J. Pathol. [JOURNAL]
Sun
200 papers
Contribution of alterations in peritubular capillary density and microcirculation to the progression of tubular injury and kidney fibrosis.
Ren Z, Shao F, Chen S … +5 more , Sun Y, Ding Z, Dong L, Zhang J, Zang Y
J Pathol · 2025 May · PMID 40103536 · Publisher ↗
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 th...
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.
Cancer-associated fibroblast heterogeneity in chordoma.
Henry JC, Cameron AJM
J Pathol · 2025 May · PMID 40088426 · Full text
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 cell...
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.
Thrombospondin-1 binds to integrin β3 to inhibit vascular calcification through suppression of NF-κB pathway.
Liu F, Liang Q, Li L … +10 more , Gong Y, Li M, Feng L, Chen A, Ye Y, Lan Z, Li Y, Ou JS, Lu L, Yan J
J Pathol · 2025 May · PMID 40084742 · Publisher ↗
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 demonstrate...
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 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.
Interleukin-11 expressed in the polyp-enriched fibroblast subset is a potential therapeutic target in Peutz-Jeghers syndrome.
Domènech-Moreno E, Lim WW, Montrose MG … +7 more , Sévigny M, Brandt A, Lemmetyinen TT, Viitala EW, Mäkelä TP, Cook SA, Ollila S
J Pathol · 2025 May · PMID 40070038 · Publisher ↗
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 therapie...
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.
The significance of PAX5 in Merkel cell carcinoma.
Chteinberg E, Kolarova J, Vogt J … +14 more , Macamo A, Bormann F, Kretzmer H, Speel EJ, van den Oord J, Schneider C, Stilgenbauer S, Becker JC, Winnepenninckx V, Biessen E, Zenke M, Kurz AK, Siebert R, Zur Hausen A
J Pathol · 2025 May · PMID 40034069 · Full text
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 coexpres...
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.
Cellular origins of mucinous ovarian carcinoma.
Meagher NS, Köbel M, Karnezis AN … +8 more , Talhouk A, Anglesio MS, Berchuck A, Gayther SA, Pharoah PP, Webb PM, Ramus SJ, Gorringe KL
J Pathol · 2025 May · PMID 40028669 · Full text
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 ova...
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.
Afadin loss induces breast cancer metastasis through destabilisation of E-cadherin to F-actin linkage.
Rätze MA, Enserink LN, Ishiyama N … +10 more , van Kempen S, Veltman CH, Nijman IJ, Haakma WE, Caldas C, Bernards R, van Diest PJ, Christgen M, Koorman T, Derksen PW
J Pathol · 2025 May · PMID 40026293 · Full text
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 tumou...
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.
Multiomic spatial atlas shows deleted in malignant brain tumors 1 (DMBT1) glycoprotein is lost in colonic dysplasia.
Green EH, Kotrannavar SR, Rutherford ME … +15 more , Lunnemann HM, Kaur H, Heiser CN, Ding H, Simmons AJ, Liu X, Lacy DB, Washington MK, Shrubsole MJ, Liu Q, Lau KS, Sears CL, Coffey RJ, Drewes JL, Markham NO
J Pathol · 2025 May · PMID 40026233 · Full text
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 causa...
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 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.
Should we worry about high-grade pancreatic neuroendocrine tumor progression and alkylating agents?.
Hackeng WM, Dreijerink KM, Brosens LA
J Pathol · 2025 May · PMID 40007046 · Publisher ↗
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 addres...
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.
Tumor immune microenvironment alterations associated with progression in human intraductal papillary mucinous neoplasms.
Jamouss KT, Damanakis AI, Cornwell AC … +16 more , Jongepier M, Trujillo MA, Pflüger MJ, Kawalerski R, Maalouf A, Hirose K, Datta S, Sipes A, Pedro BA, Gudmundsson E, Assarzadegan N, Engle L, Scharpf RB, Kawamoto S, Thompson ED, Wood LD
J Pathol · 2025 May · PMID 40001347 · Full text
Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge due to late-stage diagnoses. To improve patient outcomes, early intervention in precursor lesions such as intraductal papillary mucinous neoplasm (IPM...
Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge due to late-stage diagnoses. To improve patient outcomes, early intervention in precursor lesions such as intraductal papillary mucinous neoplasm (IPMN) is crucial. However, early intervention must be balanced against overtreatment of low-risk lesions that are unlikely to progress, underscoring the need to better understand molecular alterations in neoplastic cells and changes in the tumor microenvironment (TME) that drive the progression of IPMNs. In this study, we characterized alterations in the TME of IPMNs as they progressed to high-grade dysplasia, using immunohistochemistry to quantify immune cell density and activation status in more than 100 well-characterized human IPMN samples. Analyses revealed progression to a more immunosuppressive TME in high-grade IPMN compared with low-grade IPMN, characterized by elevated expression of immune checkpoint molecules (PD-L1, TIM3, VISTA), increased density of macrophages, and decreased density of cytotoxic T cells. Intriguingly, the alterations in macrophages were limited to focal regions of high-grade dysplasia, while T-cell alterations affected the entire IPMN. Additionally, elevated VISTA expression was associated with poorer clinical outcome after IPMN resection in an independent cohort. These findings provide important insights into the interplay between the immune microenvironment and IPMN progression, highlighting potential targets to modify the TME for cancer interception. © 2025 The Pathological Society of Great Britain and Ireland.
Platelet C3G protects from liver fibrosis, while enhancing tumor growth through regulation of the immune response.
Baquero C, Iniesta-González M, Palao N … +14 more , Fernández-Infante C, Cueto-Remacha M, Mancebo J, de la Cámara-Fuentes S, Rodrigo-Faus M, Valdecantos MP, Valverde AM, Sequera C, Manzano S, Cuesta ÁM, Gutierrez-Uzquiza A, Bragado P, Guerrero C, Porras A
J Pathol · 2025 Apr · PMID 39989399 · Full text
Primary liver cancer usually occurs in the context of chronic liver disease (CLD), in association with fibrosis. Platelets have emerged as important regulators of CLD and liver cancer, although their precise function and...
Primary liver cancer usually occurs in the context of chronic liver disease (CLD), in association with fibrosis. Platelets have emerged as important regulators of CLD and liver cancer, although their precise function and mechanism of action need to be clarified. C3G (RapGEF1) regulates platelet activation, adhesion, and secretion. Here we evaluate the role of platelet C3G in chemically induced fibrosis and liver cancer associated with fibrosis using genetically modified mouse models. We found that while overexpression of full-length C3G in platelets decreased liver fibrosis induced by chronic treatment with CCl, overexpressed C3G lacking the catalytic domain did not, although in both cases platelet recruitment to the liver was similar. In addition, C3G deletion in platelets (PF4-C3GKO mouse model) increased CCl-induced liver damage and hepatic fibrosis, reducing liver platelets and macrophages. Moreover, early liver immune response to CCl was altered in PF4-C3GKO mice, with a remarkable lower activation of macrophages and increased monocyte-derived macrophages compared to WT mice. On the other hand, in response to DEN+CCl, PF4-C3G WT mice exhibited more and larger liver tumors than PF4-C3GKO mice, accompanied by the presence of more platelets, despite having less fibrosis in previous steps. Liver immune cell populations were also differentially regulated in PF4-C3GKO mice, highlighting the higher number of macrophages, likely with a pro-inflammatory phenotype, present in the liver in response to chronic DEN+CCl treatment. Proteins upregulated or downregulated in platelet-rich plasma from PF4-C3GKO compared to WT mice might regulate the immune response and tumor development. In this regard, enrichment analyses using proteomic data showed changes in several proteins involved in platelet activation and immune response pathways. Additionally, the higher secretion of CD40L by PF4-C3GKO platelets could contribute to their antitumor effect. Therefore, platelet C3G presents antifibrotic and protumor effects in the liver, likely mediated by changes in the immune response. © 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.
PI3 expression predicts recurrence after chemotherapy with DNA-damaging drugs in gastric cancer.
Harada K, Sakamoto N, Kitaoka T … +17 more , Nakamura Y, Kondo R, Morisue R, Hashimoto H, Yamamoto Y, Ukai S, Maruyama R, Sakashita S, Kojima M, Tanabe K, Ohdan H, Shitara K, Kinoshita T, Ishii G, Yasui W, Ochiai A, Ishikawa S
J Pathol · 2025 Apr · PMID 39980125 · Full text
Despite recent advances in gastric cancer therapy, chemotherapy resistance and lack of methods for selecting combination regimens remain major problems. Organoids, which provide a culture system that more closely resembl...
Despite recent advances in gastric cancer therapy, chemotherapy resistance and lack of methods for selecting combination regimens remain major problems. Organoids, which provide a culture system that more closely resembles tumor cell organization than traditional cell lines, can be established from surgical specimens with a high success rate and are widely used for drug sensitivity assays. In this study, we aimed to identify a novel biomarker for predicting multidrug resistance using gastric cancer organoids (GCOs). We evaluated 5-fluorouracil or oxaliplatin-resistant GCOs to find novel biomarkers that reflect multidrug resistance in gastric cancer. To examine the resistance mechanisms, RNA-sequencing analysis and ex vivo drug sensitivity testing were performed. The association of biomarkers with patient prognosis and chemotherapy efficacy was evaluated using three original cohorts with a total of 230 cases. The results were also validated with two independent public cohorts and single-cell RNA sequence data. Increased expression of peptidase inhibitor 3 (PI3) was detected in all 5-fluorouracil or oxaliplatin-resistant GCOs. Our findings suggest a potential association of PI3 expression with ribosome biosynthesis and RNA metabolism under organoid conditions. We also found that PI3 overexpression promoted 5-fluorouracil/oxaliplatin/cisplatin resistance but not paclitaxel resistance. Immunohistochemical evaluation of PI3 expression revealed that the PI3-positive gastric cancer group had a poorer outcome, especially in terms of time to recurrence. PI3 positivity was also an independent predictor of relapse after chemotherapy with DNA-damaging agents. PI3 promotes DNA-damaging drug resistance through multiple downstream regulations related to RNA and ribosomal metabolism. PI3 may be useful as a biomarker for the therapeutic selection of non-DNA-damaging agents. © 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.
Spatial profiling of ANO7 in prostate tissue: links to AR-signalling-associated lipid metabolism and inflammation.
Metsälä O, Wahlström G, Goel N … +3 more , Miihkinen M, Taimen P, Schleutker J
J Pathol · 2025 Apr · PMID 39978863 · Publisher ↗
Prostate cancer (PrCa) is highly prevalent in the Western world. Currently, however, there are many unmet needs in PrCa care, for example in distinguishing between clinically significant and indolent cases in early phase...
Prostate cancer (PrCa) is highly prevalent in the Western world. Currently, however, there are many unmet needs in PrCa care, for example in distinguishing between clinically significant and indolent cases in early phases of the disease. ANO7 is a prostate-specific gene associated with PrCa risk and prognosis, but its exact function in the prostate remains unclear. This study investigates the role of ANO7 in benign prostatic epithelium using spatial transcriptomics by examining differences between ANO7-expressing and non-expressing epithelial regions and their corresponding stromal compartments. A total of 18,676 protein-coding genes were assessed from prostatectomy samples collected from patients with localised prostate cancer. In the collected sample cohort, ANO7 exhibited a distinct, heterogeneous, on-off epithelial expression pattern, enabling an in-depth analysis of ANO7-dependent processes. ANO7-positive epithelium was predominantly enriched with luminal epithelial cells and a specific NK cell subtype, CD56bright. In contrast, ANO7-negative regions were characterised by enrichment of club cells, inflammation, and features of proliferative inflammatory atrophy. Gene-set enrichment analysis revealed that ANO7 expression is associated with androgen receptor (AR) signalling and lipid metabolism. A detailed analysis of differentially expressed genes identified an ANO7- signature, which consisted of genes co-expressed with ANO7 in luminal cells, that demonstrated high consistency in bulk RNA-sequencing (RNA-seq) data. The ANO7-signature was enriched for AR-regulated genes, which highlighted lipid metabolism processes, particularly arachidonic acid metabolism, as a key metabolic feature of the ANO7-positive epithelium. Furthermore, the ANO7-signature demonstrated clinical significance in low-grade PrCa, correlating with a better response to therapy. In summary, these results highlight the potential role of ANO7 in regulating lipid metabolism associated with androgen signalling in benign luminal cells and low-grade cancer, reinforcing the hypothesis that ANO7 functions as a tumour suppressor. © 2025 The Pathological Society of Great Britain and Ireland.
Distinct spatial N-glycan profiles reveal glioblastoma-specific signatures.
Angerstein AO, Young LEA, Thanasupawat T … +10 more , Vriend J, Grimsley G, Lun X, Senger DL, Sinha N, Beiko J, Pitz M, Hombach-Klonisch S, Drake RR, Klonisch T
J Pathol · 2025 Apr · PMID 39967571 · Publisher ↗
This study explored the complex interactions between glycosylation patterns, tumour biology, and therapeutic responses to temozolomide (TMZ) in human malignant glioma, specifically CNS WHO grade 3 oligodendroglioma (ODG)...
This study explored the complex interactions between glycosylation patterns, tumour biology, and therapeutic responses to temozolomide (TMZ) in human malignant glioma, specifically CNS WHO grade 3 oligodendroglioma (ODG) and glioblastoma (GB). Using spatial imaging of N-glycans in formalin-fixed paraffin-embedded (FFPE) tissue sections via MALDI-MSI, we analysed the N-glycome in primary and recurrent GB tissues and orthotopic xenografts of patient-derived brain tumour-initiating cells (BTIC) sensitive or resistant to TMZ. We identified unique N-glycosylation profiles, with nontumor brain (NTB) and ODG showing higher levels of bisecting and tri-antennary structures, while GB exhibited more tetra-antennary and sialylated N-glycans. Distinctive sialylation patterns were observed, with specific α2,6 and α2,3 isomeric linkages significantly altered in GB. Moreover, comparative analysis of primary and recurrent GB tissues revealed elevated high mannose N-glycans in primary GB and fucosylated bi- and tri-antennary N-glycans in recurrent GB tissues. Next, in the orthotopic xenografts of TMZ-sensitive and TMZ-resistant patient brain tumour initiating cells (BTIC), we identified potential N-glycan markers for TMZ treatment response and resistance. Finally, we found significantly altered expression of genes involved in N-glycan biosynthesis in malignant glioma, highlighting the crucial role of N-glycans in glioma and therapy resistance. This study lays the foundation for developing glycosylation-based diagnostic biomarkers and targeted therapies, potentially improving clinical outcomes for GB patients. © 2025 The Pathological Society of Great Britain and Ireland.
A deep-learning model for predicting tyrosine kinase inhibitor response from histology in gastrointestinal stromal tumor.
Kong X, Shi J, Sun D … +6 more , Cheng L, Wu C, Jiang Z, Zheng Y, Wang W, Wu H
J Pathol · 2025 Apr · PMID 39950223 · Publisher ↗
Over 90% of gastrointestinal stromal tumors (GISTs) harbor mutations in KIT or PDGFRA that can predict response to tyrosine kinase inhibitor (TKI) therapies, as recommended by NCCN (National Comprehensive Cancer Network)...
Over 90% of gastrointestinal stromal tumors (GISTs) harbor mutations in KIT or PDGFRA that can predict response to tyrosine kinase inhibitor (TKI) therapies, as recommended by NCCN (National Comprehensive Cancer Network) guidelines. However, gene sequencing for mutation testing is expensive and time-consuming and is susceptible to a variety of preanalytical factors. To overcome the challenges associated with genetic screening by sequencing, in the current study we developed an artificial intelligence-based deep-learning （DL） model that uses convolutional neural networks (CNN) to analyze digitized hematoxylin and eosin staining in tumor histological sections to predict potential response to imatinib or avapritinib treatment in GIST patients. Assessment with an independent testing set showed that our DL model could predict imatinib sensitivity with an area under the curve (AUC) of 0.902 in case-wise analysis and 0.807 in slide-wise analysis. Case-level AUCs for predicting imatinib-dose-adjustment cases, avapritinib-sensitive cases, and wildtype GISTs were 0.920, 0.958, and 0.776, respectively, while slide-level AUCs for these respective groups were 0.714, 0.922, and 0.886, respectively. Our model showed comparable or better prediction of actual response to TKI than sequencing-based screening (accuracy 0.9286 versus 0.8929; DL model versus sequencing), while predictions of nonresponse to imatinib/avapritinib showed markedly higher accuracy than sequencing (0.7143 versus 0.4286). These results demonstrate the potential of a DL model to improve predictions of treatment response to TKI therapy from histology in GIST patients. © 2025 The Pathological Society of Great Britain and Ireland.
Redefining phenotypic intratumor heterogeneity of pancreatic ductal adenocarcinoma: a bottom-up approach.
Hilmi M, Delecourt F, Raffenne J … +12 more , Bourega T, Dusetti N, Iovanna J, Blum Y, Richard M, Neuzillet C, Couvelard A, Tihy M, de Mestier L, Rebours V, Nicolle R, Cros J
J Pathol · 2025 Apr · PMID 39935174 · Full text
Pancreatic ductal adenocarcinoma (PDAC) tumor interpatient heterogeneity has been well described with two major prognostic subtypes (classical and basal-like). An important intrapatient heterogeneity has been reported bu...
Pancreatic ductal adenocarcinoma (PDAC) tumor interpatient heterogeneity has been well described with two major prognostic subtypes (classical and basal-like). An important intrapatient heterogeneity has been reported but has not yet been studied extensively due to the lack of standardized, reproducible, and easily accessible high-throughput methods. We built an immunohistochemical (IHC) tool capable of differentiating RNA-defined classical and basal-like tumors by selecting relevant antibodies using a multistep process. The successive stages of (i) an in silico selection from a literature review and a bulk transcriptome analysis of 309 PDACs, (ii) a tumor-specific selection from 30 patient-derived xenografts and single-cell data, followed by (iii) the validation on tissue microarrays in 50 PDAC were conducted. We used our final IHC panel on two independent cohorts of resected PDAC (n = 95, whole-slide, n = 148, tissue microarrays) for external validation. After digitization and registration of pathology slides, we performed a tile-based analysis in tumor areas to identify relevant marker combinations. Sequential marker selection led to the following panel: GATA6, CLDN18, TFF1, MUC16, S100A2, KRT17, PanBasal. Four different phenotypes were identified: one classical, one intermediate (KRT17+), and two basal-like (MUC16+ versus S100A2+) with specific biological properties. The presence of a minor basal contingent drastically reduced overall survival [hazard ratio (HR) = 1.90, p = 0.03], even in classical predominant PDACs. Analysis of preneoplastic lesions suggested that pancreatic carcinogenesis might follow a progressive evolution from classical toward a basal through an early intermediate phenotype. In conclusion, our IHC panel redefined and easily assessed the high degree of intra- and intertumoral heterogeneity of PDAC. © 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.
Comprehensive characterization of micropapillary colorectal adenocarcinoma.
Äijälä VK, Härkönen J, Mantere T … +23 more , Elomaa H, Sirniö P, Pohjanen VM, Sirkiä O, Karjalainen H, Kastinen M, Tapiainen VV, Väyrynen SA, Pölönen P, Ahtiainen M, Helminen O, Wirta EV, Rintala J, Meriläinen S, Saarnio J, Rautio T, Pylkäs K, Seppälä TT, Böhm J, Mecklin JP, Tuomisto A, Mäkinen MJ, Väyrynen JP
J Pathol · 2025 Apr · PMID 39917902 · Full text
Micropapillary colorectal adenocarcinoma is a morphologic subtype of colorectal cancer (CRC) with insufficiently characterized prognostic significance and biological features. We analyzed the histopathological, immunolog...
Micropapillary colorectal adenocarcinoma is a morphologic subtype of colorectal cancer (CRC) with insufficiently characterized prognostic significance and biological features. We analyzed the histopathological, immunological, and prognostic features of micropapillary adenocarcinoma in two independent CRC cohorts (N = 1,876). We found that micropapillary adenocarcinomas accounted for 4.9% and 6.4% of CRCs in the two cohorts. A micropapillary growth pattern was associated with advanced stage and lymphovascular invasion (p < 0.001), but also with shorter overall survival independent of these factors and other prognostic parameters (Cohort 1: hazard ratio [HR] 1.76, 95% confidence interval [CI] 1.08-2.87; Cohort 2: HR 1.47, 95% CI 1.08-2.00). Multiplex immunohistochemistry and machine learning-assisted image analysis showed that the micropapillary growth pattern was associated with decreased CD3 T-cell and CD14HLA-DR monocytic cell densities. Molecular features of micropapillary adenocarcinoma were studied using bioinformatic analyses in The Cancer Genome Atlas (TCGA) cohort (N = 629) and validated with optical genome mapping and immunohistochemistry. These analyses revealed that micropapillary adenocarcinomas frequently present with chromosome region 8q24 copy number gain, TP53 mutation, and overexpression of UPK2, MUC16, and epithelial-mesenchymal transition involved genes, such as L1CAM. These results indicate that micropapillary colorectal adenocarcinoma is an aggressive morphologic subtype of CRC characterized by shorter overall survival, decreased antitumorigenic immune response, and unique molecular features. Our findings support the classification of micropapillary adenocarcinoma as a distinct, high-risk subtype of CRC, which should be systematically evaluated in patient care. © 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.
Unveiling the intriguing relationship: oncogenic KRAS, morphological shifts, and mutational complexity in pancreatic mucinous cystic neoplasms.
Schulte LA, Beck A, Marienfeld R … +20 more , Azoitei N, Barth TF, Beutel A, Benes V, Büchler MW, Gaisa NT, Kilani K, Giese N, Michalski CW, Möller P, Perkhofer L, Rausch T, Repky S, Roger E, Scheible J, Seufferlein T, Schirmacher P, Berger AW, Hackert T, Kleger A
J Pathol · 2025 Apr · PMID 39906959 · Full text
Pancreatic ductal adenocarcinoma (PDAC) often arises from preexisting cystic lesions such as intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN). This study investigated the molecular hete...
Pancreatic ductal adenocarcinoma (PDAC) often arises from preexisting cystic lesions such as intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN). This study investigated the molecular heterogeneity and mutational landscape of MCN in relation to PDAC, highlighting the significance of KRAS mutations in tumor progression. Utilizing targeted next-generation sequencing on low-grade MCN and invasive PDAC samples, we identified a substantial overlap in mutational profiles, particularly mutations in KRAS, TP53, and FBXW7. Specifically, 69.2% of MCN exhibited somatic mutations, with KRAS mutations being a predominant oncogenic driver. The characterization of mutant versus wildtype KRAS variant allele frequencies (VAF) indicated higher mutation levels in PDAC compared to MCN, suggesting an evolutionary trajectory toward malignancy. Further histological analysis of 12 additional MCN cases revealed significant intratumor heterogeneity, with variant KRAS mutation distributions correlating with distinct cellular morphologies and dysplastic features. Additionally, we explored the potential of liquid biopsies, demonstrating a concordance rate of 71.4% for KRAS mutation detection in circulating tumor DNA (ctDNA) relative to tissue biopsies across cohorts. Our findings underscore the relevance of evaluating KRAS mutations-herein referred to as VAF per microdissected region-as they relate to histopathological markers of dysplasia, contributing to improved stratification of pancreatic lesions and facilitating personalized treatment strategies. In conclusion, this comprehensive analysis of MCN highlights the importance of KRAS as a crucial biomarker for both malignant progression and therapeutic decision-making in pancreatic pathology. Ultimately, our study suggests that characterizing the mutational landscape and histological features of MCN can enhance early detection and intervention strategies for at-risk patients. © 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.
Clonal dynamics of chronic myelomonocytic leukemia progression: paired-sample comparison.
Kao HW, Kuo MC, Ou CW … +6 more , Huang TY, Chang H, Lin TL, Hung YS, Wu JH, Shih LY
J Pathol · 2025 Apr · PMID 39905935 · Publisher ↗
This study investigated the clonal evolution of chronic myelomonocytic leukemia (CMML) progression to secondary acute myeloid leukemia (sAML) by next-generation sequencing and pyrosequencing for variant allele frequency...
This study investigated the clonal evolution of chronic myelomonocytic leukemia (CMML) progression to secondary acute myeloid leukemia (sAML) by next-generation sequencing and pyrosequencing for variant allele frequency (VAF) of gene mutations and SNP microarray for copy neutral loss of heterozygosity (CN-LOH) in 38 paired samples from CMML/sAML patients of Taiwanese origin. The median interval between CMML and sAML samples collection was 14.9 months (1.0-89.6). RUNX1 (57%), TET2 (46%), SRSF2 (37%), and ASXL1 (28%) mutations were frequent at CMML diagnosis. Baseline VAF in epigenetic regulator genes was high (>35%) in 83% of mutational events at the CMML phase, remained stable in 78% (VAF changes <10%), and increased in 20% (increased VAF > 10%) during progression to sAML. Transcription factor genes showed high VAF (>35%) in 51% at the CMML phase, and stable VAF in 60% during progression. VAF of spliceosome genes was high (>35%) in 70% at CMML phase, and stable in 61% during progression. Activated signaling genes exhibited acquisition or loss during progression. TET2 mutations were often founding clones, and SRSF2, ASXL1, DNMT3A, EZH2, or spliceosome genes also acted as ancestral mutations. RUNX1 mutations were typically later events and occasionally ancestral hits or germline mutations. Acquisition of cytogenetic changes, signaling pathways genes (PTPN11, FLT3, NRAS, CBL), or AML-defined genes (NPM1, CEBPA, CBFB::MYH11) by linear or branching evolution occurred during sAML progression. CN-LOH was noted in EZH2, CBL, TET2, and DNMT3A genes. CEBPA mutation and concurrent biallelic TET2 with NRAS mutations at CMML diagnosis were risk factors for time to AML progression and overall survival. A characteristic ASXL1/RUNX1/Spliceosome/signaling genetic profile was associated with monocyte counts of 0.5-1.0 × 10/l. This study highlights the complexity and heterogeneity of dynamic changes in clonal architecture during CMML progression, emphasizing its importance in pathogenesis, phenotype, risk stratification, and therapeutic strategy. © 2025 The Pathological Society of Great Britain and Ireland.
Downregulation of AATK enhances susceptibility to ferroptosis by promoting endosome recycling in gefitinib-resistant lung cancer cells.
Lee WC, Moi SH, Yang SF … +2 more , Tseng HH, Liu YP
J Pathol · 2025 Apr · PMID 39871626 · Publisher ↗
Ferroptosis has been characterised by disruption of the cell membrane through iron-related lipid peroxidation. However, regulation of iron homeostasis in lung cancer cells that are resistant to epidermal growth factor re...
Ferroptosis has been characterised by disruption of the cell membrane through iron-related lipid peroxidation. However, regulation of iron homeostasis in lung cancer cells that are resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) remains unclear. Transcriptome analysis identified a significant downregulation of apoptosis-associated tyrosine kinase (AATK) mRNA expression in gefitinib-resistant PC9 (PC9-GR) cells, which were found to be more susceptible to ferroptosis inducers. An in-depth analysis of publicly available datasets revealed that downregulation of AATK mRNA was associated with lymph node metastasis and poor prognosis in patients with lung adenocarcinoma. Knockdown of AATK-sensitised PC9, HCC827, and H441 cells to the ferroptosis inducer RSL3, whereas ectopic expression of AATK reduced RSL3-induced cell death in PC9-GR and HCC827-GR cells. Compared to PC9 cells, PC9-GR cells exhibited higher transferrin uptake, endosome recycling rate, and increased intracellular iron levels. Blocking iron transport reduced RSL3-induced ferroptosis in PC9-GR cells. Mechanistic studies showed that AATK localised to both early and recycling endosomes. Knockdown of AATK facilitated endosome recycling and elevated intracellular ferrous iron (Fe) levels in PC9 cells. Conversely, ectopic expression of AATK delayed endosome recycling and reduced intracellular Fe levels in PC9-GR cells. Inhibition of AATK downregulation-induced iron accumulation decreased RSL3-induced ferroptosis. Taken together, our study indicates that the downregulation of AATK contributes to endosome recycling and iron accumulation, leading to an increased susceptibility to ferroptosis in EGFR-TKI-resistant lung cancer cells. © 2025 The Pathological Society of Great Britain and Ireland.
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