Cancer Communications最新文献

{"title":"Helicobacter pylori CagA elevates FTO to induce gastric cancer progression via a “hit-and-run” paradigm","authors":"Bing He,&nbsp;Yiyang Hu,&nbsp;Yuyun Wu,&nbsp;Chao Wang,&nbsp;Limin Gao,&nbsp;Chunli Gong,&nbsp;Zhibin Li,&nbsp;Nannan Gao,&nbsp;Huan Yang,&nbsp;Yufeng Xiao,&nbsp;Shiming Yang","doi":"10.1002/cac2.70004","DOIUrl":"10.1002/cac2.70004","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p><i>Helicobacter pylori</i> (<i>H. pylori</i>) infection contributes significantly to gastric cancer (GC) progression. The intrinsic mechanisms of <i>H. pylori</i>-host interactions and their role in promoting GC progression need further investigation. In this study, we explored the potential role of fat mass and obesity-associated protein (FTO) in mediating Cytotoxin-associated gene A (CagA)-induced GC progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The effects of <i>H. pylori</i> infection on N⁶-methyladenosine (m⁶A) modification were evaluated in both human samples and GC cell lines. The function of FTO in the progression of GC was elucidated through in vitro and in vivo studies. A series of techniques, including methylated RNA immunoprecipitation sequencing, RNA sequencing, RNA binding protein immunoprecipitation, and chromatin immunoprecipitation assays, were utilized to investigate the mechanism by which FTO mediates the capacity of <i>cagA</i>-positive <i>H. pylori</i> to promote GC progression. Furthermore, the therapeutic potential of the FTO inhibitor meclofenamic acid (MA) in impeding GC progression was evaluated across GC cells, animal models, and human GC organoids.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Infection with <i>cagA</i>-positive <i>H. pylori</i> upregulated the expression of <i>FTO</i>, which was essential for CagA-mediated GC metastasis and significantly associated with a poor prognosis in GC patients. Mechanistically, CagA delivered by <i>H. pylori</i> enhanced <i>FTO</i> transcription via Jun proto-oncogene. Elevated FTO induced demethylation of m⁶A and inhibited the degradation of heparin-binding EGF-like growth factor (HBEGF), thereby facilitating the epithelial-mesenchymal transition (EMT) process in GC cells. Interestingly, eradication of <i>H. pylori</i> did not fully reverse the increases in FTO and HBEGF levels induced by <i>cagA</i>-positive <i>H. pylori</i>. However, treatment with a combination of antibiotics and MA substantially inhibited <i>cagA</i>-positive <i>H. pylori</i>-induced EMT and prevented GC metastasis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our study revealed that FTO mediates the “hit-and-run” mechanism of CagA-induced GC progression, which suggests that the therapeutic targeting of FTO could offer a promising approach to the prevention of CagA-induced cancer progression.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 5","pages":"608-631"},"PeriodicalIF":20.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Copper in cancer: friend or foe? Metabolism, dysregulation, and therapeutic opportunities","authors":"Dan Shan,&nbsp;Jinling Song,&nbsp;Yuqing Ren,&nbsp;Yuyuan Zhang,&nbsp;Yuhao Ba,&nbsp;Peng Luo,&nbsp;Quan Cheng,&nbsp;Hui Xu,&nbsp;Siyuan Weng,&nbsp;Anning Zuo,&nbsp;Shutong Liu,&nbsp;Xinwei Han,&nbsp;Jinhai Deng,&nbsp;Zaoqu Liu","doi":"10.1002/cac2.70005","DOIUrl":"10.1002/cac2.70005","url":null,"abstract":"<p>Copper, one of the essential nutrients for the human body, acts as an electron relay in multiple pathways due to its redox properties. Both deficiencies and excesses of copper lead to cellular fragility. Therefore, it can manifest pro- and anti-cancer properties in tumors. Therefore, it is crucial to clarify the copper activity within the cell. We have thoughtfully summarized the metabolic activities of copper from a macro and micro perspective. Cuproptosis, as well as other forms of cell death, is directly or indirectly interfered with by Cu²⁺, causing cancer cell death. Meanwhile, we did pan-cancer analysis of cuproptosis-related genes to further clarify the roles of these genes. In addition, copper has been found to be involved in multiple pathways within the metastasis of cancer cells. Given the complexity of copper's role, we are compelled to ask: is copper a friend or a foe? Up to now, copper has been used in various clinical applications, including protocols for measurement of copper concentration and bioimaging of radioactive ⁶⁴Cu. But therapeutically it is still a continuation of the old medicine, and new possibilities need to be explored, such as the use of nanomaterials. Some studies have also shown that copper has considerable interventional power in metabolic cancers, which provides the great applications potential of copper therapy in specific cancer types. This paper reviews the dual roles played by cuproptosis in cancer from the new perspectives of oxidative stress, cell death, and tumor metastasis, and points out the value of its application in specific cancer types, summarizes the value of its testing and imaging from the perspective of clinical application as well as the current feasible options for the new use of the old drugs, and emphasizes the prospects for the application of nano-copper.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 5","pages":"577-607"},"PeriodicalIF":20.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sunitinib in metastatic renal cell carcinoma: clinical outcomes across risk groups in a Turkish Oncology Group Kidney Cancer Consortium","authors":"Hatice Bolek,&nbsp;Omer Faruk Kuzu,&nbsp;Elif Sertesen Camoz,&nbsp;Saadet Sim,&nbsp;Serhat Sekmek,&nbsp;Hilal Karakas,&nbsp;Selver Isık,&nbsp;Murad Guliyev,&nbsp;Aysun Fatma Akkus,&nbsp;Deniz Tural,&nbsp;Cagatay Arslan,&nbsp;Sema Sezin Goksu,&nbsp;Ozlem Nuray Sever,&nbsp;Nuri Karadurmus,&nbsp;Cengiz Karacin,&nbsp;Mehmet Ali Nahit Sendur,&nbsp;Emre Yekedüz,&nbsp;Yuksel Urun","doi":"10.1002/cac2.70003","DOIUrl":"10.1002/cac2.70003","url":null,"abstract":"&lt;p&gt;Renal cell carcinoma (RCC) is responsible for an estimated 434,419 new cases and 155,702 deaths, which amounts to 2.2% of all new cancer globally [&lt;span&gt;1&lt;/span&gt;]. Despite the advent of new combination therapies, the 3-year overall survival (OS) in metastatic RCC (mRCC) remains around 60% [&lt;span&gt;2-4&lt;/span&gt;]. To stratify the patients according to their prognosis, the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model and the Memorial Sloan Kettering Cancer Center (MSKCC) model, are well developed and used before the initiation of the treatment. Sunitinib was the standard of care after showing superiority over interferon alfa in mRCC until immunotherapy (IO) combinations gained approval [&lt;span&gt;5&lt;/span&gt;]. While IO and anti-vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) combinations are recommended first-line, they have not shown a significant OS benefit in patients with IMDC favorable risk and remain costly, limiting access in resource-constrained settings. This study evaluates clinical outcomes of mRCC patients treated with first-line sunitinib and aims to identify factors impacting these outcomes.&lt;/p&gt;&lt;p&gt;We conducted a retrospective cohort study using data from the Turkish Kidney Cancer Consortium (TKCC) database. The study included patients aged 18 and older diagnosed with mRCC and treated with sunitinib as a first-line therapy. The primary objectives were to evaluate time to treatment failure (TTF) across risk groups and identify factors affecting TTF. Secondary objectives included assessing OS by risk group, factors affecting OS, and objective response rate (ORR). TTF was defined as the time from treatment start to discontinuation due to any cause, while OS was defined as the time from treatment start to death. ORR represented the percentage achieving complete response (CR) or partial response (PR).&lt;/p&gt;&lt;p&gt;Statistical analyses were performed using IBM SPSS Statistics Version 24.0. Survival curves were estimated with the Kaplan-Meier method, and multivariate analyses included variables with &lt;i&gt;P&lt;/i&gt; ≤ 0.20 in univariate analyses. Cox regression calculated hazard ratios (HRs) with 95% confidence intervals (CIs), with &lt;i&gt;P&lt;/i&gt; &lt; 0.05 considered statistically significant.&lt;/p&gt;&lt;p&gt;A total of 531 patients with median age of 57.3 (interquartile range = 12.5) years were included the study. Baseline characteristics and of patients were summarized in Supplementary Table S1. Median TTF was 10.25 (95% CI = 8.94-11.55) months (Figure 1A). Median TTF was 10.12 (95% CI = 8.55-11.69) months for clear cell histology and 10.86 (95% CI = 8.14-13.21) months for non-clear cell histology (&lt;i&gt;P&lt;/i&gt; = 0.653). TTF was 15.70 (95% CI = 11.76-19.64), 11.36 (95% CI = 9.89-12.84), and 4.89 (95% CI = 3.83-5.95) months for IMDC favorable, intermediate and poor risk groups, respectively. There was no difference in TTF between patients with IMDC favorable risk and IMDC intermediate risk with 1 risk factor (15.70 months vs","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 5","pages":"572-576"},"PeriodicalIF":20.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Breaking barriers: Smart vaccine platforms for cancer immunomodulation","authors":"Mohammad Mahmoudi Gomari,&nbsp;Taha Ghantabpour,&nbsp;Nima Pourgholam,&nbsp;Neda Rostami,&nbsp;Stephen M. Hatfield,&nbsp;Farzaneh Namazifar,&nbsp;Shadi Abkhiz,&nbsp;Seyed Sadegh Eslami,&nbsp;Mahsa Ramezanpour,&nbsp;Mahsa Darestanifarahani,&nbsp;Igor Astsaturov,&nbsp;Sidi A. Bencherif","doi":"10.1002/cac2.70002","DOIUrl":"10.1002/cac2.70002","url":null,"abstract":"<p>Despite significant advancements in cancer treatment, current therapies often fail to completely eradicate malignant cells. This shortfall underscores the urgent need to explore alternative approaches such as cancer vaccines. Leveraging the immune system's natural ability to target and kill cancer cells holds great therapeutic potential. However, the development of cancer vaccines is hindered by several challenges, including low stability, inadequate immune response activation, and the immunosuppressive tumor microenvironment, which limit their efficacy. Recent progress in various fields, such as click chemistry, nanotechnology, exosome engineering, and neoantigen design, offer innovative solutions to these challenges. These achievements have led to the emergence of smart vaccine platforms (SVPs), which integrate protective carriers for messenger ribonucleic acid (mRNA) with functionalization strategies to optimize targeted delivery. Click chemistry further enhances SVP performance by improving the encapsulation of mRNA antigens and facilitating their precise delivery to target cells. This review highlights the latest developments in SVP technologies for cancer therapy, exploring both their opportunities and challenges in advancing these transformative approaches.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 5","pages":"529-571"},"PeriodicalIF":20.1,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of cervical cancer screening strategies in women living with HIV in Thailand","authors":"Patumrat Sripan,&nbsp;Myrtille Prouté,&nbsp;Nicole Ngo-Giang-Huong,&nbsp;Samreung Rangdaeng,&nbsp;Chaiwat Putiyanun,&nbsp;Guttiga Halue,&nbsp;Prattana Leenasirimakul,&nbsp;Suchart Thongpaen,&nbsp;Sudanee Buranabanjasatean,&nbsp;Sophie Le Coeur,&nbsp;Tristan Delory","doi":"10.1002/cac2.70000","DOIUrl":"10.1002/cac2.70000","url":null,"abstract":"&lt;p&gt;Women living with human immunodeficiency viruses (WLHIV) are six times more likely to develop cervical cancer than the general population; they represent less than 1% of the world's population, but account for more than 5% of cervical cancers [&lt;span&gt;1&lt;/span&gt;]. WLHIV also have higher prevalence of human papilloma virus (HPV) infection with high-risk oncogenic genotypes (HR-HPV) than the general population [&lt;span&gt;2&lt;/span&gt;]. In Asia, an estimated 35% (95% confidence interval [95% CI]: 30%-39%) of WLHIV carry HR-HPV infection [&lt;span&gt;3&lt;/span&gt;]. Before 2021, Thailand's national cervical cancer screening program recommended cervical cytology. Since then, the Thai Ministry of Public Health, in line with the World Health Organization (WHO), has approved screening of all women aged 30-60 years (including those living with HIV) with standalone (primary) HPV test every 5 years [&lt;span&gt;4&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;In this context, to determine the optimal cervical cancer screening strategy for WLHIV, we used data from the PapilloV cohort (NCT01792973) in which WLHIV had yearly screening for cervical cancer using cytology, HPV-DNA testing with full genotype subtyping (PapilloCheck&lt;sup&gt;®&lt;/sup&gt;, Greiner Bio-One, Germany), and histology if necessary. Women in the cohort were all receiving antiretroviral therapy (ART), their HIV infection was well-controlled and they were highly compliant with the screening study protocol: 90% with at least 2 visits and 81% with at least 3 visits.&lt;/p&gt;&lt;p&gt;We designed 17 screening strategies (Supplementary Figure S1), including cytology alone, primary HPV testing alone, reflex HPV testing (HPV test after abnormal cytology), reflex cytology (cytology after positive HPV testing), and co-testing (simultaneous cytology and HPV testing). For HPV testing, we considered four genotype combinations, among those prevalent in Asia and associated with cancer: “HR-HPV 16/18”, “HR-HPV 16/18/31/33/52”, “any HR-HPV”, and “any HR-HPV or potentially HR (pHR)-HPV” [&lt;span&gt;3, 5&lt;/span&gt;–&lt;span&gt;7&lt;/span&gt;]. Methods are detailed in Supplementary Materials and Methods.&lt;/p&gt;&lt;p&gt;Among 179 WLHIV who underwent a total of 251 check-up visits with three interpretable screening tests (cytology, HPV test, and biopsy) over the 3-year follow-up, we diagnosed 40 (15.9%, 95% CI: 11.9%-20.9%) cervical intraepithelial neoplasia grade 2 or higher (CIN2+) and 24 (9.6%, 95% CI: 6.5%-13.8%) CIN3+ at biopsy. The population selection and its characteristics including HIV infection history, cytology, histology and HPV testing results are detailed in Supplementary Tables S1-S2 and Supplementary Figure S2.&lt;/p&gt;&lt;p&gt;We estimated the diagnostic performance of each screening strategy and its probability of not detecting high-grade cervical lesions. Depending on the strategy, 4 to 40 CIN2+ lesions could be detected with a sensitivity ranging from 16% to 100%, specificity from 3% to 93%, positive predictive value from 16% to 53%, and negative predictive value from 77% to 100% (Supplementary Table S3). Th","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 5","pages":"525-528"},"PeriodicalIF":20.1,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70000","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cuproplasia and cuproptosis, two sides of the coin","authors":"Kaizhong Lu,&nbsp;Chandra Sugiarto Wijaya,&nbsp;Qinghua Yao,&nbsp;Hongchuan Jin,&nbsp;Lifeng Feng","doi":"10.1002/cac2.70001","DOIUrl":"10.1002/cac2.70001","url":null,"abstract":"<p>Copper is an essential micronutrient in the human body, mainly acting as a crucial cofactor required for a wide range of physiological processes across nearly all cell types. Recent advances revealed that tumor cells seize copper to fulfill their rapid proliferation, metastasis, immune evasion, and so on by reprogramming the copper regulatory network, defined as cuproplasia. Thus, targeting copper chelation to reduce copper levels has been considered a rational tumor therapy strategy. However, overloaded copper ions could be toxic, which leads to the aggregation of lipoylated mitochondrial proteins and the depletion of iron-sulfur clusters, ultimately resulting in cell death, termed cuproptosis. Upon its discovery, cuproptosis has attracted great interest from oncologists, and targeting cuproptosis by copper ionophores exhibits as a potential anti-tumor therapy. In this review, we present the underlying mechanisms involved in cuproplasia and cuproptosis. Additionally, we sum up the chemicals targeting either cuproplasia or cuproptosis for cancer therapy. Further attention should be paid to distinguishing cancer patients who are suitable for targeting cuproplasia or cuproptosis.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 5","pages":"505-524"},"PeriodicalIF":20.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover Image, Volume 45, Issue 1","authors":"Jiali Yao,&nbsp;Linlin Ji,&nbsp;Guang Wang,&nbsp;Jin Ding","doi":"10.1002/cac2.12551","DOIUrl":"https://doi.org/10.1002/cac2.12551","url":null,"abstract":"<p>The cover image is based on the article <i>Effect of neutrophils on tumor immunity and immunotherapy resistance with underlying mechanisms</i> by Jiali Yao et al., https://doi.org/10.1002/cac2.12613.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12551","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143118821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating tumor cells share RNA modules with early embryo trophectoderm and with metastatic cancer","authors":"Stefano Volinia,&nbsp;Anna Terrazzan,&nbsp;Tomasz S. Kaminski,&nbsp;Krystian Jadzewski,&nbsp;Eva Reali,&nbsp;Nicoletta Bianchi,&nbsp;Jeff Palatini","doi":"10.1002/cac2.12664","DOIUrl":"10.1002/cac2.12664","url":null,"abstract":"&lt;p&gt;Metastasis is the primary cause of cancer-related deaths, accounting for an estimated 66% to 90% of fatalities [&lt;span&gt;1&lt;/span&gt;]. It is a multistep process involving the dissemination of circulating tumor cells (CTCs) and their colonization of distant organs [&lt;span&gt;2, 3&lt;/span&gt;]. A higher number of detected CTCs in cancer patients is associated with shorter survival [&lt;span&gt;4&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;We analyzed 544 single-cell RNA sequencing (scRNA-seq) profiles of bona fide CTCs, identified as keratin-positive and aneuploid, from over 3,000 putative CTC profiles available in public databases, as detailed in Supplementary Table S1. Most of the CTCs originated from patients with breast cancer (&lt;i&gt;n&lt;/i&gt; = 502, 92.3%), while a smaller number were derived from patients with prostate cancer (&lt;i&gt;n&lt;/i&gt; = 42). All experimental methods are described in the Supplementary Materials and Methods.&lt;/p&gt;&lt;p&gt;All bona fide CTCs were positive for KRT18 and negative for PTPRC (CD45), as expected. Three main CTC subgroups were identified (Supplementary Figure S1). We labeled the two epithelial (EPCAM&lt;sup&gt;+&lt;/sup&gt;) subgroups as epithelial A (epiA) and epithelial B (epiB), while the third subgroup was mesenchymal (VIM&lt;sup&gt;+&lt;/sup&gt;/EPCAM&lt;sup&gt;−&lt;/sup&gt;). CAV1 and AXL showed the highest specificity for mesenchymal CTCs, whereas LY6E was the most distinctive gene for epiB CTCs (Supplementary Tables S2–S4). Further analysis revealed that mesenchymal and epiB, but not epiA CTCs, were actively engaged in the cell cycle, as inferred using the R package Tricycle (Supplementary Figure S1). The biological implications of these three CTC subgroups are highly relevant. Mesenchymal CTCs expressed significantly lower levels of KRT18 and other keratins, such as KRT19 and KRT7, compared to epithelial CTCs. Conversely, vimentin, another class of intermediate filaments, was highly expressed in mesenchymal CTCs. The shift from keratins to vimentin is a hallmark molecular event in epithelial-to-mesenchymal transition (EMT). EMT regulators ZEB1, ZEB2, and SNAI2 were upregulated in mesenchymal CTCs, indicating that EMT was responsible for their origin. These findings highlight the need to prioritize the detection and targeting of epiB and mesenchymal CTCs. PD-L1 (CD274), an important target for immunotherapy in clinical practice, was expressed in only a small fraction of mesenchymal CTCs and even less in epithelial CTCs (Supplementary Figure S2). In contrast, two other immune checkpoint genes, CD276 (B7-H3) and PVR (CD155), were highly expressed in CTCs, comparable to their expression in trophoblasts. This suggests an immuno-evasive phenotype common to most CTCs, driven by the expression of CD276 and PVR.&lt;/p&gt;&lt;p&gt;Is there a functional relationship between CTCs and trophoblast cells, as suggested by the co-expression of genes such as CD276, SP6, and LY6E (Supplementary Figure S3)? To address this question, we examined potential links between CTCs and the placenta or early embryo by integrating scRNA-seq profi","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 5","pages":"500-504"},"PeriodicalIF":20.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12664","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143032318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of SMARCB1 evokes targetable epigenetic vulnerabilities in epithelioid sarcoma","authors":"Jia Xiang Jin,&nbsp;Fabia Fuchslocher,&nbsp;Martha Carreno-Gonzalez,&nbsp;Felina Zahnow,&nbsp;A. Katharina Ceranski,&nbsp;Rainer Will,&nbsp;Dominic Helm,&nbsp;Felix Bestvater,&nbsp;Ana Banito,&nbsp;Roland Imle,&nbsp;Shunya Ohmura,&nbsp;Florencia Cidre-Aranaz,&nbsp;Thomas G. P. Grünewald","doi":"10.1002/cac2.12665","DOIUrl":"10.1002/cac2.12665","url":null,"abstract":"&lt;p&gt;Epithelioid sarcoma (EpS) is a high-grade malignancy of unknown histogenesis first described in 1970 [&lt;span&gt;1&lt;/span&gt;], characterized by high rates of relapse and metastasis, with 5-year survival rates of 60%-75% [&lt;span&gt;2&lt;/span&gt;]. The only Food and Drug Administration (FDA)-approved targeted therapy, the enhancer of zeste homology 2 (EZH2) inhibitor tazemetostat, achieved transient responses in only 15% of patients [&lt;span&gt;2&lt;/span&gt;]. To establish a solid mechanistic basis, we investigated the role of SWI/SNF related BAF chromatin remodeling complex subunit B1 (&lt;i&gt;SMARCB1&lt;/i&gt;) via multi-omics analyses. We engineered isogenic cell line models single-cell-cloned to minimize genetic variability, featuring doxycycline-(DOX)-inducible &lt;i&gt;SMARCB1&lt;/i&gt; expression systems alongside respective empty vector controls. The cell lines (FU-EPS-1; HS-ES-1, -2M, -2R; NEPS; VA-ES-BJ) exhibited homozygous &lt;i&gt;SMARCB1&lt;/i&gt; deletion and represented proximal and distal subtypes, with prominent &lt;i&gt;SMARCB1&lt;/i&gt; re-expression upon DOX-treatment (Figure 1A). DOX concentrations were adjusted to achieve SYBR/TaqMan-qPCR-controlled &lt;i&gt;SMARCB1&lt;/i&gt; levels comparable to &lt;i&gt;SMARCB1&lt;/i&gt;-proficient Ewing sarcoma (EwS) cell lines, minimizing experimental artefacts associated with supraphysiological expression (Supplementary Figure S1A-B). Western blots demonstrated that SMARCB1 underwent nuclear translocation and re-incorporation into the SWI/SNF complex (Figure 1B). Transcriptome profiling using Affymetrix Clariom D microarrays (GEO: GSE276634) and Weighted Gene Correlation Network Analysis (WGCNA) based on Gene Set Enrichment Analysis (GSEA) revealed downregulated signatures related to DNA-repair and epigenetic regulation, alongside upregulated developmental pathways upon &lt;i&gt;SMARCB1&lt;/i&gt; re-expression (Figure 1C). These findings were accompanied by dose-dependent reductions in clonogenicity (Figure 1D, Supplementary Figure S1C), while propidium-iodide-(PI)-based flow-cytometric cell-cycle-analysis showed delayed G1-to-S-phase transition (Supplementary Figure S1D). Orthotopic subcutaneous (s.c.) xenotransplantation experiments using VA-ES-BJ in immunocompromised &lt;i&gt;Nod/Scid/gamma&lt;/i&gt; (NSG) mice recapitulated the typical EpS morphology (Supplementary Figure S1E). After tumors became palpable, &lt;i&gt;SMARCB1&lt;/i&gt; re-expression via DOX supplementation in drinking water resulted in significantly reduced tumor growth (Figure 1E).&lt;/p&gt;&lt;p&gt;Since these findings underscored significant &lt;i&gt;SMARCB1&lt;/i&gt;-associated epigenetic regulation (Figure 1C) [&lt;span&gt;3&lt;/span&gt;], we next investigated SWI/SNF chromatin-remodeling functionality via Assay for Transposase-Accessible Chromatin using Sequencing (ATAC-Seq; GEO: GSE281434) in FU-EPS-1, HS-ES-2M, NEPS and VA-ES-BJ to compare the effects of &lt;i&gt;SMARCB1&lt;/i&gt;-deficient and physiological SWI/SNF assemblies. &lt;i&gt;SMARCB1&lt;/i&gt; re-expression increased chromatin accessibility at putative enhancer sites (box 1) and gene bodies (box 2) (Figure 1F). Conversely, SWI/SNF-inhibi","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 5","pages":"494-499"},"PeriodicalIF":20.1,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12665","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of mTOR attenuates the initiation and progression of BRCA1-associated mammary tumors","authors":"Hye Jung Baek,&nbsp;Geun Hee Han,&nbsp;Eun Joo Cho,&nbsp;Jihao Xu,&nbsp;Min Kyung Ki,&nbsp;Eun Jung Park,&nbsp;Tae Hyun Kim,&nbsp;Dong Hoon Shin,&nbsp;Heesun Cheong,&nbsp;Chu-Xia Deng,&nbsp;Sung Chul Lim,&nbsp;Chang-il Hwang,&nbsp;Daehee Hwang,&nbsp;Sang Soo Kim","doi":"10.1002/cac2.12663","DOIUrl":"10.1002/cac2.12663","url":null,"abstract":"&lt;p&gt;Inherited mutation in breast cancer susceptibility gene 1 (&lt;i&gt;BRCA1&lt;/i&gt;) is strongly associated with mammary tumors that exhibit triple-negative characteristics, are insensitive to endocrine-targeted therapies, and show basal-like properties, including aggressive phenotypes [&lt;span&gt;1, 2&lt;/span&gt;]. It has been reported that the average cumulative risk of breast cancer for &lt;i&gt;BRCA1&lt;/i&gt; mutation carriers by age 70 years is 57% (95% confidence interval [CI]: 47%-66%) [&lt;span&gt;3&lt;/span&gt;]. Despite the high incidence and aggressive characteristics of &lt;i&gt;BRCA1&lt;/i&gt;-associated breast cancer, few substantial improvements in preventing or treating this cancer have been made, largely due to the challenges of clinic-based cohort studies. During malignant transformation, cancer progression is facilitated by metabolic reprogramming–one of the hallmark characteristics of cancer. Previously, we found that inhibition of AKT is a potential strategy for the prevention and therapeutic management of &lt;i&gt;Brca1&lt;/i&gt;-mutant mammary tumors. However, pharmacological inhibition proved less effective and less safe compared to genetic perturbation, limiting its potential for clinical application [&lt;span&gt;4&lt;/span&gt;]. Meanwhile, mTOR, a key regulator of metabolism and a downstream target of the PI3K/AKT signaling pathway, has emerged as a promising therapeutic target for several diseases, including treatment of cancer [&lt;span&gt;5&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;In addition to identifying the contribution of mTOR signaling to BRCA1-deficient cells (Supplementary Figure S1), we provide genetic and pharmacological evidence using multi-orthogonal preclinical models [&lt;span&gt;6-8&lt;/span&gt;] that mTOR is closely involved in the development and growth of &lt;i&gt;Brca1&lt;/i&gt;-mutated mammary tumors (Figure 1A). To investigate the role of mTOR in the absence of BRCA1, we assessed the development of mammary glands in post-pubertal &lt;i&gt;Brca1/Mtor&lt;/i&gt;-mutant mice by examining ductal and lobular development of the fourth mammary gland. Measurements of mammary gland density using the Branch software (ver. 1.1 [&lt;span&gt;9&lt;/span&gt;]) showed that ductal length and branching were significantly diminished in the mammary glands of &lt;i&gt;Brca1&lt;sup&gt;co/co&lt;/sup&gt;Mtor&lt;sup&gt;co/co&lt;/sup&gt;MMTV-Cre&lt;/i&gt; mice (Figure 1B,C, Supplementary Figure S2). To determine whether mTOR contributes to BRCA1-deficient mammary tumor formation, we examined tumor formation in cohorts of &lt;i&gt;Brca1&lt;sup&gt;co/co&lt;/sup&gt;&lt;/i&gt; (&lt;i&gt;n&lt;/i&gt; = 28), &lt;i&gt;Brca1&lt;sup&gt;co/co&lt;/sup&gt;Mtor&lt;sup&gt;co/co&lt;/sup&gt;&lt;/i&gt; (&lt;i&gt;n&lt;/i&gt; = 30), &lt;i&gt;Brca1&lt;sup&gt;co/co&lt;/sup&gt;MMTV-Cre&lt;/i&gt; (&lt;i&gt;n&lt;/i&gt; = 24), and &lt;i&gt;Brca1&lt;sup&gt;co/co&lt;/sup&gt;Mtor&lt;sup&gt;co/co&lt;/sup&gt;MMTV-Cre&lt;/i&gt; (&lt;i&gt;n&lt;/i&gt; = 29) mice (Top left of Figure 1A). &lt;i&gt;Brca1&lt;sup&gt;co/co&lt;/sup&gt;&lt;/i&gt; and &lt;i&gt;Brca1&lt;sup&gt;co/co&lt;/sup&gt;Mtor&lt;sup&gt;co/co&lt;/sup&gt;&lt;/i&gt; mice showed no signs of mammary abnormalities, including tumors, up to 24 months of age. In contrast, &lt;i&gt;Brca1&lt;sup&gt;co/co&lt;/sup&gt;MMTV-Cre&lt;/i&gt; mutant mice developed breast cancer, reaching a high incidence (37.5%; 9/24) by 24 months of age. During the s","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"486-490"},"PeriodicalIF":20.1,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12663","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}