The Journal of Pathology最新文献

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.