J. Pathol. [JOURNAL]
Sun
200 papers
Advancing homebrew AI in diagnostic practice: opportunities and barriers.
Khoury ZH, Sultan AS
J Pathol · 2025 Dec · PMID 40999996 · Full text
In a recent issue of The Journal of Pathology, Calderaro et al present a timely and persuasive argument advocating for the integration of homebrew artificial intelligence (AI) models in diagnostic pathology. Their articl...
In a recent issue of The Journal of Pathology, Calderaro et al present a timely and persuasive argument advocating for the integration of homebrew artificial intelligence (AI) models in diagnostic pathology. Their article is a robust defense of local model development within pathology departments as a pathway to democratizing digital diagnostics. This commentary expands on their premise, critically examining the real-world implications, practical limitations, and unmet needs of practicing pathologists. The commentary outlines both the opportunities and challenges for the widespread adoption of homebrew AI in pathology practice. Without institutional backing, digital infrastructure, and sustained training efforts, the promise of homebrew AI may falter. © 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.
Dysregulated mitochondrial energy metabolism drives the progression of mucosal field effects to invasive bladder cancer.
Lee S, Jung SY, Kuś P … +18 more , Bondaruk J, Lee JG, Jaksik R, Putluri N, Dinh KN, Cogdell D, Chen H, Wang Y, Chen J, Navai N, Dinney C, Mendelsohn C, McConkey D, Behringer RR, Guo CC, Wei P, Kimmel M, Czerniak B
J Pathol · 2025 Nov · PMID 40996337 · Full text
Multiplatform mutational and gene expression profiling complemented with proteomic and metabolomic spatial mapping were used on the whole-organ scale to identify the molecular profile of bladder cancer evolution from fie...
Multiplatform mutational and gene expression profiling complemented with proteomic and metabolomic spatial mapping were used on the whole-organ scale to identify the molecular profile of bladder cancer evolution from field effects. Analysis of the mutational landscape identified three types of mutations, referred to as α, β, and γ. Time modeling of the mutations revealed that carcinogenesis may span 30 years and can be divided into dormant and progressive phases. The α mutations developed in the dormant phase. The progressive phase lasted 5 years and was signified by expanding β mutations, but it was driven to invasive cancer by γ mutations. The mutational landscape emerged on a background of disorganized urothelial differentiation, activated epithelial-mesenchymal transition, and enhanced immune infiltration with T-cell exhaustion. Complex dysregulation of mitochondrial energy metabolism with downregulation of oxidative phosphorylation emerged as the leading mechanism driving the progression of mucosal field effects to invasive cancer. © 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.
Tracing metastatic spread in pediatric solid tumors using copy number and targeted deep sequencing.
Andersson N, Ferro M, Jansson C … +3 more , Chattopadhyay S, Karlsson J, Gisselsson D
J Pathol · 2025 Nov · PMID 40985487 · Full text
The most common cause of death in pediatric cancer patients is a treatment-resistant tumor, compounded by metastatic spread, making surgery, radiation therapy, and chemotherapy unfeasible as curative treatment options. H...
The most common cause of death in pediatric cancer patients is a treatment-resistant tumor, compounded by metastatic spread, making surgery, radiation therapy, and chemotherapy unfeasible as curative treatment options. However, the mechanisms behind metastatic spread in pediatric tumors remain largely unexplored. We conducted whole-genome copy number profiling on 171 primary tumor and metastases samples from 17 patients with neuroblastoma, Wilms tumor, or gonadal tumors, and performed targeted deep sequencing on a subset. Phylogenetic reconstruction enabled spatiotemporal tracking of subclones. In total, 11 of 17 patients displayed at least one metastasis arising earlier, defined as occurring before the most recent common ancestor in the primary tumor. In eight patients, metastatic spread was observed several times during tumor evolution, with different subclones from the same primary tumor having metastatic capability, even colonizing the same site. Strikingly, dissemination between metastases (intermetastatic spread) occurred in eight of nine patients with metastases in at least two different sites, indicating that this is a common phenomenon in pediatric malignancy. © 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.
Chromosomal instability and genomic alterations in cholangiocarcinoma from Northeastern Thailand.
Deenonpoe R, Guscott MA, Watcharadetwittaya S … +4 more , McNeill IL, Moralli D, Shaikh N, McClelland SE
J Pathol · 2025 Nov · PMID 40952339 · Full text
Cholangiocarcinoma (CCA) is a lethal cancer of the bile duct and is a major health concern in several parts of the world, including northeastern Thailand, where CCA incidence is the highest due to the endemic liver fluke...
Cholangiocarcinoma (CCA) is a lethal cancer of the bile duct and is a major health concern in several parts of the world, including northeastern Thailand, where CCA incidence is the highest due to the endemic liver fluke Opisthorchis viverrini. Multiple studies have characterised genomic alterations in CCA tumours, and specific chromosomal alterations can predict prognosis. However, it is not known whether chromosomal instability (CIN), ongoing genomic alteration characteristic of most cancer types, is present in CCA tumours. In this study we leveraged a panel of cancer cell lines derived from fluke-positive CCA patients, as well as a matched normal cholangiocyte line as a control, to characterise CIN in CCA. We observed elevated rates of chromosome segregation errors compared to normal cells, although overall CIN rates were lower than those for highly genomically unstable cancers, such as colorectal or ovarian cancer. Chromosome segregation errors in CCA cell lines were potentially driven by elevated DNA replication stress and centrosome duplication. Single-cell genome sequencing and karyotyping of the cell lines showed extensive structural and numerical chromosomal aberrations, as well as copy number alterations that were heterogeneous between individual cells, supporting the presence of ongoing CIN in these cell line models. Low-pass whole-genome sequencing of 33 CCA tumour samples with matched normal tissue from northeastern Thailand, a liver fluke-endemic region showed increased whole and subchromosomal level alterations, with a higher extent of genomic alterations in intrahepatic tumours compared to extrahepatic. Eight tumours carried focal amplifications and/or deletions involving known cancer genes, as well as potential chromosomal instability-associated genes, including CCNE1 amplifications and a rare amplification of BRCA1. This study provides increased understanding of the rate and potential mechanisms of CIN in CCA that may inform new therapeutic strategies that synergise with specific ongoing CIN mechanisms. © 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.
Periostin-IHH feedforward loop promotes hepatocellular carcinoma development by enhancing hepatic fibrosis and tumor cell proliferation.
Liu B, Li X, Zhang M … +5 more , Liu X, Sun J, Deng M, Ouyang G, Wu T
J Pathol · 2025 Nov · PMID 40936244 · Publisher ↗
The extracellular matrix protein periostin plays a critical role in the progression of hepatic fibrosis and hepatocellular carcinoma (HCC). However, little is known about how periostin regulates both hepatic fibrosis and...
The extracellular matrix protein periostin plays a critical role in the progression of hepatic fibrosis and hepatocellular carcinoma (HCC). However, little is known about how periostin regulates both hepatic fibrosis and tumor growth in the progression of HCC. Here we demonstrate that periostin deficiency impairs HCC development and decreases tissue stiffness of liver tumors in DEN/CCl-treated mice. Increased matrix stiffness enhanced periostin expression in hepatic stellate cells (HSCs). The combination of periostin and increased stiffness synergistically promoted HCC cell proliferation in vitro. Moreover, periostin deficiency in HSCs impaired both HSC-promoted and stiffness-increased HCC cell proliferation in vivo. We further demonstrated that periostin promotes Indian hedgehog (IHH) expression in HCC cells through the integrin-PYK2-TAZ pathway. Conversely, IHH increased the expression of periostin in HSCs via GLI2. Periostin expression positively correlates with fibrotic features and IHH signaling in clinical HCC tissues. Collectively, these findings indicate that periostin and IHH cooperatively contribute to the development of HCC by regulating the tumor-stroma crosstalk via the periostin-integrin-PYK2-TAZ-IHH pathway in tumor cells and IHH-GLI2-periostin signaling in HSCs. © 2025 The Pathological Society of Great Britain and Ireland.
Investigating the mechanisms of indocyanine green tumour uptake in sarcoma cell lines and ex vivo human tissue.
Chan CD, Brookes MJ, Pringle TA … +6 more , Pal R, Tanwani R, Burt AD, Knight JC, Kumar AT, Rankin KS
J Pathol · 2025 Nov · PMID 40928629 · Full text
Indocyanine green (ICG) is a well-established near-infrared dye which has been used clinically for several decades. Recently, it has been utilised for fluorescence-guided surgery in a range of solid cancer types, includi...
Indocyanine green (ICG) is a well-established near-infrared dye which has been used clinically for several decades. Recently, it has been utilised for fluorescence-guided surgery in a range of solid cancer types, including sarcoma, with the aim of reducing the positive margin rate. The increased uptake and retention of ICG within tumours, compared with normal tissue, gives surgeons a visual reference to aid resection when viewed through a near-infrared camera. However, the mechanisms of this process are poorly understood. We performed in vitro ICG cellular uptake studies across a panel of sarcoma cell lines exhibiting varying proliferation rates and phenotypes. The effects of ICG concentration, incubation time, inhibition of clathrin-mediated endocytosis, and cell line proliferation rate on the cellular uptake of ICG were investigated using fluorescence microscopy and flow cytometry. Subcellular localisation of intracellular ICG was assessed via colocalization with a lysosomal marker. The spatial distribution of ICG in patient tumour tissue following fluorescence-guided surgery was assessed by high-resolution tissue imaging and quantified using fluorescence lifetime imaging. In vitro results showed that the cell line proliferation rate correlated significantly with ICG uptake (Spearman's rank correlation coefficient = 1.00, p < 0.001), and maximum ICG uptake was observed after 24 h incubation. ICG cellular uptake was significantly reduced by inhibition of clathrin-mediated endocytosis (p = 0.0004), and intracellular ICG significantly colocalized with a lysosomal marker within 30 min (Pearson's r = 0.8). On histological analysis of tumour tissue from three different sarcoma subtypes, ICG was observed within sarcoma cells as well as accumulating in paucicellular areas of haemorrhage and necrosis within the tumour microenvironment. Through quantification of fluorescence lifetime imaging of ICG, we were able to differentiate sarcoma cells from haemorrhage and necrosis within tumour tissue. Combining in vitro data with analysis of patient tissue, we propose that the uptake and accumulation of ICG in sarcomas is driven by a synergistic mechanism involving the enhanced permeability and retention effect combined with active tumour cell endocytosis of the dye. © 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.
Sparking malignancy: nicotine as a driver of stemness and metastasis in triple-negative breast cancer.
Simpkins C, Toska E
J Pathol · 2025 Dec · PMID 40923665 · Publisher ↗
Triple-negative breast cancer (TNBC) lacks expression of estrogen receptor (ER), progesterone receptor (PR), and HER2, and remains one of the most aggressive and therapeutically challenging breast cancer subtypes, marked...
Triple-negative breast cancer (TNBC) lacks expression of estrogen receptor (ER), progesterone receptor (PR), and HER2, and remains one of the most aggressive and therapeutically challenging breast cancer subtypes, marked by early relapse, metastasis, and limited targeted treatment options. In a recent study published in The Journal of Pathology, Kuo et al provide compelling evidence that nicotine exposure, whether from tobacco smoke or e-cigarette vapor, drives TNBC progression by promoting stem-like and metastatic phenotypes. Integrating clinical datasets, patient tissues, cell lines, and in vivo models, the authors demonstrate that nicotine enhances tumor aggressiveness via coordinated upregulation of CHRNA9 and IGF1R. Silencing either receptor attenuates nicotine-induced stemness, invasion, and metastasis, revealing a therapeutically actionable axis. High expression of CHRNA9 and IGF1R correlates with poor clinical outcomes and may define a nicotine-exposed TNBC subgroup that could benefit from IGF1R-targeted therapy or repurposed nicotinic receptor antagonists. These findings underscore the role of environmental exposures in shaping tumor biology and offer a mechanistic basis for the poorer prognosis observed in smokers with breast cancer. © 2025 The Pathological Society of Great Britain and Ireland.
Impact of NLRP1 Met1154Val and IL1B variants on gestational malaria: an unexplored role of NLRP1 in inflammasome activation by Plasmodium spp.
Leal VN, Ribeiro JA, Marra LG … +6 more , Rio AT, Reis EC, Wunderlich G, Dombrowski JG, Marinho CR, Pontillo A
J Pathol · 2025 Nov · PMID 40923647 · Full text
We hypothesized that variants in inflammasome-related genes could influence susceptibility to gestational malaria (GM). To test this, we conducted an association study in a cohort of pregnant women from a malaria-endemic...
We hypothesized that variants in inflammasome-related genes could influence susceptibility to gestational malaria (GM). To test this, we conducted an association study in a cohort of pregnant women from a malaria-endemic region in northern Brazil, assessing whether specific functional single nucleotide variants (SNVs) in inflammasome genes affect (1) the response to Plasmodium infection and (2) the development of placental malaria. Our findings revealed that the NLRP1 p.Met1154Val variant was associated with a protective effect against Plasmodium infection. Moreover, IL1B SNVs appeared more prevalent in severe cases. Additionally, multivariate analyses incorporating placental blood cytokines, growth factors, and immunohistochemical features revealed that the NLRP1 p.Met1154Val variant correlated with a healthier placental state, highlighting a potential protective role of the NLRP1 inflammasome in GM. For the first time, we showed that infected red blood cells induce NLRP1- and caspase-1-dependent pyroptosis in BeWo trophoblast cells, identifying a novel inflammasome pathway involved in GM pathogenesis. Our study identifies a genetic variant underlying NLRP1 contribution to GM and suggests that NLRP1 may be an under-explored inflammasome receptor in malaria and infected erythrocytes' sensing. © 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.
Cell state dynamics during early stages of serous endometrial carcinoma.
Flesken-Nikitin A, Pirtz MG, Ashe CS … +4 more , Ellenson LH, Yemelyanova A, Cosgrove BD, Nikitin AY
J Pathol · 2025 Nov · PMID 40923619 · Full text
Serous endometrial carcinoma (SEC) is one of the most lethal types of uterine cancer, responsible for about 40% of all endometrial cancer-related deaths. Cell state dynamics during the early stages of SEC remain largely...
Serous endometrial carcinoma (SEC) is one of the most lethal types of uterine cancer, responsible for about 40% of all endometrial cancer-related deaths. Cell state dynamics during the early stages of SEC remain largely unknown, thereby hindering early detection and treatment of this disease. Here, we provide a comprehensive census of cell types and their states for normal, predysplastic, and dysplastic endometrium in a genetic mouse model of SEC. We report that predysplastic changes are characterized by increasingly diverse immature luminal epithelial cell populations. The decrease in differentiated cell states is accompanied by the emergence of a 'single-cell and spatial transcriptome dysregulation' gene signature. This signature contains seven genes that predict poor patient prognosis and are promising diagnostic markers and therapeutic targets. In summary, our results suggest an important role of the luminal epithelial cell state in SEC pathogenesis and validate our mouse SEC model as a capable comparative platform for preclinical studies. © 2025 The Pathological Society of Great Britain and Ireland.
High-fat diets influence breast cancer progression by modulating CAF-immune cell interactions through PLAT signaling.
Li W, He J, Li J … +2 more , Xie X, Zhou P
J Pathol · 2025 Nov · PMID 40899255 · Publisher ↗
Breast cancer progression is profoundly influenced by interactions within the tumor microenvironment, particularly between cancer-associated fibroblasts and immune cells. This study investigated how cancer-associated fib...
Breast cancer progression is profoundly influenced by interactions within the tumor microenvironment, particularly between cancer-associated fibroblasts and immune cells. This study investigated how cancer-associated fibroblasts impact immune cells in the context of high-fat diets, focusing on key genes involved in these interactions. By analyzing breast cancer-related single-cell and bulk RNA sequencing data, we identified candidate genes in cancer-associated fibroblasts that influence immune cell behavior. Using the TCGA-BRCA dataset, we assessed the correlation between these genes and patient survival, as well as their role in immune cell infiltration and their association with clinical and immunological features. Our findings revealed significant cellular communication under high-fat diet conditions, with the cancer-associated fibroblast marker gene PLAT emerging as a key player linked to immune cell infiltration. Analysis of patient data from the GEO and TCGA-BRCA datasets revealed that in high-fat diet-induced breast cancer, patients exhibited reduced stromal scores, and stromal, immune, and ESTIMATE scores were significantly associated with clinical outcomes. In vivo murine experiments indicated that high-fat diets promoted tumor-associated macrophage infiltration while inhibiting CD4 T-cell activation. In vitro experiments confirmed that reduced PLAT expression facilitated M2 macrophage polarization and promoted cancer cell invasion and migration. Overall, our results highlight that high-fat diets can reshape the tumor microenvironment and accelerate breast cancer progression by modulating cancer-associated fibroblast-immune cell interactions, specifically via PLAT signaling. © 2025 The Pathological Society of Great Britain and Ireland.
Overexpression of mG writers METTL1 and BUD23 confers oncogenicity in kidney renal clear cell carcinoma.
Su A, Tieng J, Xu XS … +3 more , Tan RP, Feng Y, Wong JJ
J Pathol · 2025 Sep · PMID 40879514 · Full text
Emerging evidence shows that N7-methylguanosine (mG) modification and its writers contribute to the development of diverse cancers. However, the role of mG writers in kidney renal clear cell carcinoma (KIRC) remains uncl...
Emerging evidence shows that N7-methylguanosine (mG) modification and its writers contribute to the development of diverse cancers. However, the role of mG writers in kidney renal clear cell carcinoma (KIRC) remains unclear. In this study we show that the catalytic components of mG writers, METTL1 and BUD23, are overexpressed in advanced KIRC and are associated with worse overall survival. Knockdown of METTL1 or BUD23 inhibited cell proliferation, colony formation, and migration in KIRC cell lines, indicating their oncogenic role in KIRC. Furthermore, we observed that METTL1 and BUD23 expression was negatively correlated with the expression of key tumor suppressor genes commonly dysregulated in KIRC. We observed METTL1-mediated mG methylation in mRNAs expressed by these tumor suppressor genes, indicating that METTL1 may regulate these genes via mG modification. Overall, our study highlights the oncogenic role of METTL1 and BUD23 in KIRC and their potential as prognostic biomarkers and therapeutic targets in KIRC. © 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.
APC-related multiple salivary gland lesions: spatial transcriptomic analysis reveals progressive WNT activation.
Chan-Pak-Choon F, Beaumont C, Camacho Valenzuela J … +10 more , Leblanc J, Dahlum S, Siebert R, Thuot F, Pusztaszeri M, Chênevert J, Polak P, Cruz Marino T, Rivera B, Foulkes WD
J Pathol · 2025 Nov · PMID 40879644 · Full text
Attenuated familial adenomatous polyposis (AFAP) is a disorder caused by germline pathogenic variants in APC and is characterized by the presence of <100 colonic polyps and a high lifetime risk of developing colorectal c...
Attenuated familial adenomatous polyposis (AFAP) is a disorder caused by germline pathogenic variants in APC and is characterized by the presence of <100 colonic polyps and a high lifetime risk of developing colorectal cancer. Salivary gland basal cell tumours are uncommon and have not previously been reported in AFAP. We present a family with AFAP and multiple salivary gland tumours, including basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC). The colon and salivary gland tumours showed abnormal nuclear β-catenin staining. Genomic analysis of both parotid BCACs showed copy-number-neutral loss of heterozygosity (CNN-LOH) at the APC locus, implicating loss of full-length APC in the aetiology of parotid BCACs. In contrast, the submandibular BCAC showed a p.(Ile35Thr) CTNNB1 mutation. Spatial transcriptomic analysis revealed a stepwise increase in the expression of WNT pathway genes across the proband's salivary lesions, from benign (intercalated duct hyperplasia and BCAs) to malignant (BCACs). Our results showcase BCA and BCAC as potential new phenotypes of AFAP. © 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.
Characteristic miRNA profiles represent clinicopathological diversity of small cell lung cancer.
Horie M, Takumida H, Koba H … +11 more , Ueda T, Tanaka H, Suzuki M, Ito Y, Ito A, Kondo M, Suzuki HI, Matsumoto I, Yano S, Saito A, Maeda D
J Pathol · 2025 Oct · PMID 40842416 · Full text
Small cell lung cancer (SCLC) is classified into distinct molecular subtypes based on the expression patterns of four transcription regulators: achaete-scute homolog 1 (ASCL1), neuronal differentiation 1 (NEUROD1), POU c...
Small cell lung cancer (SCLC) is classified into distinct molecular subtypes based on the expression patterns of four transcription regulators: achaete-scute homolog 1 (ASCL1), neuronal differentiation 1 (NEUROD1), POU class 2 homeobox 3 (POU2F3), and yes-associated protein 1 (YAP1). MicroRNAs (miRNAs) play critical roles in cancer cellular processes but their subtype-specific implications in SCLC remain underexplored. Out of 46 surgically resected SCLC samples, miRNA visualization through in situ hybridization identified high expression of miR-375 in the ASCL1, NEUROD1, and ASCL1/NEUROD1 subtypes, and miR-9-5p in the POU2F3 subtype. Comprehensive enhancer profiling using SCLC cell lines indicated that miR-375 and miR-9-5p were regulated by super-enhancers in a subtype-specific manner. Multiplex immunohistochemistry by imaging mass cytometry found that the miR-9-5p-high SCLC was characterized by a higher stromal area ratio, increased numbers of CD8 T cells and CD163 macrophages in the intra-tumoral area, and an increased number of plasma cells in the stromal area, as compared with the miR-9-5p-low SCLC. Finally, clinicopathological analysis revealed that the miR-375-high SCLC was associated with YAP1 downregulation, increased serum pro-gastrin-releasing peptide levels, and poor prognosis. These findings highlight the critical role of super-enhancer-related miRNAs in the diversity of SCLC, and underscore the potential for novel diagnostic and prognostic biomarkers based on these subtype-specific miRNAs. © 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.
STING inhibition alleviates experimental peritoneal damage: potential therapeutic relevance for peritoneal dialysis.
Marchant V, García-Giménez J, González-Mateo GT … +10 more , Sandoval P, Tejedor-Santamaria L, Rayego-Mateos S, Ramos R, Jiménez-Heffernan JA, Ortiz A, Raby AC, López-Cabrera M, Ramos AM, Ruiz-Ortega M
J Pathol · 2025 Oct · PMID 40810380 · Full text
Peritoneal dialysis (PD) is a widely used kidney replacement therapy for patients with end-stage kidney disease. Nevertheless, long-term exposure to PD fluid can damage the peritoneal membrane, leading to ultrafiltration...
Peritoneal dialysis (PD) is a widely used kidney replacement therapy for patients with end-stage kidney disease. Nevertheless, long-term exposure to PD fluid can damage the peritoneal membrane, leading to ultrafiltration failure and, ultimately, discontinuation of PD. Investigation of the molecular mechanisms underlying this damage is essential for identifying new therapeutic targets to mitigate peritoneal deterioration in PD patients. To this end, we employed RNA sequencing in a preclinical model of peritoneal injury, induced by prolonged chlorhexidine (CHX) exposure, which revealed cytosolic DNA-sensing signaling as a novel pathway. Next, we demonstrated that key players in this pathway, such as the stimulator of interferon genes (STING) and its downstream signaling effectors (interferon regulatory factor 3, interferon-stimulated genes, and nuclear factor-κB signaling), were upregulated in experimental peritoneal damage. Moreover, increased STING expression was observed in human peritoneal biopsies from patients with PD. Subsequent studies in STING-deficient mice showed reduced proinflammatory gene expression and immune cell infiltration, together with inhibited nuclear factor-κB pathway activation at both early (10 days) and late (30 days) stages of CHX-induced peritoneal injury. STING deficiency also reduced peritoneal membrane thickening, fibrosis, and mesothelial-to-mesenchymal transition (MMT)-related changes in advanced CHX-induced damage. Furthermore, pharmacological inhibition of STING with C-176 attenuated CHX-induced peritoneal inflammation. Macrophages were identified as one of the STING-expressing cell types in the injured peritoneum. Hence, in vitro STING blockade in activated macrophages inhibited MMT in cultured mesothelial cells, suggesting that STING activation in this population may drive peritoneal fibrosis. Additionally, STING deficiency reduced peritoneal inflammation in S. epidermidis-induced peritonitis and decreased adhesion scores in a postsurgical intra-abdominal adhesion model. These findings identify STING as a pivotal mediator of peritoneal injury and support its potential as a novel therapeutic target to prevent PD-associated ultrafiltration failure. © 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.
Activation of PI3K and deletion of p53 in keratin 15-expressing mouse mammary cells induces tumor heterogeneity and plasticity modeling metaplastic breast cancer.
Nguyen KA, McLemore LE, Ke Y … +9 more , DePledge LN, Smith LP, Bian L, Aleman JD, Debretsion D, Wong E, Manning N, Wang XJ, Young CD
J Pathol · 2025 Oct · PMID 40804766 · Full text
Although relatively rare, metaplastic breast cancer responds poorly to traditional therapies compared to other subtypes. Accordingly, there is a need for novel animal models to understand its pathogenesis and plasticity....
Although relatively rare, metaplastic breast cancer responds poorly to traditional therapies compared to other subtypes. Accordingly, there is a need for novel animal models to understand its pathogenesis and plasticity. Since alterations in PIK3CA and TP53 genes are common in metaplastic breast cancer, we generated a mouse model of metaplastic breast cancer by driving Pik3ca activation and Trp53 loss in keratin 15-expressing mammary cells. In this model, male and female mice developed spontaneous mammary lesions, with malignancy reliant on loss of both Trp53 alleles. Importantly, tumors of this model are heterogeneous and resemble the mixed histology of metaplastic breast cancer by exhibiting squamous cell carcinoma, carcinosarcoma, and sarcoma features. We developed mammary cell lines from mouse tumors representing these different histological subtypes. These Pik3ca-activated tumor cells were more sensitive to alpelisib, a p110α-selective inhibitor approved by the FDA for the treatment of some PIK3CA mutant cancers, compared to Pik3ca WT cells. Additionally, some of these cell lines expressed the androgen receptor, a hormone receptor targeted in prostate cancer and currently under investigation as a therapeutic target in breast cancer. Transplantation of these cell lines into recipient mice maintained histological heterogeneity. Additionally, transplantation of either Epcam+ or Epcam- sorted cells, representing epithelial cell-like and nonepithelial cell-like, respectively, from a carcinosarcoma cell line, initiated tumor formation. Both sorted populations formed tumors with mixed histologic features, demonstrating plasticity arising from different tumor-initiating components. These new models of metaplastic breast cancer from relevant genetic drivers serve as a platform for identifying mechanisms driving plasticity that could inform therapeutic strategies based on histology and reveal how plasticity alters treatment efficacy. © 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.
MS4A4A-positive tumor-associated macrophages associate with poor prognosis and T-cell exhaustion in patients with urothelial carcinoma of the bladder.
Yang T, Sun X, Chen J … +8 more , Li J, Liu C, Yu J, Meng W, Wang Y, Yu H, Huang J, Wang B
J Pathol · 2025 Oct · PMID 40804697 · Publisher ↗
Tumor-associated macrophages (TAMs) have multiple potent functions in cancer representing important therapeutic targets. MS4A4A is a functional TAM marker with controversial implications for prognosis. This study aimed t...
Tumor-associated macrophages (TAMs) have multiple potent functions in cancer representing important therapeutic targets. MS4A4A is a functional TAM marker with controversial implications for prognosis. This study aimed to evaluate the association between MS4A4A TAM infiltration and clinical outcomes in urothelial carcinoma of the bladder (UCB), as well as their impact on the immune landscape. A total of 400 UCB patients from cohorts at Sun Yat-sen Memorial Hospital were analyzed. Immunohistochemistry was used to quantify MS4A4A TAMs and assess their spatial distribution alongside various immune components, evaluate the benefit of Bacillus Calmette-Guérin (BCG) immunotherapy, and analyze survival outcomes. Additionally, matched UCB tissues were examined before and after recurrence or progression. We observed that MS4A4A TAMs were present at higher levels in the stromal region compared to the intratumoral region, and correlated with advanced tumor stage and poor prognosis in both regions. No significant difference was observed in the number of MS4A4A TAMs before and after recurrence/progression in the same patient. Stromal MS4A4A TAMs were negatively correlated with BCG efficacy and recurrence-free survival. These TAMs were positively associated with CD8 T cells, Foxp3 regulatory T cells, immune checkpoints (PD-1, LAG-3, HAVcr-2, TIGIT), and anti-inflammatory molecules (TGF-β1, IL-4) in the same respective regions. Additionally, MS4A4A TAMs expressed high levels of TGF-β1 and HAVcr-2 in UCB tissues. In vitro, IL-4 induced MS4A4A expression in mouse bone marrow-derived macrophages, while Ms4a4a knockdown reduced the anti-inflammatory molecule Arg1 and increased pro-inflammatory molecule Nos2 expression. These findings demonstrate that MS4A4A is a reliable prognostic marker and predictor of BCG response in UCB, highlighting its role in shaping the immune landscape and immunotherapy outcomes. © 2025 The Pathological Society of Great Britain and Ireland.
Spatial transcriptomics exploration of the primary neuroblastoma microenvironment in archived FFPE samples unveils novel paracrine interactions.
Siaw JT, Merseburger P, Borenäs M … +8 more , Jansson C, Karlsson J, Claeys A, Jennische E, Lind DE, Gisselsson Nord D, Palmer RH, Van den Eynden J
J Pathol · 2025 Oct · PMID 40778592 · Full text
High-risk neuroblastomas exhibit a high degree of intratumoral heterogeneity. Single-cell RNA sequencing has greatly improved our understanding of these tumors, but the method lacks cellular tissue context and spatial in...
High-risk neuroblastomas exhibit a high degree of intratumoral heterogeneity. Single-cell RNA sequencing has greatly improved our understanding of these tumors, but the method lacks cellular tissue context and spatial information about local signaling dynamics. To address this, we profiled untreated and chemotherapy-treated high-risk neuroblastomas from archived, formalin-fixed, paraffin-embedded (FFPE) tissues from two patients using spatial transcriptomics. We confirmed the transcriptional and cellular heterogeneous nature of the neuroblastoma microenvironment and identified several unique spatial niches and patterns. In one of the treated tumors, a spatially constrained cluster of undifferentiated and 11p-gained cancer cells was identified, surrounded by a rim of macrophages. A signaling interaction between the chemokine CCL18 and its receptor PITPNM3 was predicted between these cells. In the other tumor, we identified a stromal cluster with high transcriptional similarity to the adrenal cortex. These adrenocortical-like cells expressed several oncogenic ligand-encoding genes (e.g. ALKAL2 and NRTN), which were predicted to communicate with neighboring cancer cells that expressed the corresponding receptors (e.g. ALK, RET). Several of these interactions were further validated experimentally and were shown to be clinically relevant. Collectively, our spatial analysis identifies multiple previously unrecognized signaling axes that may offer novel therapeutic options in neuroblastoma. © 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.
Revisionist history uncovers a simplified molecular-based classification of differentiated thyroid cancer.
Asa SL, Baloch Z, Jung CK … +6 more , Cipriani NA, Gamboa-Domínguez A, Juhlin CC, Riddle ND, Stojanov IJ, Mete O
J Pathol · 2025 Oct · PMID 40762994 · Full text
The diagnostic classification of differentiated thyroid cancer has been a longstanding topic of debate among pathologists, largely due to high interobserver variability. This complexity has increased with the expansion o...
The diagnostic classification of differentiated thyroid cancer has been a longstanding topic of debate among pathologists, largely due to high interobserver variability. This complexity has increased with the expansion of tumor types and subtypes. However, molecular studies have revealed a simpler and less controversial approach, categorizing these lesions into RAS-like and BRAF p.V600E-like neoplasms. In this review, the authors propose a classification that is based on, but does not require, the confirmation of molecular alterations. This approach aligns with and helps inform the pattern-based assessment of tumor growth and cytologic atypia that is already widely used in clinical practice for preoperative patient stratification and tumor diagnosis, and promises a simpler conceptual understanding. © 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.
Increased expression of the PIEZO2 mechanoreceptor in fibroblasts and endothelial cells within the lymphatic and vascular vessels of keloids.
Akita S, Ikehara S, Kiuchi M … +13 more , Kokubo K, Azuma K, Ohki S, Matsuyama H, Kadarman JT, Hosokawa Y, Akimoto Y, Inaba Y, Hanaoka H, Mitsukawa N, Hirahara K, Nakayama T, Ikehara Y
J Pathol · 2025 Sep · PMID 40742741 · Full text
Keloids are scars that grow abnormally due to excessive extracellular matrix production by fibroblasts and increased angiogenesis. Chronic tension is implicated in their growth, but the exact pathology remains unclear. T...
Keloids are scars that grow abnormally due to excessive extracellular matrix production by fibroblasts and increased angiogenesis. Chronic tension is implicated in their growth, but the exact pathology remains unclear. This study investigated the increased expression of molecules responsible for sensing pressure in keloids compared with lymphedema, which is also a non-tumorous fibroproliferative disease caused by another etiology. Higher expression levels of COL1A2, PIEZO2, and POSTN were observed in the keloid group compared with the lymphedema group. PIEZO2 expression levels showed a strong correlation with both COL1A2 (r = 0.9252, 95% CI 0.8474-0.9641, p < 0.001) and POSTN (r = 0.9118, 95% CI 0.8213-0.9575, p < 0.001). Additionally, PIEZO2 expression levels were significantly higher in recurrent keloids than in non-recurrent keloids (3,032.5 ± 1,090.2 versus 1,241.9 ± 860.7, p = 0.032). Analysis of gene expression at the single-cell level found upregulation of PIEZO2 in vascular and lymphatic endothelial cells, and a subgroup of fibroblasts. Additionally, COL1A1, COL1A2, COL3A1, and POSTN expression was also increased in the fibroblast subgroup. Furthermore, in fibroblasts with high PIEZO2 expression, extracellular matrix collagen production signaling was augmented. Histological analysis confirmed the presence of PIEZO2-positive cells in the perivascular stroma active area of keloid tissue, together with inflammatory cells. Therefore, since PIEZO2-positive cells are highly expressed specifically in keloids and are deeply involved in their recurrence and activity, we propose that the pathogenesis of keloids is constructed by PIEZO2-positive cells. © 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.
Partial-EMT cell state correlates with single cell pattern of invasion in head and neck SCC keratinocytes.
Park PH, Israel LE, Alexander MH … +6 more , Tartaglia G, South HG, Han S, Curry JM, Luginbuhl AJ, South AP
J Pathol · 2025 Sep · PMID 40736379 · Full text
The presence of a single metastatic lesion significantly decreases overall survival in patients with head and neck squamous cell carcinoma (HNSCC), and invasion of malignant keratinocytes is one of the initial steps requ...
The presence of a single metastatic lesion significantly decreases overall survival in patients with head and neck squamous cell carcinoma (HNSCC), and invasion of malignant keratinocytes is one of the initial steps required for HNSCC metastasis. Histological grading of tumor cell invasion predicts outcome in HNSCC, yet the molecular factors that determine the extent of invasion, and subsequent grading are not fully understood. Using a 3D organ culture model and multiple patient-derived HNSCC keratinocytes representing all major anatomical subsites of the disease, we identified a range of cell states that represent a continuum of epithelial-to-mesenchymal (EMT) characteristics. We also demonstrated how these cell states change in response to TGF-beta stimulation and co-culture with cancer-associated fibroblasts in organ cultures. Using 3D culture models that recapitulate the pattern of invasion seen in primary tumors from which the keratinocytes were derived, we identified distinct clusters of partial-EMT marker expression in individual patient HNSCC keratinocyte populations. Partial-EMT transcription factors were correlated with separate invasive characteristics, and we demonstrated that ZEB2 (a known EMT driver) and HIC1 (a novel EMT driver) are central nodes in HNSCC keratinocyte invasion. Collectively, our findings refine the concepts of partial-EMT and tumor cell invasion, and identify potential therapeutic targets for future development. © 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.
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