelling processes. Testican-1 (SPOCK1), an excretory m...
The extracellular matrix (ECM) plays a pivotal role in facilitating tumour development, invasiveness, metastasis, and immunoevasive processes through dynamic ECM remodelling processes. Testican-1 (SPOCK1), an excretory matricellular proteoglycan, is suggested to exert a role in the facilitation of ECM remodelling processes through interacting with matrix metalloproteases (MMPs) and even its less known forms. The structural mechanisms of interactions between testican-1 and MMPs were studied, and their roles in tumour-promotion pathway processes were also examined using a computational approach and immunofluorescence validated by colocalisation technique analysis. A computational analysis using docking, molecular dynamics (MD), and systems biology analysis was employed. HDock and GROMACS were chosen to analyse binding affinity and testican-1 stability with 28 different MMPs. H-bond, free energy, and root mean square fluctuation (RMSF) analyses were performed to confirm the interactions in the testican-1-MMP complexes. The systems biology toolkit implemented in this study consisted of STRING, BioGRID, and Cytoscape, which were employed for testican-1 interaction network and pathway analysis. Kaplan-Meier survival analysis using the GEPIA2 tool was utilised to correlate SPOCK1 gene expression and clinical survival measures for various malignancies. The docking analysis showed robust interactions between testican-1 and MMP23, MMP25, and MMP28. Additionally, testican-1-MMP complexes were confirmed to form stable interfaces based on comprehensive MD analysis, suggesting solid binding interfaces with the MMP-unique domain of testican-1. Our systems biology experiment indicated testican-1 as a central hub for interactions between immunoevasive and ECM remodelling processes. SPOCK expression was also shown to correlate with significant survival measures for different malignancies, revealing clinical implications in cancer. The testican-1-MMP computational analysis suggests testican-1 plays a pivotal role as a therapeutic target for a wide range of malignancies. SPOCK-MMP interactions could be targeted to interrupt tumour-promoting processes by arresting dynamic changes in the ECM, thereby improving patient survival. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Identifying therapeutic targets in low-grade serous ovarian carcinomas with no specific molecular profile.
Pishas KI, Cowley KJ, Marinovic E … +18 more , Köbel M, Llaurado-Fernandez M, Kim H, Bao SC, Mizikovsky D, Palpant NJ, Shrestha R, Vary R, Luu J, Meunier L, Semple T, Blancafort P, Golden E, Cohen PA, Carey MS, Campbell IG, Simpson KJ, Cheasley D
J Pathol · 2026 May · PMID 42138099 · Publisher ↗
Low-grade serous ovarian carcinoma (LGSOC) is a rare, indolent ovarian cancer subtype with limited effective therapies. Approximately 40% of cases lack canonical MAPK/ERK or PI3K/AKT/mTOR pathway alterations and are clas...
Low-grade serous ovarian carcinoma (LGSOC) is a rare, indolent ovarian cancer subtype with limited effective therapies. Approximately 40% of cases lack canonical MAPK/ERK or PI3K/AKT/mTOR pathway alterations and are classified as having no specific molecular profile (NSMP). These patients have poor responses to chemotherapy, MEK inhibitors, and hormonal therapies, highlighting the need for alternative strategies. This study aimed to identify novel therapeutic targets in NSMP LGSOC. A high-throughput drug screen of 3,436 compounds (including FDA-approved, clinically tested, and investigational agents) was conducted across 12 LGSOC and one control ovarian epithelial cell line. EGFR inhibitors emerged as selective hits in NSMP cell lines and were further tested in two NSMP and two MAPK-mutant lines in combination with standard-of-care chemotherapy agents, carboplatin and paclitaxel. EGFR expression was assessed using RNA sequencing, DNA methylation profiling, and immunohistochemistry in primary tumors, followed by survival analysis based on expression levels. Unsupervised clustering of drug response data revealed subtype-specific vulnerabilities, with EGFR inhibitors showing marked cytotoxicity in all five NSMP lines (robust Z-score ≤ -2), and minimal activity in MAPK- and USP9X-mutant lines. EGFR inhibitors (avitinib, AV-412) showed selective, low-dose synergy with standard-of-care chemotherapy in NSMP models, with minimal and inconsistent effects in MAPK-mutant lines. NSMP tumors showed elevated EGFR mRNA and EGFR protein expression, associated with poor survival, advanced disease stage, and peritoneal involvement, and inversely correlated with MAPK mutations. These findings position EGFR overexpression as a defining and targetable feature of NSMP LGSOC and support further preclinical validation of EGFR inhibitors as a treatment strategy for this understudied cancer subtype. © 2026 The Pathological Society of Great Britain and Ireland.
An oncogenic role for EBV-encoded BILF1 in nasopharyngeal carcinoma.
Wong AK, Rajendran V, Mundo L … +14 more , Wei W, Bell AI, Robinson M, Bellan C, Lazzi S, Leahy C, Rajadurai P, Liew YT, Prepageran N, Young LS, Lo KW, Murray PG, Paterson IC, Yap LF
J Pathol · 2026 May · PMID 42099008 · Publisher ↗
It is widely recognized that latent infection is the predominant mode of Epstein-Barr virus (EBV) infection in nasopharyngeal carcinoma (NPC) in which a specific set of latent genes is responsible for driving the develop...
It is widely recognized that latent infection is the predominant mode of Epstein-Barr virus (EBV) infection in nasopharyngeal carcinoma (NPC) in which a specific set of latent genes is responsible for driving the development of the disease. However, the expression of these latent genes does not adequately explain the various transformed phenotypes of NPC cells. Using an established high-throughput quantitative reverse transcription PCR array, we found that several EBV lytic genes were more widely expressed in primary NPC tissues than previously recognized. We focused on a lytic gene, BILF1, which encodes a constitutively active G protein-coupled receptor (GPCR). We showed that BILF1 was expressed in tumour cells from primary NPC tissues at both mRNA and protein levels, and in the absence of BZLF1 expression. RNA sequencing analysis of BILF1-expressing immortalised nasopharyngeal epithelial (NPE) cells demonstrated that the profile of BILF1-regulated genes significantly overlapped with gene signatures of micro-dissected NPC, indicating that the expression of BILF1 is relevant to the pathogenesis of NPC. In accordance with these observations, pathway analysis of the transcriptome of BILF1-expressing cells showed the involvement of BILF1 in key biological processes typically deregulated in NPC. To examine whether BILF1 expression influenced epithelial cell behaviour, functional studies showed that BILF1 enhanced cell proliferation, migration, invasion and colony formation. In addition, BILF1 increased AKT activation in NPE cells, which was responsible for the increase in cell migration. Taken together, our data convincingly point to an oncogenic role for BILF1 in NPC. © 2026 The Pathological Society of Great Britain and Ireland.
Genetic analysis of primary lung interdigitating dendritic cell sarcomas.
Ermakov MS, Filipe JF, Eidenhammer S … +4 more , Ott G, Halbwedl I, Kashofer K, Popper H
J Pathol · 2026 May · PMID 42092301 · Publisher ↗
Interdigitating dendritic cell sarcomas (IDCSs) are rare tumors that commonly arise in the hematopoietic system and rarely outside. The genetic drivers of IDCS carcinogenesis are unknown; therefore, therapeutic options a...
Interdigitating dendritic cell sarcomas (IDCSs) are rare tumors that commonly arise in the hematopoietic system and rarely outside. The genetic drivers of IDCS carcinogenesis are unknown; therefore, therapeutic options are limited. We investigated somatic gene mutations and copy-number alterations (CNAs) in nine IDCSs arising in the lung by whole-exome sequencing (WES) paired with shallow whole-genome sequencing (sWGS). Using a panel of immunohistochemical markers, follicular dendritic sarcomas and Langerhans cell sarcomas were excluded, and inflammatory myofibroblastic tumors were excluded based on morphology. The Ki-67 score was used to stratify the tumors into low-grade (≤ 20%) and high-grade (> 20%) tumors. The main question addressed by the study was whether genetic aberrations can be identified in IDCSs and whether these are druggable. High-grade IDCSs showed a higher fraction of genome altered by CNA (48.42%) than low-grade IDCSs (18.15%) and tended to have greater tumor mutation burden (7.56 versus 0.88 mut/Mb; not significant). Heterogeneous gains on chromosome 17 were characteristic of almost all IDCS cases (eight of nine cases, 89%), independent of grade. CNA in cancer-actionable genes was independent of clinicopathological characteristics and included amplifications in EGFR, MYC, MDM4, ERBB2, CCNE1, and BRAF and losses in MTAP, CDKN2A, CDKN2B, MLH1, and VHL, as well as homozygous losses in SMAD2/4, ATM, and TP53. Somatic gene mutations in cancer-related genes were identified in seven of nine IDCSs. No common driver mutations were identified. The heterogeneous genetic landscape suggests a mixed etiology of IDCS carcinogenesis and genomic instability in high-grade tumors. Distinct druggable biomarkers have been identified in almost all tumors, providing novel therapeutic options. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Unraveling the spatial landscape of dystrophinopathies: a transcriptomic approach to Becker and Duchenne muscular dystrophies.
Heezen LG, Mao Q, Nicolau S … +12 more , Rausell CN, van der Weerd J, Kueckelhaus J, Gokul Nath R, Diaz-Manera J, Kan HE, Niks EH, van Putten M, Aartsma-Rus A, Flanigan KM, Mahfouz A, Spitali P
J Pathol · 2026 Jul · PMID 42067897 · Full text
Dystrophinopathies are caused by pathogenic variants in the DMD gene, resulting in partial (Becker) or complete loss (Duchenne) of dystrophin. Becker (BMD) and Duchenne muscular dystrophy (DMD) are characterized by progr...
Dystrophinopathies are caused by pathogenic variants in the DMD gene, resulting in partial (Becker) or complete loss (Duchenne) of dystrophin. Becker (BMD) and Duchenne muscular dystrophy (DMD) are characterized by progressive muscle wasting, fatty replacement, fibrosis, and loss of function. To study histopathological changes, we used Visium spatial transcriptomics to profile skeletal muscle biopsies of patients affected by dystrophinopathy (n = 8) and healthy controls (n = 4). We estimated the proportion of cell types and their spatial localization across samples applying a deconvolution strategy using previously published single-nucleus RNA-sequencing data. We identified genes enriched in fat patches and cell types such as fibroadipogenic progenitors (FAPs) in areas of active pathology. Using expression data of ligand-receptor pairs, we highlight cell-cell communications leading to fibrotic and adipogenic lesions. Finally, analysis of gene expression gradients in areas of adjacent muscle and fat, allowed the identification of genes associated with muscle areas committed to becoming fat. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Transcriptomic comparative study between canalicular adenoma and HMGA2::WIF1 canalicular-like pleomorphic adenoma.
Alsugair Z, Champagnac A, Fieux M … +6 more , Philouze P, Ceruse P, Thamphya B, Pissaloux D, Tirode F, Benzerdjeb N
J Pathol · 2026 Apr · PMID 42052924 · Publisher ↗
Canalicular adenoma (CA) is a benign salivary gland tumor predominantly affecting the upper lip and is characterized by monomorphic epithelial cells arranged in branching cords within a loose and vascularized stroma. Unl...
Canalicular adenoma (CA) is a benign salivary gland tumor predominantly affecting the upper lip and is characterized by monomorphic epithelial cells arranged in branching cords within a loose and vascularized stroma. Unlike pleomorphic adenoma (PA), CA lacks a chondroid matrix and exhibits specific histological features, such as high cuboidal to columnar cells arranged in one to two cell layers. A recently identified PA subtype, named 'HMGA2-canalicular-like PA', mimics the morphology of CA but affects major salivary glands, and harbors the HMGA2::WIF1 fusion. Immunohistochemical markers including SOX10 positivity and p40/p63 negativity are shared between these entities, raising questions about their molecular differences. Therefore, the current study aimed to extensively compare the molecular profiles of CAs and HMGA2-canalicular-like PAs to better understand the mechanisms underlying their oncogenesis. In the present study, CAs and the HMGA2-canalicular-like PAs mostly shared similar histology and immunostaining, while the clinical presentations regarding tumor site and transcriptomic profiles were different. A novel finding was the overexpression of SOX2 in patients diagnosed with CA, in comparison to those diagnosed with HMGA2-canalicular-like PA. The CAs displayed significantly higher enrichment of hallmarks for Hedgehog signaling, IL2/STAT5 signaling, and apical surface, and significantly lower enrichment of hallmarks for apoptosis and mitotic spindle. Additionally, Gene Ontology enrichment analysis displayed significant enrichment of biological process for CAs in comparison to HMGA2-canalicular-like PAs for myofibril assembly, muscle filament sliding, actin-myosin filament sliding, and sarcomere organization. CAs and HMGA2-canalicular-like PAs exhibited similar histology and immunostaining but differed significantly in tumor site and transcriptomic profiles. The latter revealed significant activation of muscle-related transcriptional pathways, and overexpression of SOX2 in CAs. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Immunological mechanisms underlying the clinical heterogeneity of Kikuchi disease: the potential role of atypical memory B cells.
Yu SC, Chang KC, Chen TC … +2 more , Chen CN, Yang TL
J Pathol · 2026 Apr · PMID 42052902 · Publisher ↗
Building on our previous research, which classified Kikuchi disease into three subtypes based on predominant symptoms and fever status - febrile type, febrile lymphadenopathy (FebLAP), and afebrile lymphadenopathy (aLAP)...
Building on our previous research, which classified Kikuchi disease into three subtypes based on predominant symptoms and fever status - febrile type, febrile lymphadenopathy (FebLAP), and afebrile lymphadenopathy (aLAP) - we further investigated the underlying mechanisms contributing to their distinct clinical differences. Using NanoString nCounter technology, we analyzed the gene expression profiles of 35 Kikuchi disease lymph node specimens and compared them across the subtypes. Compared with the febrile type, aLAP exhibited higher AICDA expression, a trend observed in both germinal center positive and negative cases. The aLAP specimens also showed higher expression of B-cell markers; however, CD20 immunohistochemical staining did not reveal an increased number of B cells in aLAP. We therefore hypothesize that aLAP contains a higher proportion of atypical memory B cells, characterized by elevated AICDA and B-cell marker expression compared with other B-cell subsets. Immunohistochemical staining demonstrated that IRTA1+ atypical memory B cells were present in 64% (23/36) of aLAP cases, significantly higher than in FebLAP (0/8, 0%) and the febrile type (2/11, 18%) (p < 0.001). This finding confirms that aLAP is more likely to contain atypical memory B cells compared with the other subtypes. Pathway analysis revealed that the febrile type upregulates pathways associated with TLR2 and TLR4 signaling and neutrophil degranulation, while aLAP upregulates the TNFR2 non-canonical NF-κB pathway. RNAscope in situ hybridization demonstrated higher TLR4 expression in the febrile type compared with the aLAP type. These findings suggest that the triggering microbes for each subtype may differ, leading to distinct immune responses and clinical presentations. Overall, these results provide new insights into the immunopathogenesis of Kikuchi disease and highlight the potential role of atypical memory B cells in shaping its distinct clinical presentations. © 2026 The Pathological Society of Great Britain and Ireland.
Tubal ligation exacerbates ovulation-driven TP53 mutagenesis and p53 signatures by depleting protective menstrual hemoglobin.
Subramani K, Su CC, Wang JH … +4 more , Huang HS, Hsu CS, Chen PC, Chu TY
J Pathol · 2026 Jul · PMID 42052633 · Publisher ↗
The fallopian tube epithelium (FTE) is the primary tissue of origin for ovarian high-grade serous carcinoma (HGSC), with ovulation implicated as a key risk factor. TP53 mutations, a hallmark of HGSC and its precursor les...
The fallopian tube epithelium (FTE) is the primary tissue of origin for ovarian high-grade serous carcinoma (HGSC), with ovulation implicated as a key risk factor. TP53 mutations, a hallmark of HGSC and its precursor lesions, such as p53 signature, are predominantly CG>TA substitutions attributed to cytidine deamination. We previously demonstrated that ovulatory follicular fluid (FF) released reactive oxygen species (ROS), which activate activation-induced cytidine deaminase (AID) and promote TP53 mutagenesis in FTE. Here, we demonstrate that hemoglobin (Hb) originating from retrograde menstruation acts as an extracellular ROS scavenger, attenuating AID-mediated TP53 deamination in fallopian tube fimbriae, both in vitro and in vivo. Peritoneal fluid from tubal-ligated women exhibited significantly lower Hb, higher ROS, and elevated hypoxanthine phosphoribosyl transferase (HPRT) mutagenic activity compared to nonligated controls (p < 0.004). Histopathological analysis of 206 fallopian tubes from 119 women undergoing opportunistic salpingectomy further revealed a significantly higher frequency of p53 signatures in ligated tubes (0.22 ± 0.64 lesions per fimbria) than in nonligated tubes (0.07 ± 0.31 lesions per fimbria) (p = 0.017). Multivariate analysis identified tubal ligation as the sole reproductive factor independently associated with p53 signatures [odds ratio (OR) = 3.32; 95% CI: 1.15-9.57]. Our findings indicate that retrograde menstrual Hb mitigates ovulation-associated ROS stress, thereby reducing AID-mediated TP53 mutagenesis in the FTE. This study uncovers a physiological, protective role for menstruation against ovulatory oxidative damage and its mutagenic consequences, while demonstrating that tubal ligation disrupts this endogenous antioxidant mechanism, resulting in an increased burden of p53 signature lesions. © 2026 The Pathological Society of Great Britain and Ireland.
WINTER MEETING, The Microenvironment & Disease, 8th Joint Meeting with the Royal Society of Medicine, 217th Scientific Meeting of the Pathological Society of Great Britain & Ireland, 20-21 January 2026.
J Pathol · 2026 Apr · PMID 42008097 · Publisher ↗
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