American Journal of Pathology最新文献_第4页

Single-Cell Sequencing Plus Spatial Transcriptomics 单细胞测序加空间转录组学：解剖肿瘤异质性、免疫抑制和ASPSCR1::TFE3肾细胞癌的潜在靶点。

IF 4.9 2区医学

American Journal of Pathology Pub Date : 2026-07-01 Epub Date: 2026-04-18 DOI: 10.1016/j.ajpath.2026.04.001

Yingjing Wang, Xia Wu, Xiao Cheng, Rong Fang, Ping Zhang, Heli Wang, Senxiao Yu, Huizhi Zhang, Ming Zhao

{"title":"Single-Cell Sequencing Plus Spatial Transcriptomics","authors":"Yingjing Wang, Xia Wu, Xiao Cheng, Rong Fang, Ping Zhang, Heli Wang, Senxiao Yu, Huizhi Zhang, Ming Zhao","doi":"10.1016/j.ajpath.2026.04.001","DOIUrl":"10.1016/j.ajpath.2026.04.001","url":null,"abstract":"<div><div><em>ASPSCR1::TFE3</em> renal cell carcinoma (RCC) is a rare subtype with frequent lymph node metastasis and poor prognosis. Its obscure pathogenesis and immune microenvironment greatly limit clinical management. Here, this study integrated single-cell sequencing and high-resolution spatial transcriptomics to profile formalin-fixed paraffin-embedded specimens of <em>ASPSCR1</em>::<em>TFE3</em> RCC and clear cell RCC. Marked distinctions in tumor and immune landscapes were identified between the two subtypes. Clear cell RCC was enriched in interferon response and hypoxia pathways, while <em>ASPSCR1</em>::<em>TFE3</em> RCC favored oxidative phosphorylation and epithelial-mesenchymal transition. Tumor cells were classified into C3/C4 clusters; the metastasis-related C3 subtype highly expressed pro-invasive genes including <em>MDK</em>, <em>MMP7</em>, and <em>VCAN</em>. <em>ASPSCR1</em>::<em>TFE3</em> RCC displayed an immunosuppressive microenvironment with abundant macrophages and exhausted T/natural killer cells. <em>MDK-LRP1</em> crosstalk between tumor cells and macrophages facilitated immune escape. These findings define <em>ASPSCR1</em>::<em>TFE3</em> RCC as a highly metastatic, immunosuppressive malignancy driven by C3 enrichment and elevated <em>MDK</em>, offering novel targets for targeted and immunotherapeutic strategies.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 7","pages":"Pages 1514-1529"},"PeriodicalIF":4.9,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147727868","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}

引用次数: 0

Characterizing the Discordance between AT-Rich Interacting Domain 1A Protein and Genotype in Endometrioid-Type Endometrial Tumors 子宫内膜样型子宫内膜肿瘤中ARID1A蛋白与基因型差异的研究

IF 4.9 2区医学

American Journal of Pathology Pub Date : 2026-07-01 Epub Date: 2026-05-07 DOI: 10.1016/j.ajpath.2026.04.010

Savannah E. LaBuda, Katherine Spence, Rahul R. Niranjan, Isurika Weeranshige, Macy L. Osborne-Frazier, Russell R. Broaddus, Andrew B. Gladden

{"title":"Characterizing the Discordance between AT-Rich Interacting Domain 1A Protein and Genotype in Endometrioid-Type Endometrial Tumors","authors":"Savannah E. LaBuda, Katherine Spence, Rahul R. Niranjan, Isurika Weeranshige, Macy L. Osborne-Frazier, Russell R. Broaddus, Andrew B. Gladden","doi":"10.1016/j.ajpath.2026.04.010","DOIUrl":"10.1016/j.ajpath.2026.04.010","url":null,"abstract":"<div><div><em>ARID1A</em> is one of the most frequently mutated genes in endometrial cancer, with approximately 40% of patients harboring an <em>ARID1A</em> mutation. However, relatively little is known about how AT-rich interacting domain 1A (ARID1A) protein loss shapes endometrial cancer pathogenesis. Mounting evidence from other malignancies suggests that ARID1A protein can be regulated post-translationally, independent of genotype. However, most studies in endometrial cancer evaluate genotype alone, overlooking the potential for alternative mechanisms of ARID1A loss. To address this gap, ARID1A protein expression and genotype were examined in endometrioid tumors, and associated transcriptional changes were characterized. Evaluation of ARID1A protein in 71 human endometrioid tumors demonstrates that protein loss can occur regardless of <em>ARID1A</em> genotype. Retention or deficiency of ARID1A protein was not significantly related to variant allele frequency or location of mutation in human tumors with mutant <em>ARID1A</em>. A human endometrial cancer cell model suggests that ARID1A protein loss can occur through proteasomal degradation. Furthermore, ARID1A protein expression was found to be a predictor of worse overall survival in The Cancer Genome Atlas cohort of <em>ARID1A</em> wild-type endometrioid tumors. Spatial transcriptomics of 16 human endometrioid tumors revealed that both genotype and protein expression of <em>ARID1A</em> play a role in shaping unique transcriptional signatures in endometrial cancer and can be used to predict patient prognosis. Suggesting evaluation of ARID1A should not be done solely by sequencing techniques.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 7","pages":"Pages 1530-1545"},"PeriodicalIF":4.9,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863407","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}

引用次数: 0

Next-Generation Disease Profiling by Integrating Histopathology with Spatial Multi-Omics Data 整合组织病理学与空间多组学数据的新一代疾病分析。

IF 4.9 2区医学

American Journal of Pathology Pub Date : 2026-07-01 Epub Date: 2026-04-20 DOI: 10.1016/j.ajpath.2026.03.014

Priyank Patel, Alexander Klimowicz

{"title":"Next-Generation Disease Profiling by Integrating Histopathology with Spatial Multi-Omics Data","authors":"Priyank Patel, Alexander Klimowicz","doi":"10.1016/j.ajpath.2026.03.014","DOIUrl":"10.1016/j.ajpath.2026.03.014","url":null,"abstract":"<div><div>The field of pathology has experienced several transformative changes in recent years with the advent of digital pathology and spatial multi-omics. These technologies have enhanced every aspect of pathology practice, from streamlining daily workflows to generating high-fidelity multi-omics data that provide pathologists with novel tools to refine disease profiling and clinical diagnosis. Each layer of multimodal data (genomic, metabolomic, proteomic, or transcriptomic) has uncovered a distinct facet of disease pathologies, and combined with machine learning/artificial intelligence–based data analysis and pattern recognition models, has provided holistic understanding of regulatory mechanisms underpinning them. However, high-dimensional data have far exceeded the volume, scale, and complexity of immunostaining methods implemented by pathologists and, thus, have generated significant challenges related to deconvolution, interpretation, and clinical translation. Furthermore, these multimodal studies have predominantly relied on computational methods to process data and extract disease-relevant insights, thus raising questions around relevance or role of a pathologist in this new era of multi-omics. This review will provide a perspective on the evolving fields of molecular histopathology and spatial -omics, leveraging them to approach disease profiling, and redefining the role of a pathologist during this process.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 7","pages":"Pages 1427-1438"},"PeriodicalIF":4.9,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759944","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}

引用次数: 0

Spatially Resolved Obesity-Driven Molecular Changes in Early Breast Cancer 空间分辨肥胖驱动的早期乳腺癌分子变化。

IF 4.9 2区医学

American Journal of Pathology Pub Date : 2026-07-01 Epub Date: 2026-05-01 DOI: 10.1016/j.ajpath.2026.03.016

Cole Hladik, Malika Sekhri, Haoning Howard Cen, Sugantha Priya Elayapillai, Schuyler Lee, Bifeng Gao, William Dooley, Ty Milligan, Haddon Hill, Alexander Filatenkov, Elizabeth A. Wellberg, Bethany N. Hannafon

{"title":"Spatially Resolved Obesity-Driven Molecular Changes in Early Breast Cancer","authors":"Cole Hladik, Malika Sekhri, Haoning Howard Cen, Sugantha Priya Elayapillai, Schuyler Lee, Bifeng Gao, William Dooley, Ty Milligan, Haddon Hill, Alexander Filatenkov, Elizabeth A. Wellberg, Bethany N. Hannafon","doi":"10.1016/j.ajpath.2026.03.016","DOIUrl":"10.1016/j.ajpath.2026.03.016","url":null,"abstract":"<div><div>Obesity is an established risk factor for invasive breast ductal carcinoma (IDC); however, the specific molecular heterogeneity distinguishing IDC from ductal carcinoma <em>in situ</em> (DCIS) within the obese tumor microenvironment is not well defined. In the current study, spatially resolved transcriptomics was used to profile the epithelial, stromal, and immune compartments of DCIS and IDC lesions stratified by host body mass index, categorized as non-obese (≤29.9 kg/m<sup>2</sup>) or obese (≥30 kg/m<sup>2</sup>). These analyses reveal that the transcriptional signatures defining the invasive state differ significantly across body mass index categories. In non-obese patients, IDC lesions exhibited canonical profiles driven by proliferation and epithelial-to-mesenchymal transition, compared with DCIS. Conversely, the obese setting was characterized by a distinct stress-adaptive phenotype, enriched for metabolic adjustment, oxidative stress response, and inflammatory signaling. The epithelial component was accompanied by a fibro-inflammatory stromal signature and an immunosuppressive niche characterized by B-cell depletion and M2 macrophage enrichment. Furthermore, sulfatase 2 (SULF2), an extracellular endosulfatase involved in extracellular matrix organization and signaling, was consistently up-regulated within the obese epithelium, providing a plausible link between metabolic stress and structural remodeling. Collectively, these data indicate obesity-associated differences consistent with an alternative invasive transcriptional program that is less dominated by classical proliferative drivers in this cohort. Consequently, standard prognostic markers may be context dependent, highlighting the need to integrate metabolic health into precision risk stratification.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 7","pages":"Pages 1471-1486"},"PeriodicalIF":4.9,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809243","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}

引用次数: 0

Meeting Abstracts 会议摘要

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2026-05-01 Epub Date: 2026-05-12 DOI: 10.1016/j.ajpath.2026.04.003

引用次数: 0

Title Page 标题页

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2026-05-01 Epub Date: 2026-05-12 DOI: 10.1016/S0002-9440(26)00104-5

引用次数: 0

Optic Atrophy 1–Mediated Mitochondrial Hyperfusion Orchestrates Yes-Associated Protein 1 Nuclear Translocation to Sustain Ameloblastoma Stemness opa1介导的线粒体低灌注协调YAP1核易位以维持成釉细胞瘤的干性。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2026-03-01 Epub Date: 2025-12-30 DOI: 10.1016/j.ajpath.2025.12.002

Jia-Jie Liang , Rui-Fang Li , Yi-Han Bian , Lu-Xuan Liu , Zhuo-Jian Li , Bing Liu , Lin-Zhou Zhang

{"title":"Optic Atrophy 1–Mediated Mitochondrial Hyperfusion Orchestrates Yes-Associated Protein 1 Nuclear Translocation to Sustain Ameloblastoma Stemness","authors":"Jia-Jie Liang , Rui-Fang Li , Yi-Han Bian , Lu-Xuan Liu , Zhuo-Jian Li , Bing Liu , Lin-Zhou Zhang","doi":"10.1016/j.ajpath.2025.12.002","DOIUrl":"10.1016/j.ajpath.2025.12.002","url":null,"abstract":"<div><div>Ameloblastoma (AM), a locally aggressive odontogenic tumor, exhibits elusive pathogenesis. Here, optic atrophy 1 (OPA1)–mediated mitochondrial hyperfusion was identified as a driver of tumor stemness and progression. Single-cell transcriptomics of primary AM specimens revealed mitochondrial fusion<sup>High</sup> epithelial subpopulations exhibiting enriched stemness pathways. A striking up-regulation of OPA1 was observed in AM tissues, establishing a robust correlation between elevated OPA1 expression and up-regulated stemness markers, whereas functional experiments demonstrated that OPA1 overexpression amplifies self-renewal capacity and invasive aggression in human telomerase reverse transcriptase (hTERT)<sup>+</sup>-AM cells. Mechanistically, mitochondrial hyperfusion suppresses Hippo signaling, enabling yes-associated protein 1 (YAP1) nuclear translocation and TEA domain transcription factor (TEAD)–dependent transcription. OPA1-overexpressing cells exhibited robust nuclear YAP1 enrichment, driving stem-like expansion. Critically, clinical analysis established OPA1<sup>High</sup> tumors as having elevated growth rates, consolidating mitochondrial hyperfusion as a prognostic determinant. Therapeutically, MYLS22—a first-in-class OPA1 inhibitor—suppressed mitochondrial hyperfusion and reduced stemness in patient-derived organoids. The present work unveils an OPA1-mediated mitochondrial fusion–YAP1 nuclear translocation axis as the cornerstone of AM stemness, proposing OPA1 as a druggable target for this recalcitrant tumor.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 3","pages":"Pages 836-849"},"PeriodicalIF":3.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888584","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}

引用次数: 0

Targeting N-Cadherin and Tubulin α 1A in Neuroblastoma Bone Marrow Metastasis 靶向CDH2和TUBA1A在神经母细胞瘤骨髓转移中的作用：来自单细胞分析和药物筛选的见解

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2026-03-01 Epub Date: 2026-01-02 DOI: 10.1016/j.ajpath.2025.12.004

Jiasi Zhang, Dedong Zhang, Yichen Lei, Siying Liu, Yongbing Zhu, Qun Hu, Xiaoyan Zhao, Aiguo Liu

{"title":"Targeting N-Cadherin and Tubulin α 1A in Neuroblastoma Bone Marrow Metastasis","authors":"Jiasi Zhang, Dedong Zhang, Yichen Lei, Siying Liu, Yongbing Zhu, Qun Hu, Xiaoyan Zhao, Aiguo Liu","doi":"10.1016/j.ajpath.2025.12.004","DOIUrl":"10.1016/j.ajpath.2025.12.004","url":null,"abstract":"<div><div>Neuroblastoma (NB) with metastasis to bone marrow (BM) usually results in dismal survival. The mechanisms underlying BM metastasis remain largely unclear. In this study, single-cell transcriptome of NB with and without BM metastasis were analyzed, and 146 marker genes of NB cells were identified. Using two-sample Mendelian randomization, N-cadherin (CDH2) and tubulin α 1A (TUBA1A) were identified as key genes possibly affecting BM metastasis. Functional investigations suggest that CDH2 regulates cell cycle and DNA replication, whereas TUBA1A impacts cell adhesion molecules and the cAMP signaling pathway. Dysregulated expression of CDH2 or TUBA1A also alters the immune microenvironment by immune cells and chemokines. Subsequent experiments validated that both CDH2 and TUBA1A were up-regulated in NB cell lines and high-risk patient samples, compared with low-risk cases. Knockdown of CDH2 or TUBA1A led to cell cycle arrest and significantly inhibited NB cell proliferation and migration. Moreover, an oxidation-reduction cycling agent, 2,3-dimethoxy-1,4-naphthoquinone, was identified as a candidate compound with inhibitory activity on NB cells by diminishing CDH2 or TUBA1A expression levels. Together, these results highlight CDH2 and TUBA1A as novel therapeutic targets for NB with BM metastases. The efficacy of 2,3-dimethoxy-1,4-naphthoquinone in suppressing NB cell growth and CDH2/TUBA1A expression suggests its potential for clinical application.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 3","pages":"Pages 816-835"},"PeriodicalIF":3.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145899122","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}

引用次数: 0

REVIEWER ACKNOWLEDGMENT 评论家承认

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2026-03-01 Epub Date: 2026-02-20 DOI: 10.1016/j.ajpath.2026.01.001

引用次数: 0

DNA Methyltransferase 3A–Dependent Suppression of Hypoxia-Inducible Factor-1α Alleviates Myopia by Reducing Scleral Ferroptosis and Fibroblast Extracellular Matrix Remodeling dnmt3a依赖性抑制HIF-1α通过减少巩膜铁下垂和成纤维细胞细胞外基质重塑来缓解近视。

IF 3.6 2区医学

American Journal of Pathology Pub Date : 2026-03-01 Epub Date: 2025-12-15 DOI: 10.1016/j.ajpath.2025.11.010

Xiaowei Peng, Zhuotao Zheng, Weiwei Xiong, Feifei Wang, Yan Deng, Jinsong Wu

{"title":"DNA Methyltransferase 3A–Dependent Suppression of Hypoxia-Inducible Factor-1α Alleviates Myopia by Reducing Scleral Ferroptosis and Fibroblast Extracellular Matrix Remodeling","authors":"Xiaowei Peng, Zhuotao Zheng, Weiwei Xiong, Feifei Wang, Yan Deng, Jinsong Wu","doi":"10.1016/j.ajpath.2025.11.010","DOIUrl":"10.1016/j.ajpath.2025.11.010","url":null,"abstract":"<div><div>Hypoxia-inducible factor-1α (HIF-1α) is associated with myopia, but the underlying mechanisms remain unclear. This study investigates the role of HIF-1α in ocular refractive development and its mechanisms. Sprague-Dawley rats were induced with myopia using the form deprivation method, and the expression of HIF-1α was analyzed by Western blot analysis. Oxidative stress levels were assessed by measuring reactive oxygen species, superoxide dismutase, and malondialdehyde. Additionally, the protein expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11/xCT) was evaluated using Western blot analysis and immunohistochemistry, and extracellular matrix remodeling was assessed by measuring matrix metalloproteinase 2 (MMP2), tissue inhibitor of MMP2 (TIMP2), α-smooth muscle actin (α-SMA), and collagen 1α1 (COL1A1). Results showed that HIF-1α expression was significantly up-regulated in form deprivation-induced myopic rats, with increased levels of oxidative stress and ferroptosis. In fibroblast cells under low oxygen conditions, MMP2 and α-SMA levels increased, whereas TIMP2 and COL1A1 levels decreased. Transfection with shRNA targeting <em>HIF1A</em> (sh-<em>HIF1A</em>) lentivirus elevated GPX4 and xCT expression, and HIF-1α knockdown reduced MMP2 and α-SMA expression while increasing TIMP2 and COL1A1 expression. However, erastin restored their levels. Furthermore, DNA methyltransferase 3A suppressed HIF-1α expression by promoting its promoter methylation. In conclusion, hypoxia-induced HIF-1α expression promotes ferroptosis and extracellular matrix remodeling, contributing to the pathogenesis of myopia. DNA methyltransferase 3A may reduce HIF-1α expression through methylation, positioning it as a potential target for myopia therapy.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"196 3","pages":"Pages 801-815"},"PeriodicalIF":3.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145773172","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}

引用次数: 0