The Journal of Pathology最新文献

Peritubular capillary (PTC) rarefaction is a common pathological feature of chronic kidney disease (CKD). The critical function of PTCs in maintaining blood supply for tubular epithelial cells renders PTCs a promising therapeutic target. However, the role of PTC rarefaction in the progression of kidney fibrosis remains elusive. In this study, we first characterized mice with altered PTC density. CD31 staining, together with microvascular network perfusion with FITC-labelled albumin and laser speckle contrast imaging, revealed a significant increase in PTC density in Flt1 heterozygous-deficient mice, whereas homozygous disruption of the plasminogen activator, urokinase receptor gene (Plaur/uPAR), led to a notable decrease in PTC density. Using these genetically distinct mice, we showed that preexisting higher PTC density protected against tubular injury and attenuated the progression of tubulointerstitial fibrosis in two distinct kidney injury models, namely, ischemia-reperfusion injury (IRI) and unilateral ureteral obstruction (UUO). By contrast, Plaur-deficient mice with established lower PTC density displayed exacerbated tubular injury and renal fibrosis when subjected to IRI or UUO. The pathophysiological significance of PTC density was associated with protective effects on tubular cell apoptosis and concomitant regeneration. Finally, vasodilation of the renal capillary with minoxidil, a clinically available drug, effectively prevented UUO-induced tubular injury and renal fibrosis. Moreover, minoxidil treatment abolished the detrimental effect of Plaur deficiency on the UUO-treated kidney, thus suggesting a causative role of PTC density in the susceptibility of Plaur knockout mice to tubular injury following fibrosis. Our results provide an overview of the pathologic significance of PTC density alterations in the progression of CKD, and show that improving peritubular microcirculation is effective in preventing tubular injury and the subsequent renal fibrosis. © 2025 The Pathological Society of Great Britain and Ireland.

In solid tumours, malignant cells develop relationships with nonmalignant stromal cells to support tumour growth, tissue structure, and nutrient supply. In a recent issue of this journal, Zheng and Guo catalogue the cellular landscape in chordoma using a combination of single-cell and spatial transcriptomics. Despite the mesenchymal nature of chordoma, malignant cells retain expression of epithelial markers, in addition to mesenchymal, partial-EMT, and stem-cell signatures. Cancer-associated fibroblasts (CAFs) are among the most abundant stromal cells and the authors define an inflammatory CAF subtype (iCAF), which is associated with poor outcome and tumour invasion. It is proposed that iCAFs arise from normal fibroblasts during malignant tumour progression and play a causative role in driving an invasive poor prognosis tumour phenotype. Recent reports by this and other groups have separately catalogued cell populations, including CAFs and immune cells in chordoma. The next challenge will be to integrate findings from these distinct studies to allow a consensus to be reached regarding cellular heterogeneity within chordoma, and to allow comparison of CAF populations with those found in other tumour types. Comparison of CAF functions in these predominantly mesenchymal tumours with epithelial solid tumours may reveal interesting lessons about the diverse phenotypes CAFs can bring to distinct tumour ecosystems. Understanding the role of CAFs in chordoma progression may also lead to therapeutic opportunities, but separation of correlation and causation in CAF regulation of tumour phenotypes remains a significant challenge. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Vascular calcification is an important risk factor related to all-cause mortality of cardiovascular events in patients with chronic kidney disease (CKD). Vascular extracellular matrix (ECM) proteins have been demonstrated to regulate vascular calcification. ECM protein thrombospondin 1 (THBS1/TSP-1) plays a critical role in the regulation of vascular diseases. However, whether THBS1 is involved in vascular calcification in CKD patients remains unclear. In this study, RNA sequencing datasets from the Gene Expression Omnibus (GEO) database GSE146638 showed that THBS1 was upregulated in the aortas of CKD rats. Enzyme-linked immunosorbent assay (elisa) revealed that serum THBS1 levels were increased in CKD patients with thoracic calcification. Western blotting and immunofluorescence analysis showed that THBS1 expression was increased in calcified vascular smooth muscle cells (VSMCs) and arteries. THBS1 knockdown exacerbated rat VSMC calcification induced by high phosphorus and calcium, as shown by Alizarin red staining and calcium content assays. Conversely, THBS1 overexpression attenuated VSMC calcification and abdominal aortic calcification in rats with CKD. Moreover, addition of recombinant THBS1 protein inhibited calcification of VSMC_S and human arterial rings. Smooth muscle cell-specific knockout of THBS1 mice treated with vitamin D3 displayed aggravated aortic calcification. Mechanistically, the protein-protein interaction database STRING (http://string-db.org/) analysis and coimmunoprecipitation assays revealed THBS1 bound to integrin β3. Reduction of integrin β3 levels abrogated the protective effect of THBS1 on vascular calcification. RNA-seq analysis revealed that THBS1 overexpression modulated the nuclear factor-kappa B (NF-κB) signaling pathway. Of note, the inhibitory effect of THBS1 overexpression on the NF-κB signal was abolished by knockdown of integrin β3. In conclusion, THBS1 interacts with integrin β3 to inhibit vascular calcification through suppression of NF-κB signal, suggesting a promising therapeutic target for vascular calcification in CKD. © 2025 The Pathological Society of Great Britain and Ireland.

Peutz-Jeghers syndrome (PJS) is associated with early-onset gastrointestinal polyposis caused by hereditary inactivating pathogenic variants in the tumor suppressor gene STK11 (LKB1). Due to lack of prophylactic therapies, management of PJS polyps requires frequent surveillance. Interestingly, studies in mouse models have revealed that stromal cells drive the polyp formation, but detailed understanding of the cell types and interactions involved has been lacking. Using single-cell RNA sequencing of PJS mouse model polyps, we here identify a polyp-enriched crypt top fibroblast (pCTF) cluster characterized by a transcriptional signature also enriched in PJS patient polyps. The pCTF signature was also noted in primary fibroblasts in vitro following acute STK11 loss. Targeted deletion of Stk11 in crypt top fibroblasts using Foxl1-Cre led to upregulation of the pCTF signature genes and later to polyposis. pCTFs displayed similarity to inflammation-associated fibroblasts, and polyposis was exacerbated by inflammation. Cell-cell communication analysis identified interleukin 11 (IL-11) as a potential pCTF inducer, and consistent with this, IL-11 was required for fibroblast reprogramming toward pCTFs following STK11 loss. Importantly, a neutralizing IL-11 antibody efficiently reduced polyp formation in a PJS model indicating a key, targetable role for IL-11 in polyp development. Together the results characterize pCTFs as a PJS polyp-enriched fibroblast subset and identify IL-11 as a key mediator of fibroblast reprogramming and a potential therapeutic target in PJS. © 2025 The Pathological Society of Great Britain and Ireland.

Merkel cell carcinoma (MCC) is a highly malignant skin cancer that expresses epithelial-, neuroendocrine-, and lymphoid-associated genes. Here, we focused on B-cell differentiation, which is characterised by the coexpression of PAX5 and TdT. PAX5 is the master regulator of B-cell commitment and is expressed in 65% of MCC cases. Yet little is known about the underlying molecular biology of the frequently reported PAX5 expression in MCC. Multi-omics analyses, including RNA next-generation sequencing, RT-qPCR, immunohistochemistry, and western blotting, were performed to assess PAX5 expression in MCC. Differential DNA methylation analysis at 61,043 PAX5 binding sites in enhancer and promoter elements was performed to detect differences between n = 14 MCC tissues and n = 91 various normal B-cell populations. RNA analysis revealed full-length PAX5 expression in MCC at the transcriptional level using both PAX5 transcription start sites. PAX5 protein expression was found in 40 of 41 MCCs and six out of seven MCC cell lines. DNA methylation array analysis revealed 1,084 hypermethylated loci of enhancer and promoter elements located in PAX5 binding sites in MCC. Of these, 702 loci were associated with 257 genes that are not expressed. The PAX5-associated regulatory elements of these 257 genes were enriched for interferon regulatory factor 4 (IRF4) and SPi-proto-oncogene (SPI1) binding motifs. Neither IRF4 or SPI1 could be detected in MCC on RNA or the protein level. Thus, because of the absence of these transcription factors, we conclude that full-length PAX5 alone cannot induce B-cell differentiation. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Colorectal cancer (CRC) is responsible for over 900,000 annual deaths worldwide. Emerging evidence supports pro-carcinogenic bacteria in the colonic microbiome are at least promotional in CRC development and may be causal. We previously showed toxigenic C. difficile from human CRC-associated bacterial biofilms accelerates tumorigenesis in Apc^Min/+ mice, both in specific pathogen-free mice and in gnotobiotic mice colonized with a defined consortium of bacteria. To further understand host-microbe interactions during colonic tumorigenesis, we combined single-cell RNA-sequencing (scRNA-seq), spatial transcriptomics, and immunofluorescence to define the molecular spatial organization of colonic dysplasia in our consortium model with or without C. difficile. Our data show a striking bipartite regulation of Deleted in Malignant Brain Tumors 1 (DMBT1) in the inflamed versus dysplastic colon. From scRNA-seq, differential gene expression analysis of normal absorptive colonocytes at 2 weeks postinoculation showed DMBT1 upregulated by C. difficile compared to colonocytes from mice without C. difficile exposure. In contrast, our spatial transcriptomic analysis showed DMBT1 dramatically downregulated in dysplastic foci compared with normal-adjacent tissue. We further integrated our datasets to generate custom colonic dysplasia scores and ligand-receptor mapping. Validation with immunofluorescence showed DMBT1 protein downregulated in dysplastic foci from three mouse models of colonic tumorigenesis and in adenomatous dysplasia from human samples. Finally, we used mouse and human organoids to implicate WNT signaling in the downregulation of DMBT1 mRNA and protein. Together, our data reveal cell type-specific regulation of DMBT1, a potential mechanistic link between bacteria and colonic tumorigenesis. Published 2025. This article is a U.S. Government work and is in the public domain in the USA. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Afadin is a multimodal scaffolding protein with essential functions in cell-cell adhesion. Although its loss of expression has been linked to breast cancer invasion and metastasis, the underlying mechanisms driving tumour progression upon mutational Afadin (AFDN) loss in breast cancers remains unclear. In the current study we identified a somatic frameshift AFDN mutation (p.Lys630fs) in an invasive breast cancer sample that coincides with loss of Afadin protein expression. Functional studies in E-cadherin-expressing breast cancer cells show that Afadin loss leads to immature and aberrant adherens junction (AJ) formation. The lack of AJ maturation results in a noncohesive cellular phenotype accompanied by Actomyosin-dependent anoikis resistance, which are classical progression hallmarks of single-cell breast cancer invasion. Reconstitution experiments using Afadin truncates show that proper F-actin organisation and epithelial cell-cell adhesion critically depend on the Coiled-Coil domain of Afadin but not on the designated C-terminal F-actin binding domain. Mouse xenograft experiments based on cell lines and primary patient-derived breast cancer organoids demonstrate that Afadin loss induces single-cell lobular-type invasion phenotypes and overt dissemination to the lungs and the peritoneum. In short, Afadin is a metastasis suppressor for breast cancer through stabilisation and maturation of a mechanical E-cadherin to F-actin outside-in link. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Mucinous ovarian carcinoma (MOC) is a rare histotype of epithelial ovarian cancer. Its origins are obscure: while many mucinous tumours in the ovary are metastases from the gastrointestinal tract, MOC can occur as an ovarian primary; however, the cell of origin is not well established. In this review we summarise the pathological, epidemiological, and molecular evidence for the cellular origins of MOC. We propose a model for the origins of the various tumours of the ovary with mucinous differentiation. We distinguish Müllerian from gastrointestinal-type mucinous differentiation. A small proportion of the latter arise from teratoma and a distinct terminology has been proposed. Other gastrointestinal mucinous tumours are associated with Brenner tumours and arise from their associated benign lesions, Walthard nests. The remaining mucinous tumours develop either through mucinous metaplasia in established Müllerian tumours or with even greater plasticity through gastrointestinal metaplasia of epithelial or mesothelial ovarian inclusions. This model remains to be validated and mechanistically understood and we discuss future research directions. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Predicting metachronous metastases in localized pancreatic neuroendocrine tumors (PanNETs) and improving survival of patients with advanced disease are some of the most important goals in PanNET research. Both are addressed by a study published recently in this journal. First, the results suggest that heterozygous DAXX mutations are already present in tumor cells but only become potentiated after a single massive chromosomal event that causes loss of heterozygosity and biallelic loss of DAXX. Second, the significant finding that the alkylating agent streptozocin may also induce a hypermutator phenotype with aggressive high-grade progression is further explored. The literature on temozolomide and peptide receptor radionuclide therapy-induced and spontaneous high-grade PanNET progression shows that the cause of high-grade progression is likely multifactorial. High-grade progressed PanNETs may show histopathological features normally seen in neuroendocrine carcinomas. Although it is not clear how often alkylating treatment induces progression, increasing evidence suggests that after an initial response, some patients indeed progress due to streptozocin or temozolomide. © 2025 The Pathological Society of Great Britain and Ireland.