The Journal of Pathology最新文献

{"title":"Cystathionine gamma-lyase-mediated hypoxia inducible factor 1-alpha expression drives clear cell ovarian cancer progression","authors":"Amal M EL-Naggar,&nbsp;Yuqin Li,&nbsp;Busra Turgu,&nbsp;Yuchen Ding,&nbsp;Longyijie Wei,&nbsp;Shary Yuting Chen,&nbsp;Genny Trigo-Gonzalez,&nbsp;Forouh Kalantari,&nbsp;Rodrigo Vallejos,&nbsp;Branden Lynch,&nbsp;Janine Senz,&nbsp;Amy Lum,&nbsp;J Maxwell Douglas,&nbsp;Clara Salamanca,&nbsp;Shelby Thornton,&nbsp;Yimei Qin,&nbsp;Kiran Parmar,&nbsp;Sandra E Spencer,&nbsp;Samuel Leung,&nbsp;Michelle MM Woo,&nbsp;Paul J Yong,&nbsp;Hai-Feng Zhang,&nbsp;Christopher S Hughes,&nbsp;Gian Luca Negri,&nbsp;Yemin Wang,&nbsp;Gregg B Morin,&nbsp;Poul H Sorensen,&nbsp;David G Huntsman","doi":"10.1002/path.6433","DOIUrl":"10.1002/path.6433","url":null,"abstract":"<p>Clear cell ovarian cancer (CCOC) is the second most common ovarian cancer subtype, accounting for 5%–11% of ovarian cancers in North America. Late-stage CCOC is associated with a worse prognosis compared to other ovarian cancer histotypes, a challenge that has seen limited progress in recent decades. CCOC typically originates within the toxic microenvironment of endometriotic ovarian cysts and is characterized by its intrinsic chemoresistance, a strong hypoxic signature, and abundant expression of cystathionine gamma-lyase (CTH). CTH is a key enzyme in the transsulfuration pathway and serves as a marker of ciliated cells derived from the Müllerian tract. CTH plays a pivotal role in <i>de novo</i> cysteine synthesis, which is essential for glutathione (GSH) production and redox homeostasis. Using an array of molecular tools and cancer models, including <i>in vivo</i> studies, we demonstrated that CTH expression was induced under various stress conditions, such as exposure to endometriotic cyst content and hypoxia. This induction enables cell survival and creates a differentiation state manifested by CCOC that potentiates tumor progression and metastasis. In addition to regulating redox homeostasis, CTH enhances hypoxia inducible factor 1-alpha (HIF1α) expression, independently of hydrogen sulfide (H₂S) production. Re-expression of HIF1α in <i>CTH</i> KO cells fully restored metastatic capacity in <i>in vivo</i> models. Co-expression of CTH and HIF1α proteins was also observed in human CCOC samples. Importantly, targeting CTH in CCOC significantly reduced its metastatic potential in <i>in vivo</i> models and enhanced sensitivity to chemotherapy. These findings underscore that CTH is both a defining feature of CCOC and a promising therapeutic target, not only for CCOC patients but also for those with other CTH-expressing cancers. © 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":"266 3","pages":"352-367"},"PeriodicalIF":5.6,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6433","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075065","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 TBXT rs2305089 SNP links the benign notochordal cell tumour and chordoma","authors":"Inga Usher,&nbsp;Paul O'Donnell,&nbsp;Lorena Ligammari,&nbsp;Dorothee Harder,&nbsp;Wendy Brown,&nbsp;David Choi,&nbsp;Paul Cool,&nbsp;Lucia Cottone,&nbsp;Adrienne M Flanagan","doi":"10.1002/path.6427","DOIUrl":"10.1002/path.6427","url":null,"abstract":"<p>The aim of this research was to investigate the pathogenesis of the bone cancer chordoma and the role of the germline rs2305089 SNP in <i>TBXT</i>. Using medical imaging and genotyping studies, we observed that benign notochordal cell tumours (BNCTs) were associated with chordomas and with the variant rs2305089 A-allele with enrichment of the AA genotype compared to controls. We engineered <i>in vitro</i> mesoderm models, representing notochord, which showed higher expression of <i>TBXT</i> and activation of its regulatory network in the presence of the variant A allele. Heterozygotes (GA) displayed enrichment of Wnt/β-catenin and epithelial mesenchymal transition pathways, faster cell migratory capacity, and altered expression of endoplasmic reticulum and intracellular transport mediators. WT lines (GG) were enriched for metabolic pathways and MTORC1 signalling, suggesting that rs2305089 genotype regulates notochord vacuoles during notochord regression. By leveraging patient-derived data and functional studies, we show that the variant rs2305089 A-allele predisposes to BNCTs and ultimately to chordomas. © 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":"266 3","pages":"247-257"},"PeriodicalIF":5.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6427","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959499","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":"Clinicopathological and molecular characterization of KRAS wild-type pancreatic ductal adenocarcinomas reveals precursor lesions with oncogenic mutations and fusions in RAS pathway genes","authors":"Kazuhiro Toriyama,&nbsp;Katsuhiro Masago,&nbsp;Noriko Shibata,&nbsp;Masataka Haneda,&nbsp;Takamichi Kuwahara,&nbsp;Seiji Natsume,&nbsp;Shota Kobayashi,&nbsp;Yasuko Fujita,&nbsp;Eiichi Sasaki,&nbsp;Kenji Yamao,&nbsp;Hiroki Kawashima,&nbsp;Yasuhiro Shimizu,&nbsp;Kazuo Hara,&nbsp;Yasushi Yatabe,&nbsp;Waki Hosoda","doi":"10.1002/path.6432","DOIUrl":"10.1002/path.6432","url":null,"abstract":"<p>Pancreatic ductal adenocarcinomas (PDACs) with wild-type <i>KRAS</i> constitute a small fraction of PDACs, and these tumors were recently shown to harbor frequent actionable oncogenic mutations and fusions. However, the clinicopathological features of <i>KRAS</i> wild-type PDAC have not been well studied. Additionally, precancerous lesions occurring in patients with <i>KRAS</i> wild-type PDACs have rarely been characterized. Here, we investigated the clinicopathological characteristics and outcomes of 75 patients with <i>KRAS</i> wild-type PDAC. Molecular analyses were performed in 40 patients using targeted DNA and whole-exome sequencing and targeted RNA sequencing. We demonstrated that patients with metastatic PDAC with wild-type <i>KRAS</i> were younger (median 59.5 years) than those with mutated <i>KRAS</i> (median 67 years, <i>p</i> &lt; 0.000055). The wild-type <i>KRAS</i> status was not a significant prognostic factor for metastatic disease. Molecularly, genes in the RAS pathway are frequently mutated or rearranged (46%, 16/35), including mutations in <i>BRAF</i>, <i>NRAS</i>, <i>HRAS</i>, <i>EGFR</i>, <i>MAP2K1</i>, <i>FGFR1</i>, <i>FGFR3</i> and <i>ERBB4</i> and fusions of <i>FGFR2</i> (<i>FGFR2</i>::<i>CCDC147</i>, <i>FGFR2</i>::<i>CAT</i>, <i>FGFR2</i>::<i>TXLNA</i>), <i>ALK</i> (<i>STRN</i>::<i>ALK</i>, <i>EML4</i>::<i>ALK</i>), and <i>BRAF</i> (<i>TRIP11</i>::<i>BRAF</i>). Mismatch repair deficiency was identified in 10% (4/39) of patients. Potentially actionable alterations were identified frequently in <i>KRAS</i> wild-type PDACs (30%, 12/40), in which nontubular-type carcinomas were significantly enriched with actionable alterations compared with tubular adenocarcinomas [67% (6/9) versus 16% (5/31); <i>p</i> = 0.007]. Finally, we investigated the precursors of PDACs in 13 pancreatectomy specimens from patients with <i>KRAS</i> wild-type PDAC. We identified three pancreatic intraepithelial neoplasias (PanINs) and two intraductal papillary mucinous neoplasms (IPMNs) harboring oncogenic fusions of <i>ALK</i> and <i>BRAF</i> and driver mutations in <i>BRAF</i> and <i>AKT1</i>. This study suggests that in the context of unmutated <i>KRAS</i>, PDAC is driven by alternative oncogenic mutations or fusions of RAS pathway genes, which may be introduced during the early phase of tumorigenesis. © 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":"266 3","pages":"337-351"},"PeriodicalIF":5.6,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6432","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964593","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":"Correction to ‘Dual inhibition of the endothelin and angiotensin receptor ameliorates renal and inner ear pathologies in Alport mice’","authors":"","doi":"10.1002/path.6425","DOIUrl":"10.1002/path.6425","url":null,"abstract":"<p>\u0000 <span>Dominic, Cosgrove</span>, <span>Michael, Anne Gratton</span>, <span>Jacob, Madison</span>, <span>Denise, Vosik</span>, <span>Gina, Samuelson</span>, <span>Daniel, Meehan</span>, <span>Duane, Delimont</span>, <span>Grady, Phillips</span>, <span>Brendan, Smyth</span>, <span>Tiziano, Pramparo</span>, <span>Diana, Jarocki</span>, <span>Mai, Nguyen</span>, <span>Radko, Komers</span> and <span>Celia, Jenkinson</span>. <i>J Pathol</i> <span>2023</span>; <span>260</span><b>:</b> <span>353</span>–<span>364</span>. https://doi.org/10.1002/path.6087\u0000 </p><p>The corresponding author has informed the editors that in this article, first published on 31 May 2023 in Wiley Online Library (wileyonlinelibrary.com), a typographical error exists in the legend of Figure 6.</p><p>The figure is correct, but the legend for panel D should read ‘(D) Hearing loss in AS-LS mice was worse compared with WT-LS mice (*<i>p</i> &lt; 0.05 WT-LS versus AS-LS)’.</p><p>The authors apologise for any inconvenience this error may have caused.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"266 3","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6425","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954537","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":"Comprehensive functional splicing analysis of non-canonical CNGB3 variants using in vitro minigene splice assays","authors":"Katharina Rawnsley,&nbsp;Nicole Weisschuh,&nbsp;Susanne Kohl,&nbsp;Peggy Reuter","doi":"10.1002/path.6431","DOIUrl":"10.1002/path.6431","url":null,"abstract":"<p>Variants in the <i>CNGB3</i> gene, encoding the B3-subunit of the cone photoreceptor cyclic nucleotide gated channel, are a major cause of autosomal recessive achromatopsia, a rare inherited retinal disease. The mutation spectrum of achromatopsia-associated <i>CNGB3</i> variants comprises all types of mutations, including those that are straightforward to evaluate in molecular genetic diagnostics, such as frame-shifting, nonsense, and canonical splice site variants. Additionally, variants have been identified within splice regions outside the conserved ±1,2 splice site dinucleotides, making their potential impact on disease association challenging to interpret. This poses a major hurdle for clinical interpretation of causality between the patient's genotype and the proposed clinical diagnosis, but also for the inclusion of such patients into clinical trials for gene augmentation therapy, for which only patients with confirmed (likely) pathogenic <i>CNGB3</i> variants are eligible. We here performed comprehensive genetic functional analysis of 21 candidate spliceogenic <i>CNGB3</i> variants—15 reported and 6 novel variants—by means of <i>in vitro</i> minigene splice assays and cDNA analysis, and characterization of spliceogenic events by subcloning, Sanger-sequencing, and capillary fragment analysis. For 16 variants, an impact on splicing was confirmed, supporting the reclassification of 86% of variants of uncertain significance as likely pathogenic or pathogenic according to the ACMG/AMP guidelines. This reclassification enables the confirmation of patients’ genotypes, both retrospectively and prospectively. © 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":"266 3","pages":"322-336"},"PeriodicalIF":5.6,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6431","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956095","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":"Comparative transcriptomics of salivary basal cell adenoma and adenocarcinoma sustain linear neoplastic evolution and intertumor heterogeneity: classification and biological implications","authors":"Yoshitsugu Mitani,&nbsp;Haneen Al-Maghrabi,&nbsp;Tatiana V Karpinets,&nbsp;Raissa T Relator,&nbsp;Lauren Hilder,&nbsp;Irene Y Chen,&nbsp;Ryan P Goepfert,&nbsp;Diana Bell,&nbsp;Jianhua Zhang,&nbsp;Renata Ferrarotto,&nbsp;Adel K El-Naggar","doi":"10.1002/path.6424","DOIUrl":"10.1002/path.6424","url":null,"abstract":"<p>It remains uncertain whether basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC) of the salivary gland represent two distinct neoplasms or temporal stages of a single entity. The issue is central to reconciling their shared phenotypic resemblance and protracted behavior with current pathologic classification. We conducted a transcriptomic analysis on a cohort of both pathologic forms and correlated the findings with the clinicopathologic features using RNA extracted from fresh frozen samples of 25 salivary basal tumors (five BCAs and 20 BCACs) and eight instances of metastatic basal cell carcinomas (BCCs) to parotid glands. Unsupervised analysis revealed shared and intertumoral transcriptome differences within and between BCA and BCAC and distinct segregation from metastatic dermal BCC. Transcriptomic profiling delineated two intermixed subgroups of salivary basal cell neoplasms (SBNs); SBN-I group enriched with adverse pathologic features and SBN-II that lacked any of these features except for a single case. The category with the most instances of adverse pathologic features (SBN-I) manifested upregulations of transcriptional factors linked to cell proliferation pathways (<i>HOXB13</i>, <i>SOX21</i>, <i>MYB</i>, and <i>EN1</i> genes), while those lacking adverse pathologic features (SBN-II) demonstrated a high expression of the <i>TFAP2B</i> transcription- and differentiation-related pathways. Our transcriptomic findings support common neoplastic evolution and intertumoral heterogeneity of both pathologic forms of basal cell neoplasms and identify molecular pathways of potential biological and clinical significance. We therefore propose a nondeterministic designation of ‘basal cell salivary neoplasms, noninvasive (adenoma)/invasive (adenocarcinoma)’ as a platform that integrates conventional phenotypic classification and transcriptomic characteristics pending a classification consensus. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"266 3","pages":"258-267"},"PeriodicalIF":5.6,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959776","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":"In-frame insertions of SOX10 are highly enriched and characterize a distinct transcriptomic profile in gastrointestinal schwannomas","authors":"Pei-Hang Lee,&nbsp;Shih-Chiang Huang,&nbsp;Jen-Chieh Lee,&nbsp;Sung-Chou Li,&nbsp;Jen-Wei Tsai,&nbsp;Yi-Ming Chang,&nbsp;Yu-Chien Kao,&nbsp;Wen-Lang Fan,&nbsp;Ching-Di Chang,&nbsp;Hui-Chun Chen,&nbsp;Chih-Hao Li,&nbsp;Chia-Fa Hu,&nbsp;Ting-Ting Liu,&nbsp;Pao-Shu Wu,&nbsp;Mann-Hua Nam,&nbsp;Shih-Chen Yu,&nbsp;Jui-Chu Wang,&nbsp;Hsuan-Ying Huang","doi":"10.1002/path.6426","DOIUrl":"10.1002/path.6426","url":null,"abstract":"<p>Gastrointestinal schwannomas are molecularly and histologically distinct from their non-gastrointestinal counterparts, lacking <i>NF2</i> alterations, although the primary drivers of these tumors are barely understood. A recent study has identified <i>SOX10</i> in-frame insertions in schwannomas, particularly in intracranial non-vestibular lesions, whereas their role in gastrointestinal schwannomas remains unexplored. Whole exome sequencing of 15 gastrointestinal and two non-gastrointestinal schwannomas revealed recurrent <i>SOX10</i> in-frame insertions in 14 gastrointestinal cases (93%) without other nerve sheath tumor-related alterations, such as <i>NF2</i> mutations or <i>SH3PXD2A</i>::<i>HTRA1</i> fusions (~14% in non-gastrointestinal cases). The prevalence, mutation spectrum, and specificity of <i>SOX10</i> insertions were validated using Sanger sequencing in a large cohort comprising 61 gastrointestinal and 98 non-gastrointestinal schwannomas, as well as 110 non-schwannomatous mesenchymal and melanocytic neoplasms. <i>SOX10</i> insertions, occurring within or near the high mobility group box domain, were significantly enriched in gastrointestinal schwannomas (91.8%) compared with non-gastrointestinal cases (5.1%). The most common insertion, p.Y173_Q174insKY, was present in 86.9% of gastrointestinal schwannomas but absent in non-gastrointestinal cases. Another recurrent insertion, p.P175_R176insKYQP, was rare and exclusively found in non-gastrointestinal schwannomas (3/98), while all non-schwannomatous controls were <i>SOX10</i>-normal. <i>SOX10</i>-inserted schwannomas exhibited histologic features characteristic of gastrointestinal schwannomas, including a microtrabecular arrangement of Schwann cells, peripheral lymphoid cuffs, and a lack of encapsulation. Both <i>SOX10</i>-inserted and <i>SOX10</i>-normal schwannomas demonstrated diffuse SOX10 immunoreactivity. The <i>SOX10</i>-inserted group was significantly associated with gastrointestinal locations (<i>p</i> &lt; 0.001), older patients (<i>p</i> &lt; 0.001), fusion negativity (<i>p</i> &lt; 0.001), and larger tumor size (<i>p</i> = 0.013). Gene expression profiling of 44 cases revealed distinct transcriptomic profiles between primarily <i>SOX10</i>-inserted and <i>SOX10</i>-normal groups, with the latter group being classifiable into fusion-poor and fusion-enriched sub-clusters. This study highlights the genetic heterogeneity of schwannomas and suggests that <i>SOX10</i> insertions play a pivotal role in the tumorigenesis of gastrointestinal schwannomas, distinctly separating them from non-gastrointestinal counterparts and contributing to their unique molecular profile. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"266 3","pages":"268-279"},"PeriodicalIF":5.6,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958073","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":"Nicotine-driven enhancement of tumor malignancy in triple-negative breast cancer via additive regulation of CHRNA9 and IGF1R","authors":"Yung-Che Kuo,&nbsp;Chi-Long Chen,&nbsp;Kha-Liang Lee,&nbsp;Hsiao-Feng Wang,&nbsp;Victor James Drew,&nbsp;Pei-Chi Lan,&nbsp;Yuan-Soon Ho,&nbsp;Yen-Hua Huang","doi":"10.1002/path.6423","DOIUrl":"https://doi.org/10.1002/path.6423","url":null,"abstract":"<p>Cigarette smoking is a significant risk factor for cancer development with complex mechanisms. This study aims to investigate the impact of nicotine exposure on the regulation of stemness- and metastasis-related properties via cholinergic receptor nicotinic alpha 9 subunit (CHRNA9) and insulin-like growth factor-1 receptor (IGF1R) and to evaluate their therapeutic potential in triple-negative breast cancer (TNBC). We performed Kaplan–Meier survival analysis of public databases and revealed that high expression of CHRNA9, IGF1R signaling molecules, and stemness genes was significantly associated with poor recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in TNBC samples. Additionally, we examined two patient cohorts to determine the clinical associations between the expression levels of different genes (<i>n</i> = 67) and proteins (<i>n</i> = 42) and showed a strong positive correlation between the expression levels of CHRNA9, IGF1R signaling molecules, and stemness markers POU5F1/NANOG in tumor tissues. We carried out nicotine treatment and knockdown of CHRNA9 and IGF1R in TNBC cells to identify the effects on stemness-related properties <i>in vitro</i>. Furthermore, primary and secondary metastatic <i>in vivo</i> animal models were examined using micro-computed tomography (μCT) screening and <i>in situ</i> hybridization with a human Alu probe to detect tumor cells. Nicotine was found to upregulate the expression of CHRNA9, POU5F1, and IGF1R, influencing stemness- and metastasis-related properties. Knockdown of CHRNA9 expression attenuated nicotine-induced stemness-related properties in a TNBC cell model. Furthermore, knockdown of IGF1R expression significantly alleviated nicotine/CHRNA9-induced stemness features and cancer cell metastasis in cell cultures and lung metastatic mouse models. These results demonstrate that nicotine triggers IGF1R signaling, thereby enhancing stemness-related properties, cell migration, invasion, and tumor metastasis, resulting in a poorer prognosis for patients with TNBC. These findings highlight IGF1R as a promising therapeutic target for reducing stemness and metastasis in TNBC patients exposed to environmental nicotine. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"266 2","pages":"230-245"},"PeriodicalIF":5.6,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143913991","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":"Nicotine-driven enhancement of tumor malignancy in triple-negative breast cancer via additive regulation of CHRNA9 and IGF1R","authors":"Yung-Che Kuo,&nbsp;Chi-Long Chen,&nbsp;Kha-Liang Lee,&nbsp;Hsiao-Feng Wang,&nbsp;Victor James Drew,&nbsp;Pei-Chi Lan,&nbsp;Yuan-Soon Ho,&nbsp;Yen-Hua Huang","doi":"10.1002/path.6423","DOIUrl":"https://doi.org/10.1002/path.6423","url":null,"abstract":"<p>Cigarette smoking is a significant risk factor for cancer development with complex mechanisms. This study aims to investigate the impact of nicotine exposure on the regulation of stemness- and metastasis-related properties via cholinergic receptor nicotinic alpha 9 subunit (CHRNA9) and insulin-like growth factor-1 receptor (IGF1R) and to evaluate their therapeutic potential in triple-negative breast cancer (TNBC). We performed Kaplan–Meier survival analysis of public databases and revealed that high expression of CHRNA9, IGF1R signaling molecules, and stemness genes was significantly associated with poor recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in TNBC samples. Additionally, we examined two patient cohorts to determine the clinical associations between the expression levels of different genes (<i>n</i> = 67) and proteins (<i>n</i> = 42) and showed a strong positive correlation between the expression levels of CHRNA9, IGF1R signaling molecules, and stemness markers POU5F1/NANOG in tumor tissues. We carried out nicotine treatment and knockdown of CHRNA9 and IGF1R in TNBC cells to identify the effects on stemness-related properties <i>in vitro</i>. Furthermore, primary and secondary metastatic <i>in vivo</i> animal models were examined using micro-computed tomography (μCT) screening and <i>in situ</i> hybridization with a human Alu probe to detect tumor cells. Nicotine was found to upregulate the expression of CHRNA9, POU5F1, and IGF1R, influencing stemness- and metastasis-related properties. Knockdown of CHRNA9 expression attenuated nicotine-induced stemness-related properties in a TNBC cell model. Furthermore, knockdown of IGF1R expression significantly alleviated nicotine/CHRNA9-induced stemness features and cancer cell metastasis in cell cultures and lung metastatic mouse models. These results demonstrate that nicotine triggers IGF1R signaling, thereby enhancing stemness-related properties, cell migration, invasion, and tumor metastasis, resulting in a poorer prognosis for patients with TNBC. These findings highlight IGF1R as a promising therapeutic target for reducing stemness and metastasis in TNBC patients exposed to environmental nicotine. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"266 2","pages":"230-245"},"PeriodicalIF":5.6,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143913990","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":"Activated immune infiltrates expand opportunities for targeted therapy in p53-abnormal endometrial carcinoma","authors":"Spencer D Martin,&nbsp;Shelby Thornton,&nbsp;Christine Chow,&nbsp;Katy Milne,&nbsp;Juliana Sobral de Barros,&nbsp;Kayleigh A Morris,&nbsp;Samuel Leung,&nbsp;Amy Jamieson,&nbsp;Brad H Nelson,&nbsp;Dawn R Cochrane,&nbsp;David G Huntsman,&nbsp;C Blake Gilks,&nbsp;Lien Hoang,&nbsp;Jessica N McAlpine,&nbsp;Allen W Zhang","doi":"10.1002/path.6429","DOIUrl":"10.1002/path.6429","url":null,"abstract":"<p>Tumor protein p53 mutated/abnormal (p53abn) endometrial carcinomas account for over 50% of deaths but comprise only 15% of all endometrial carcinomas. Most patients show limited response to standard-of-care chemotherapy with or without radiotherapy, and only a minority of cases are amenable to targeted therapies like poly-ADP ribose polymerase (PARP) inhibitors and HER2-directed therapies. Recent immunotherapy clinical trials have demonstrated remarkable efficacy, not only in mismatch repair deficient (MMRd) tumors but also in a subset of mismatch repair-proficient (MMRp) tumors. However, the immune microenvironment and its relationship to other therapeutic targets in MMRp endometrial carcinoma remains poorly understood. Here, we characterize the immune microenvironment of p53abn endometrial carcinoma, the most clinically aggressive subtype of MMRp endometrial carcinoma, and correlate antitumor immune signatures with other targetable alterations. We accrued 256 treatment-naïve p53abn endometrial carcinomas and systemically profiled T-cell, B-cell, myeloid, and tumor-cell populations with multiplex immunofluorescence to assess the tissue localization and functional status of immune cells. Shallow whole-genome sequencing was performed on a subset of 126 cases. Patterns of immune infiltration were compared to survival outcomes and mutational signatures. Mixture modeling divided p53abn endometrial carcinoma into tumor-infiltrating lymphocyte (TIL)-rich and TIL-poor subsets. Over 50% of tumors were TIL-rich. TIL-rich cases overexpressed targetable immune evasion molecules and were associated with longer overall and disease-specific survival in multivariate analysis. This effect was particularly pronounced in advanced stage disease and in patients who did not receive adjuvant chemotherapy. TIL did not associate with homologous recombination deficient mutational signatures or HER2 amplification. Our findings demonstrate a biological rationale for immunotherapy in a substantial subset of patients with p53abn endometrial cancer and may help inform combination therapies with immune checkpoint inhibition, PARP inhibitors, and anti-HER2 agents. © 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":"266 3","pages":"292-305"},"PeriodicalIF":5.6,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6429","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956472","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}