The Journal of Pathology最新文献

{"title":"Activation of PI3K and deletion of p53 in keratin 15-expressing mouse mammary cells induces tumor heterogeneity and plasticity modeling metaplastic breast cancer.","authors":"Khoa A Nguyen, Lauren E McLemore, Yao Ke, Lisa N DePledge, Lynelle P Smith, Li Bian, John D Aleman, David Debretsion, Erica Wong, Nicole Manning, Xiao-Jing Wang, Christian D Young","doi":"10.1002/path.6463","DOIUrl":"https://doi.org/10.1002/path.6463","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144843954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial transcriptomics exploration of the primary neuroblastoma microenvironment in archived FFPE samples unveils novel paracrine interactions.","authors":"Joachim T Siaw, Peter Merseburger, Marcus Borenäs, Caroline Jansson, Jenny Karlsson, Arne Claeys, Eva Jennische, Dan E Lind, David Gisselsson Nord, Ruth H Palmer, Jimmy Van den Eynden","doi":"10.1002/path.6457","DOIUrl":"https://doi.org/10.1002/path.6457","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144797703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revisionist history uncovers a simplified molecular-based classification of differentiated thyroid cancer.","authors":"Sylvia L Asa, Zubair Baloch, Chan Kwon Jung, Nicole A Cipriani, Armando Gamboa-Domínguez, C Christofer Juhlin, Nicole D Riddle, Ivan J Stojanov, Ozgur Mete","doi":"10.1002/path.6456","DOIUrl":"https://doi.org/10.1002/path.6456","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144787934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased expression of the PIEZO2 mechanoreceptor in fibroblasts and endothelial cells within the lymphatic and vascular vessels of keloids","authors":"Shinsuke Akita,&nbsp;Sanae Ikehara,&nbsp;Masahiro Kiuchi,&nbsp;Kota Kokubo,&nbsp;Kazuhiko Azuma,&nbsp;Syouta Ohki,&nbsp;Hiroyuki Matsuyama,&nbsp;Joceline Theda Kadarman,&nbsp;Yohei Hosokawa,&nbsp;Yoshihiro Akimoto,&nbsp;Yosuke Inaba,&nbsp;Hideki Hanaoka,&nbsp;Nobuyuki Mitsukawa,&nbsp;Kiyoshi Hirahara,&nbsp;Toshinori Nakayama,&nbsp;Yuzuru Ikehara","doi":"10.1002/path.6455","DOIUrl":"10.1002/path.6455","url":null,"abstract":"<p>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 <i>COL1A2</i>, <i>PIEZO2</i>, and <i>POSTN</i> were observed in the keloid group compared with the lymphedema group. <i>PIEZO2</i> expression levels showed a strong correlation with both <i>COL1A2</i> (<i>r</i> = 0.9252, 95% CI 0.8474–0.9641, <i>p</i> &lt; 0.001) and <i>POSTN</i> (<i>r</i> = 0.9118, 95% CI 0.8213–0.9575, <i>p &lt;</i> 0.001). Additionally, <i>PIEZO2</i> 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, <i>p</i> = 0.032). Analysis of gene expression at the single-cell level found upregulation of <i>PIEZO2</i> in vascular and lymphatic endothelial cells, and a subgroup of fibroblasts. Additionally, <i>COL1A1</i>, <i>COL1A2</i>, <i>COL3A1</i>, and <i>POSTN</i> expression was also increased in the fibroblast subgroup. Furthermore, in fibroblasts with high <i>PIEZO2</i> 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). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"267 1","pages":"105-119"},"PeriodicalIF":5.2,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/path.6455","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144758831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The importance of tumor microenvironment modulations in the progression of pancreatic intraductal papillary mucinous neoplasms^†.","authors":"Antonio Pea, Claudio Luchini","doi":"10.1002/path.6460","DOIUrl":"https://doi.org/10.1002/path.6460","url":null,"abstract":"<p><p>Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas have attracted substantial attention since they represent the most prevalent macroscopic precursor of pancreatic cancer. Most lesions show an epithelium with low-grade dysplasia and will remain indolent and unknown to the patient. Notably, a subgroup of IPMNs will progress to invasive cancer through a stepwise process characterized by the accumulation of specific genomic alterations and concomitant modifications of the tumor microenvironment (TME). The manuscript of Jamouss et al, recently published in The Journal of Pathology, expands the current knowledge on TME dynamics in IPMNs. The neoplastic progression of IPMNs is paralleled by a shift toward an immunosuppressive TME, with depletion of cytotoxic T cells, elevated expression of immune checkpoint molecules, including PD-L1 and VISTA, and increased density of macrophages. Overall, TME modifications are crucial in the progression of pancreatic IPMNs, calling for potential therapeutic strategies focused on TME modulations for cancer interception. © 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.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Partial-EMT cell state correlates with single cell pattern of invasion in head and neck SCC keratinocytes","authors":"Pyung Hun Park,&nbsp;Lauren E Israel,&nbsp;Michael H Alexander,&nbsp;Grace Tartaglia,&nbsp;Harvey G South,&nbsp;Suhao Han,&nbsp;Joseph M Curry,&nbsp;Adam J Luginbuhl,&nbsp;Andrew P South","doi":"10.1002/path.6454","DOIUrl":"10.1002/path.6454","url":null,"abstract":"<p>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). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"267 1","pages":"92-104"},"PeriodicalIF":5.2,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12313228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New insights into the genetic progression of cancer through longitudinal analysis of oral lesions.","authors":"Leon J Wils, Jos B Poell, Arjen Brink, Laura An Peferoen, Ilkay Evren, Elisabeth R Brouns, Jan Gam de Visscher, Erik H van der Meij, Elisabeth Bloemena, Ruud H Brakenhoff","doi":"10.1002/path.6449","DOIUrl":"https://doi.org/10.1002/path.6449","url":null,"abstract":"<p><p>Genetic progression models of cancer continue to determine the roadmap of carcinogenesis, although the sequence of genetic events is inferred rather than empirically determined through longitudinal analyses. Here, we present a unique longitudinal study of oral leukoplakia lesions that transformed into carcinoma. Lesions were followed from initial diagnosis through to malignant transformation. For each lesion, biopsies at baseline, the carcinoma, and all available intermediate biopsies were studied for the presence of dysplasia, genomic copy number aberrations, and mutations in selected head and neck cancer genes. Using this information, the phylogenetic history of all carcinomas was reconstructed within the context of applied interventions. In total, 71 biopsies of 21 lesions were studied. The median time to malignant transformation was 60 months. Oral carcinogenesis emerged as a multi-(sub)clonal process. Treatment interventions appeared to impact clonal selection, although lesions always remained after excision. Notably, the lesions demonstrated different routes of progression. A canonical pattern of progression was observed, characterized by longitudinal accumulation of abnormal morphology and genetic changes. However, some lesions followed an alternative, stable pattern of oncogenic progression, with no apparent increase in morphological changes or accumulation of genetic aberrations. This latter pattern appeared to be associated with the development of previously identified 'copy number quiet' head and neck tumors. This study provides a novel perspective on the temporal evolution of oral leukoplakia and the different routes to cancer progression and highlights the key role of multiclonal field cancerization in lesion recurrence and cancer 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.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maternal-foetal immune rejection: parallels between placental CHI and allograft rejection^†.","authors":"Panicos Shangaris, María Teresa Martín Monreal","doi":"10.1002/path.6459","DOIUrl":"https://doi.org/10.1002/path.6459","url":null,"abstract":"<p><p>Chronic histiocytic intervillositis (CHI) is a rare placental inflammatory lesion increasingly viewed through maternal-foetal immune rejection. In this invited commentary, we discuss how a recent study bolsters the paradigm that CHI represents maternal immune rejection of the semi-allogeneic foetus, analogous to antibody-mediated rejection in organ transplantation. We highlight the shared histological and molecular features between CHI and kidney allograft rejection, including macrophage-dominated inflammation, complement activation, and interferon-gamma-driven gene expression signatures and explore the implications of this common pathogenesis for clinical practice. Recognising CHI as an alloimmune process opens new avenues for early prediction, diagnosis, and intervention. We particularly emphasise the need for early identification of CHI, even in a first pregnancy, where no prior obstetric history exists to raise suspicion. Finally, we outline how transplant immunotherapy principles (e.g. immunosuppression and immune modulation) could transform the management of CHI, and we call for forward-looking research that bridges immune pathology, maternal-foetal medicine, and translational therapeutics to improve pregnancy outcomes. © 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.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LncRNA GAS5 ameliorates intestinal barrier injury by targeting the miR-223-3p/FBXW7 axis and inactivating NF-κB signaling in vitro and in vivo","authors":"Zhen Wang,&nbsp;Jin Yuan,&nbsp;Xuemei Qin,&nbsp;Hongzhen Yin,&nbsp;Changshun Zhong,&nbsp;Rui Qu,&nbsp;Guannan Wang","doi":"10.1002/path.6440","DOIUrl":"10.1002/path.6440","url":null,"abstract":"<p>Sepsis is a potentially lethal syndrome that leads to multiple organ dysfunction. LncRNA <i>GAS5</i> is closely related to sepsis; however, its detailed functions and mechanism in sepsis-triggered intestinal barrier dysfunction are unclear. In this study, NCM460 cells were stimulated with lipopolysaccharide (LPS) to mimic septic intestinal injury <i>in vitro</i>, and a sepsis mouse model was established via the cecum ligation and perforation method. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining was performed for cell apoptosis evaluation. RNA and protein levels were examined by RT-qPCR and western blotting, respectively. Additionally, cell permeability and intestinal mucosa permeability were measured. ELISA was utilized to detect inflammatory cytokine production. H&amp;E staining was conducted for histologic examination of the intestine. Luciferase reporter and RNA pull-down assays were employed to verify the interaction between <i>GAS5</i>, <i>miR-223-3p</i>, and <i>FBXW7</i>. The results showed that <i>GAS5</i> was downregulated in LPS-exposed NCM460 cells as well as the intestine of septic mice. <i>GAS5</i> overexpression mitigated LPS-triggered intestinal epithelial cell damage and apoptosis <i>in vitro</i> and reduced pathological damage, inflammation, and intestinal hyperpermeability in septic mice. <i>GAS5</i> upregulated <i>FBXW7</i> by interacting with <i>miR-223-3p</i>. Depletion of <i>FBXW7</i> reversed the protective effects of <i>GAS5</i> overexpression <i>in vitro</i>. Additionally, <i>GAS5</i> overexpression inactivated NF-κB signaling in LPS-stimulated NCM460 cells. NF-κB inactivation exerted effects in septic mice similar to those observed with <i>GAS5</i> overexpression. In conclusion, <i>GAS5</i> ameliorates sepsis-triggered intestinal barrier disruption by mediating the <i>miR-223-3p</i>/<i>FBXW7</i> axis and inactivating NF-κB signaling. © 2025 The Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"267 1","pages":"25-39"},"PeriodicalIF":5.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial transcriptomics identifies SPARC as a prognostic marker in interstitial lung diseases","authors":"Takayuki Niitsu,&nbsp;Toshiaki Kataoka,&nbsp;Kiyoharu Fukushima,&nbsp;Daisuke Motooka,&nbsp;Shigeyuki Shichino,&nbsp;Yayoi Natsume-Kitatani,&nbsp;Hideya Kitamura,&nbsp;Takashi Niwa,&nbsp;Tomohisa Baba,&nbsp;Daisuke Okuzaki,&nbsp;Atsushi Kumanogoh,&nbsp;Shizuo Akira,&nbsp;Koji Okudela,&nbsp;Takashi Ogura","doi":"10.1002/path.6451","DOIUrl":"10.1002/path.6451","url":null,"abstract":"<p>Interstitial lung diseases (ILDs) encompass a diverse group of pulmonary disorders, with progressive fibrosis leading to poor prognosis. Here we aimed to identify key molecules involved in progressive fibrosis across various ILDs, using spatial transcriptomics (ST). ST analysis (Visium) was performed on lung cryobiopsy specimens from five patients with various ILDs. Two cases, rich in young fibrotic lesions, as defined by fibroblastic foci and destructive alveolar organization, were selected for spatial high-dimensional weighted gene coexpression network analysis (hdWGCNA) to identify key gene networks with biological significance in active fibrosis. We utilized public single-cell RNA sequencing datasets of various ILDs, performed enrichment analysis and trajectory-based differential expression analysis, and quantified cell–cell communication to evaluate the involvement of the spatially extracted module in fibrosis. Immunohistochemical staining of the extracted molecules was performed. Using hdWGCNA, we identified a distinct gene module (the SM2 module) enriched in young fibrotic lesions. The SM2 module was characterized by distinct features of fibroblast activation that were represented across various lesions. Key hub genes within this module, including <i>COL1A2</i>, <i>COL3A1</i>, <i>COL1A1</i>, and <i>SPARC</i>, formed a robust coexpression network. Immunohistochemical staining showed that SPARC, a component of the SM2 module, was highly expressed in young fibrotic lesions, but not in old scarring lesions, across various ILDs. To assess the prognostic significance of SPARC immunohistochemical expression, we extended our analysis to a cohort of 71 patients with unclassifiable ILDs (uILDs), a particularly heterogeneous subtype with unclear pathogenesis and limited treatment options. Higher SPARC levels in the upper, lower, or both lung lobes in uILD were significantly associated with poor overall survival. In summary, an integrated cross-disease approach using ST revealed key gene expression patterns central to active fibrosis and successfully identified SPARC as a potentially beneficial prognostic marker. © 2025 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"267 1","pages":"79-91"},"PeriodicalIF":5.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/path.6451","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}