Pathology, research and practice最新文献

{"title":"METTL1 drives glioma progression by promoting N7-methylguanosine (m7G) modification of glycolysis-related enzyme PGK1","authors":"Bo Fan ,&nbsp;Yakun Wang ,&nbsp;Xiaoning Qin ,&nbsp;Zhongjie Yan ,&nbsp;Wei Du","doi":"10.1016/j.prp.2025.156174","DOIUrl":"10.1016/j.prp.2025.156174","url":null,"abstract":"<div><div>Glioma is a common brain malignancy with a poor prognosis. N7-methylguanosine (m7G) modification is involved in cancer progression, and methyltransferase 1 (METTL1) is a m7G methyltransferase. Here, we aimed to study the role of METTL1 in glioma and the potential mechanism. The proliferation of glioma cells was evaluated using cell counting kit-8 and 5-ethynyl-2’-deoxyuridine (EdU) assays, and the glycolysis was assessed using glucose uptake and lactate content kits and seahorse analysis. The regulation of METTL1 on phosphoglycerate kinase 1 (PGK1) was analyzed using methylated RNA immunoprecipitation, RNA immunoprecipitation, quantitative real-time polymerase chain reaction, western blotting, and RNA stability assay. The results showed that METTL1 expression was upregulated in glioma tissues and cells. Silencing of METTL1 inhibited the proliferation and glycolysis of glioma cells and impeded tumor growth in mice. Moreover, METTL1 knockdown suppressed internal m7G modification of PGK1 and decreased its half-life. PGK1 overexpression counteracted the inhibition of glioma cell proliferation and glycolysis induced by METTL1 knockdown. In conclusion, METTL1 functions as an oncogene to accelerate glioma progression by promoting m7G modification of PGK1, providing a potential therapeutic target for glioma.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"274 ","pages":"Article 156174"},"PeriodicalIF":3.2,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144830217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Presence of microscopic skipping growth pattern correlated with KRAS or GNAS mutations in pulmonary mucinous adenocarcinoma","authors":"Yang Zhou,&nbsp;Longyun Chen,&nbsp;Ji Li,&nbsp;Hui Zhang,&nbsp;Yinbo Xiao,&nbsp;Yumeng Cai,&nbsp;Hao Wang,&nbsp;Yining Zhen,&nbsp;Zhiyong Liang,&nbsp;Xiaohua Shi","doi":"10.1016/j.prp.2025.156165","DOIUrl":"10.1016/j.prp.2025.156165","url":null,"abstract":"<div><h3>Introduction</h3><div>Mucinous adenocarcinoma is a special subtype of non-small cell lung carcinoma (NSCLC). Currently, it remains unclear whether the molecular alterations are associated with its clinicopathological characteristics.</div></div><div><h3>Methods</h3><div>A total of 93 cases of pulmonary mucinous adenocarcinoma were assessed in this study. DNA and RNA sequencing were performed and clinical pathological characteristics were collected. Correlation analyses were conducted to explore associations between molecular alterations, pathological features, and clinical outcomes.</div></div><div><h3>Results</h3><div>The <em>KRAS</em> mutation frequency was 49 %. The group with <em>KRAS</em> mutations had low to intermediate nuclear grade (p &lt; 0.001), microscopic skip lesions (p = 0.005), and a lower proportion of patients with vascular invasion (p = 0.030). While vascular invasion (p = 0.044), intermediate to high nuclear grade, especially high nuclear grade (p = 0.007), and tumors with a maximum diameter greater than 4 cm (p = 0.012) were commonly observed in patients with <em>TP53</em> mutations, which also was correlated with a shorter time to progression (TTP).</div></div><div><h3>Conclusions</h3><div>In this study, we found that mucinous adenocarcinomas of the lung with <em>KRAS</em> mutations tended to be pure-type mucinous adenocarcinomas with low to intermediate-grade nuclei, microscopic skip lesions, and the absence of vascular invasion. Tumors with <em>TP53</em> mutations tended to be larger in size and exhibit higher nuclear grade as well as frequent vascular invasion. These morphological features may suggest that the tumor is accompanied by some kind of molecular alteration. If this is found in the puncture biopsy specimen, the patient may be advised to undergo molecular testing with a view to finding a suitable targeted agent for treatment.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"274 ","pages":"Article 156165"},"PeriodicalIF":3.2,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144861041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP32 stabilizes SEMA4C to promote malignant behavior of colon cancer cells","authors":"Shurong Huang,&nbsp;Zongda Cai,&nbsp;Yangqiang Wang,&nbsp;Wei Zheng,&nbsp;Shiyang Zhan,&nbsp;Mingjin Huang,&nbsp;Jinping Chen","doi":"10.1016/j.prp.2025.156162","DOIUrl":"10.1016/j.prp.2025.156162","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is a prevalent and deadly malignancy. SEMA4C has been found to promote CRC progression, although the regulatory mechanisms behind SEMA4C expression in CRC tissues remain elusive. In this study, we examined 40 ubiquitin-specific proteases (USPs) that may influence SEMA4C stability and identified USP32 as a potent stabilizer. Through bioinformatics analysis, we discovered that USP32 mRNA expression is elevated in CRC tissues. Suppressing USP32 led to decreased cell viability, cell cycle arrest, reduced migration and invasion capabilities, and lower levels of proteins associated with epithelial-to-mesenchymal transition (EMT). USP32 directly interacts with SEMA4C in CRC cells, and its knockdown heightened SEMA4C ubiquitination and accelerated its degradation. Moreover, USP32 enhances the protein stability of SEMA4C by regulating its K48 ubiquitination. Overexpressing SEMA4C strengthened the weakened malignant behaviors of USP32-deficient CRC cells. These results indicate that USP32 acts as an oncogene in CRC by stabilizing SEMA4C, highlighting a new mechanism in CRC pathogenesis and suggesting USP32 as a novel potential therapeutic target for CRC treatment.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"274 ","pages":"Article 156162"},"PeriodicalIF":3.2,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144852988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uterine fibrosarcomatous dermatofibrosarcoma protuberans (FS-DFSP) with COL1A1::PDGFB fusion and concurrent TP53/ERBB2 mutations: Case report and molecular characterization","authors":"Jinchuan Yu ,&nbsp;Haiyan Shi ,&nbsp;Bingjian Lu","doi":"10.1016/j.prp.2025.156149","DOIUrl":"10.1016/j.prp.2025.156149","url":null,"abstract":"<div><div>Uterine dermatofibrosarcoma protuberans (DFSP) with <em>COL1A1::PDGFB</em> fusion is an exceptionally rare sarcoma, and its high-grade variant remains poorly characterized. We reported a 39-year-old Chinese woman with a high-grade uterine sarcoma exhibiting morphological features of fibrosarcomatous DFSP (FS-DFSP), including spindle cells arranged in storiform and herringbone patterns, focal myoid/epithelioid differentiation, and myxoid changes. Immunohistochemistry revealed variable CD34 expression, focal desmin/SMA positivity, and aberrant p53 overexpression. Targeted next-generation sequencing identified a <em>COL1A1-PDGFB (C5:P2)</em> fusion, a pathogenic <em>TP53</em> (c.832 C&gt;G; p.P278A) and <em>ERBB2</em> (c.2524 G&gt;A; p.V842I) mutation. Dual-color fluorescence in situ hybridization confirmed <em>COL1A1-PDGFB</em> fusion. This represented the first report of high-grade uterine DFSP with concurrent <em>TP53</em> and <em>ERBB2</em> mutations, expanding the molecular spectrum of this entity and suggesting potential therapeutic implications for dual PDGFR/HER2 inhibition in aggressive cases.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"273 ","pages":"Article 156149"},"PeriodicalIF":3.2,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144772500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic characteristics of primary bone marrow large B-cell lymphoma","authors":"Yi-Chen Yeh ,&nbsp;Kung-Chao Chang ,&nbsp;Chih-Yi Hsu ,&nbsp;Ching-Fen Yang","doi":"10.1016/j.prp.2025.156157","DOIUrl":"10.1016/j.prp.2025.156157","url":null,"abstract":"<div><div>Primary bone marrow large B-cell lymphoma (PBM-LBCL) is a rare entity with poorly defined genetic features. We performed whole-exome sequencing on bone marrow specimens from 19 PBM-LBCL cases and compared them with 11 cases of conventional diffuse large B-cell lymphoma (DLBCL) with secondary bone marrow involvement. Clinicopathological characteristics, including hemophagocytic lymphohistiocytosis (HLH), hepatosplenomegaly, International Prognostic Index (IPI) score, treatment with chemotherapy plus rituximab, CD5 expression, histopathological patterns, germinal center B-cell-like subtype and follow-up duration, did not differ significantly between the two groups. Both IPI score and treatment regimen emerged as independent predictors of survival. Sequencing analysis revealed 7974 moderate- to high-impact variants. The MCD molecular subtype predominated in both cohorts, while the EZB subtype was observed exclusively in PBM-LBCL. A distinct 16-gene mutational signature differentiated PBM-LBCL from DLBCL. Among these, 10 genes (<em>KMT2D</em>, <em>APOB</em>, <em>BBS9</em>, <em>CFAP46</em>, <em>EIF4G3</em>, <em>FAT1</em>, <em>MED12L</em>, <em>TG</em>, <em>TNR</em>, <em>ZFHX4</em>) were uniquely mutated in PBM-LBCL, and three genes (<em>CNTNAP3B</em>, <em>IL16</em>, <em>ZNF814</em>) were exclusive to DLBCL. Mutations in <em>COL5A3</em>, <em>PCNT</em>, <em>HMCN2</em>, and <em>OSBPL10</em> were associated with HLH. Notably, <em>BTG1</em> mutation was significantly associated with poor prognosis in both univariate and elastic net–regularized multivariate analyses. In summary, PBM-LBCL harbors a distinct genetic profile, characterized by a unique 16-gene signature that distinguishes it from DLBCL with secondary bone marrow involvement. <em>BTG1</em> mutation is associated with adverse outcomes, highlighting their potential as prognostic biomarkers or therapeutic targets. These findings advance our understanding of the molecular landscape and prognostic stratification of PBM-LBCL.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"273 ","pages":"Article 156157"},"PeriodicalIF":3.2,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144780648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the ATG12–ATG3 protein-protein interaction: From structural insights to therapeutic opportunities in autophagy modulation","authors":"Emadeldin M. Kamel ,&nbsp;Sally Mostafa Khadrawy ,&nbsp;Ahmed A. Allam ,&nbsp;Noha A. Ahmed ,&nbsp;Faris F. Aba Alkhayl ,&nbsp;Al Mokhtar Lamsabhi","doi":"10.1016/j.prp.2025.156156","DOIUrl":"10.1016/j.prp.2025.156156","url":null,"abstract":"<div><div>Autophagy sustains cellular metabolism, shapes immune signaling and, when dysregulated, contributes to cancer progression and cytokine-storm syndromes. A crucial catalytic step is conjugation of microtubule-associated protein 1 light chain 3 (LC3) to phosphatidylethanolamine, driven by direct binding of the E2-like enzyme autophagy-related protein 3 (ATG3) to the ubiquitin-like protein autophagy-related protein 12 (ATG12). Disrupting this ATG12–ATG3 protein–protein interaction (PPI) could silence both the degradative and secretory arms of autophagy with high pathway selectivity. Here we review the rapid evolution of ATG12–ATG3 inhibition from structural insight to drug-like chemical matter. High-resolution crystallography pinpointed a hydrophobic pocket around ATG12 Trp73 that accommodates ATG3 Met157, revealing an “anchor-and-latch”—a motif in which one residue (‘anchor’) buries deeply while flanking residues (‘latch’) secure the complex— topology ideal for small-molecule competition. A split <em>Gaussia</em> luciferase screen of more than 40 000 compounds, guided by in-silico pocket bias, yielded 17 micromolar disruptors; systematic structure–activity-relationship (SAR) exploration transformed an off-target casein kinase 2 (CK2) hit into naphthalene lead compound 189, which binds ATG12 directly (dissociation constant, <em>K</em>_D ≈ 5 µM). This lead collapses autophagic flux at single-digit micromolar concentrations, arrests autophagy-addicted tumor cells and suppresses interleukin-1β (IL-1β) secretion from macrophages—all without kinase or lysosomal liabilities. Medicinal-chemistry principles distilled from more than 150 analogues define the hydrophobic “plug,” polar “claw,” and polarity-tuning handles that govern potency and selectivity. An integrated assay toolbox—spanning surface plasmon resonance (SPR), dual-color LC3 flux reporters and disease-relevant phenotypes—now drives nanomolar optimization and safety profiling. We conclude by mapping future directions: covalent-reversible chemotypes, proteolysis-targeting chimera (PROTAC) degraders, targeted-delivery platforms and combination regimens poised to translate ATG12–ATG3 disruption into first-in-class therapeutics for oncology, immunology and infectious disease.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"273 ","pages":"Article 156156"},"PeriodicalIF":3.2,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144766870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methyl jasmonate mitigates cisplatin-induced nephrotoxicity via modulation of Caspase-3/COX-2/ NF-κB signalling pathway: In silico, In vitro, and In vivo investigations","authors":"Ujwal N. Katolkar,&nbsp;Sanjay J. Surana","doi":"10.1016/j.prp.2025.156153","DOIUrl":"10.1016/j.prp.2025.156153","url":null,"abstract":"<div><div>Cisplatin is a widely used chemotherapeutic agent; however, its clinical utility is limited due to several organ toxicities, including nephrotoxicity, which is primarily mediated through oxidative stress, inflammation, and apoptosis. This study examines the protective effect of methyl jasmonate (MeJA) in mitigating cisplatin-induced nephrotoxicity by modulating the caspase-3/COX-2/NF-κB signaling pathway. Initially, we performed molecular docking to evaluate the binding affinity of MeJA against the caspase-3, cyclooxygenase-2 (COX-2), and nuclear factor kappa B (NF-κB) proteins in the presence of the reference drug amifostine. Further, <em>in vitro</em> cell cytotoxicity on Madin-Darby canine kidney (MDCK) cells via MTT assay, oxidative stress, and proinflammatory markers. We have also performed an <em>in vivo</em> analysis of MeJA on cisplatin-induced nephrotoxicity in experimental rats by employing several biochemical parameters and histopathological investigation on rat kidney tissues. <em>In silico</em> molecular docking analysis revealed strong binding interactions between MeJA, key apoptotic and inflammatory mediators, suggesting its potential to regulate cisplatin-induced toxicity. <em>In vitro</em> studies using MDCK cells demonstrated that MeJA significantly reduced cisplatin-induced cytotoxicity, oxidative stress, and proinflammatory markers. <em>In vivo</em> experiments in rats further confirmed the nephroprotective effects of MeJA, as evidenced by improved renal function markers, and histopathological preservation of renal tubules and glomerulus tissues of rat kidneys. While ELISA testing revealed that MeJA downregulates caspase-3 and COX-2 expression and suppresses NF-κB activation. These findings collectively highlight the therapeutic potential of MeJA in alleviating cisplatin-induced nephrotoxicity through modulation of apoptosis and inflammatory pathways. MeJA may serve as a promising nephroprotective agent, warranting further clinical investigation for its potential application in oncology settings.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"273 ","pages":"Article 156153"},"PeriodicalIF":3.2,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144780647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revisiting the biological role of the Warburg effect: Evolving perspectives on cancer metabolism","authors":"Diego De Leon-Oliva ,&nbsp;Paula González-Prieto ,&nbsp;Patricia De Castro-Martinez ,&nbsp;Diego Liviu Boaru ,&nbsp;Pilar Laguna-Hernández ,&nbsp;Oscar Fraile-Martinez ,&nbsp;Cielo García-Montero ,&nbsp;Luis G. Guijarro ,&nbsp;Laura López-González ,&nbsp;Raul Díaz-Pedrero ,&nbsp;Melchor Álvarez-Mon ,&nbsp;Miguel A. Saez ,&nbsp;Miguel A. Ortega","doi":"10.1016/j.prp.2025.156151","DOIUrl":"10.1016/j.prp.2025.156151","url":null,"abstract":"<div><div>Cancer cells exhibit metabolic reprogramming towards a glycolysis-dominant profile. This shift, known as the Warburg effect, enhances cancer cell survival, growth, and metastasis by increasing glucose uptake and lactate production. It also meets the high anabolic demands of proliferation by providing important biosynthetic precursors. Despite its long-standing discovery, the origins and roles of the Warburg effect in cancer remain unclear. Recent research has provided deeper insights into its cellular origins and involvement in cancer progression and metastasis. Therefore, this review aims to provide a comprehensive and updated understanding of the significance of glycolysis in cancer. Initially, a brief overview of the glycolytic pathway will be presented, followed by an in-depth discussion of how this pathway is altered in cancer, its biological significance, and its regulatory mechanisms. We highlight that lactate production in cancer cells may not solely reflect a metabolic inefficiency, but rather a compensatory mechanism to regenerate cytosolic NAD⁺ when mitochondrial NADH shuttles become saturated, thereby sustaining glycolytic flux under rapid proliferative demands. Finally, the review will explore the translational implications of glycolysis research in the clinical context.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"273 ","pages":"Article 156151"},"PeriodicalIF":3.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144739518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SPINK1 immunohistochemistry: An ancillary tool to diagnose urothelial carcinoma in situ and urothelial dysplasia","authors":"Francesca Khani ,&nbsp;Shaham Beg ,&nbsp;Kyung Park ,&nbsp;Kathy Kawaguchi ,&nbsp;Ya-Lin Chiu ,&nbsp;Brian D. Robinson ,&nbsp;Rosina Lis ,&nbsp;Edward C. Stack ,&nbsp;Douglas S. Scherr ,&nbsp;Jonathan E. Rosenberg ,&nbsp;Massimo Loda ,&nbsp;Arul M. Chinnaiyan ,&nbsp;Mark A. Rubin ,&nbsp;Juan Miguel Mosquera","doi":"10.1016/j.prp.2025.156148","DOIUrl":"10.1016/j.prp.2025.156148","url":null,"abstract":"<div><div>Expression of SPINK1 (Serine protease inhibitor Kazal type I), also known as tumor associated trypsin inhibitor (TATI), has been demonstrated in a wide spectrum of benign, inflammatory, and neoplastic conditions. Based on our prior results of its expression in urothelial carcinoma, in this study we further characterized SPINK1 expression in a spectrum of urothelial lesions and investigated its potential diagnostic utility. A total of 396 samples comprising a spectrum of urothelial lesions including benign, premalignant, and malignant lesions were evaluated for SPINK1 expression by immunohistochemistry and amplification by fluorescence <em>in situ</em> hybridization (FISH). In a subset of lesions, immunohistochemistry for CK20, CD44, and p53 was also performed. SPINK1 expression was restricted to umbrella cells or lost in 93 % of normal urothelium. Overexpression of SPINK1 in reactive urothelial atypia, urothelial dysplasia, carcinoma <em>in situ</em> (CIS), and papillary urothelial carcinoma (invasive and non-invasive) was seen in 21 %, 36 %, 87 % and 54 % of cases, respectively. Increasing frequency of SPINK1 loss was observed with higher pathologic stage (48.5 % in pT1, 50 % in pT2, 62.5 % in pT3). When compared with other markers, SPINK1 positivity itself has a sensitivity of 90 % for detecting CIS, a 97 % sensitivity when combined with CK20, and a 98 % sensitivity when combined with p53. No amplification of SPINK1 was detected by FISH in any case. Our study illustrates the differential expression of SPINK1 in various urothelial lesions and shows that SPINK1 immunohistochemistry can be utilized as an ancillary tool with high sensitivity and specificity for diagnosing urothelial dysplasia and CIS in challenging cases.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"273 ","pages":"Article 156148"},"PeriodicalIF":3.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144739521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative transcriptomic and single-cell protein characterization of colorectal carcinoma delineates distinct tumor immune microenvironments associated with overall survival","authors":"Erika Hissong ,&nbsp;Bhavneet Bhinder ,&nbsp;Junbum Kim ,&nbsp;Kentaro Ohara ,&nbsp;Hiranmayi Ravichandran ,&nbsp;Majd Al Assaad ,&nbsp;Sarah Elsoukkary ,&nbsp;Michael Shusterman ,&nbsp;Uqba Khan ,&nbsp;Kenneth Wha Eng ,&nbsp;Rohan Bareja ,&nbsp;Jyothi Manohar ,&nbsp;Michael Sigouros ,&nbsp;Andre F. Rendeiro ,&nbsp;Jose Jessurun ,&nbsp;Allyson J. Ocean ,&nbsp;Andrea Sboner ,&nbsp;Olivier Elemento ,&nbsp;Juan Miguel Mosquera ,&nbsp;Manish A. Shah","doi":"10.1016/j.prp.2025.156150","DOIUrl":"10.1016/j.prp.2025.156150","url":null,"abstract":"<div><h3>Purpose</h3><div>Colorectal carcinoma (CRC) is a heterogeneous group of tumors with varying therapeutic response and prognosis, and evidence suggests the tumor immune microenvironment (TIME) plays a pivotal role. Using advanced molecular and spatial biology technologies, we aimed to evaluate the TIME in patients with CRC to determine whether specific characteristics of immune composition correlated with prognosis.</div></div><div><h3>Methods</h3><div>We identified primary and metastatic tumor samples from 31 consented patients, which were profiled with whole-exome sequencing and bulk RNA-seq. Immune cell deconvolution followed by gene set enrichment analysis and unsupervised clustering was performed. A subset of tumors underwent <em>in situ</em> analysis of the TIME spatial composition at single-cell resolution through Imaging Mass Cytometry.</div></div><div><h3>Results</h3><div>Gene set enrichment analysis revealed two distinct groups of advanced CRC, one with an immune activated phenotype and the other with a suppressed immune microenvironment. The activated TIME phenotype contained increased Th1 cells, activated dendritic cells, tertiary lymphoid structures, and higher counts of CD8 + T cells whereas the inactive or suppressed TIME contained increased macrophages enriched for immunosuppressive M2 macrophages. Our findings were further supported by RNA-seq data analysis from the TCGA CRC database, in which the ratio of inactivated to activated dendritic cells within the CRC TIME correlated with a lower overall survival probability (HR 1.66, p = 0.007).</div></div><div><h3>Conclusion</h3><div>We identified distinct immunologic tumor microenvironments in colorectal cancer. Cancers harboring an activated TIME are associated with improved survival. Identifying key molecular drivers of the CRC TIME may offer opportunities to improve patient survival.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"273 ","pages":"Article 156150"},"PeriodicalIF":3.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144739520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}