Cancer Communications最新文献

{"title":"Cover Image, Volume 45, Issue 11","authors":"Jiaqi Liang,&nbsp;Guoshu Bi,&nbsp;Xiaolong Huang,&nbsp;Zhijie Xu,&nbsp;Yiwei Huang,&nbsp;Yunyi Bian,&nbsp;Guangyao Shan,&nbsp;Wei Guo,&nbsp;Yuanliang Yan,&nbsp;Qihai Sui,&nbsp;Xiaodong Yang,&nbsp;Zhencong Chen,&nbsp;Tao Lu,&nbsp;Huan Zhang,&nbsp;Qun Wang,&nbsp;Wei Jiang,&nbsp;Cheng Zhan","doi":"10.1002/cac2.70081","DOIUrl":"https://doi.org/10.1002/cac2.70081","url":null,"abstract":"<p>The cover image is based on the article <i>CD24 is a promising immunotherapeutic target for enhancing efficacy of third-generation EGFR-TKIs on EGFR-mutated lung cancer</i> by Jiaqi Liang et al., https://doi.org/10.1002/cac2.70068.\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 11","pages":""},"PeriodicalIF":24.9,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70081","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145547162","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":"Efficacy and safety of combining bevacizumab and fractionated stereotactic radiotherapy for extensive brain metastases in patients with non-small cell lung cancer: a prospective phase II study (GASTO-1053)","authors":"Rui Zhou,&nbsp;Shiyang Zheng,&nbsp;Daquan Wang,&nbsp;Fang Dong,&nbsp;Hongmei Zhang,&nbsp;Tao Zhang,&nbsp;Qiaoting Luo,&nbsp;Biaoshui Liu,&nbsp;Hui Liu,&nbsp;Jun Zhang,&nbsp;Fangjie Liu,&nbsp;Bin Wang,&nbsp;Likun Chen,&nbsp;Yonggao Mou,&nbsp;Kangqiang Peng,&nbsp;Bo Qiu,&nbsp;Hui Liu","doi":"10.1002/cac2.70078","DOIUrl":"10.1002/cac2.70078","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The prognosis for non-small cell lung cancer (NSCLC) patients with extensive brain metastases (BMs) treated with radiotherapy alone remains poor. Based on the synergistic potential of radiotherapy and angiogenesis inhibitors, we initiated this phase II study to assess the efficacy and safety of combining bevacizumab (Bev) with fractionated stereotactic radiotherapy (FSRT) in managing extensive BMs in NSCLC patients who had stable extracranial disease.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Patients with extensive BMs from NSCLC, deemed unsuitable for stereotactic radiosurgery, were prospectively enrolled following multidisciplinary tumor board evaluation. Patients received FSRT (40 Gy in 10 fractions or 30 Gy in 5 fractions) in combination with Bev (7.5 mg/kg on day 1 prior to FSRT and on day 21 post-FSRT). The primary endpoint was intracranial progression-free survival (IPFS). Secondary endpoints included overall survival, progression-free survival, quality of life (QOL), and toxicities. For comparison, NSCLC patients with extensive BMs treated with whole-brain radiotherapy (WBRT) plus FSRT or FSRT alone were matched 1:1 with the study group (Bev + FSRT) using the propensity score matching.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;One hundred and six patients were included in the Bev + FSRT group, with a median follow-up duration of 35.8 months. The median IPFS was 18.3 months (95% confidence interval, 15.2-23.3 months). The Bev + FSRT group showed a significant improvement in IPFS compared to both the WBRT + FSRT group (9.6 months, P &lt; 0.001) and the FSRT alone group (8.9 months, P &lt; 0.001). Treatment was well tolerated, with grade 1 radiation necrosis in 1 patient. Bev + FSRT treatment significantly reduced tumor volume (&lt;i&gt;P&lt;/i&gt; &lt; 0.001), peritumoral edema volume (&lt;i&gt;P&lt;/i&gt; = 0.004), and vascular leakage (&lt;i&gt;P&lt;/i&gt; &lt; 0.001). Furthermore, QOL was significantly improved after Bev + FSRT treatment, particularly in patients with symptomatic extensive BMs.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;These findings support the combination of Bev and FSRT as a safe and effective treatment strategy for extensive BMs in NSCLC patients, offering improved intracranial disease control and symptom relief while avoiding the neurotoxicity associated with WBRT. A randomized trial is warranted to validate the findings of the current study.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Trial registration&lt;/h3&gt;\u0000 \u0000 &lt;p","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 12","pages":"1739-1754"},"PeriodicalIF":24.9,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12728488/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145511785","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":"Pan-cyclin-dependent kinase inhibition is a potential treatment for adenoid cystic carcinoma that downregulates the MYB::NFIB fusion and induces tumor regression","authors":"Junchi Huang,&nbsp;Peter Larsson,&nbsp;Maryam Kakay Afshari,&nbsp;Paloma Tejera Nevado,&nbsp;Tajana Tešan Tomić,&nbsp;André Fehr,&nbsp;Fredrik Jäwert,&nbsp;Göran Stenman,&nbsp;Mattias K. Andersson","doi":"10.1002/cac2.70079","DOIUrl":"10.1002/cac2.70079","url":null,"abstract":"&lt;p&gt;Adenoid cystic carcinoma (ACC) is an aggressive glandular cancer primarily affecting the major and minor salivary glands but may also occur in other anatomical locations such as the breast, prostate, lungs, and skin [&lt;span&gt;1, 2&lt;/span&gt;]. ACC has a poor long-term prognosis due to frequent recurrences and distant metastases and is unresponsive to all so far tested systemic therapies. The &lt;i&gt;MYB&lt;/i&gt; proto-oncogene, transcription factor (&lt;i&gt;MYB&lt;/i&gt;), is a key oncogenic driver activated by gene fusions in ACC [&lt;span&gt;3-7&lt;/span&gt;]. We have previously demonstrated that the canonical &lt;i&gt;MYB&lt;/i&gt;::nuclear factor I B (&lt;i&gt;NFIB&lt;/i&gt;) fusion (&lt;i&gt;MYB::NFIB&lt;/i&gt;) is targetable by insulin-like growth factor 1 receptor/AKT serine-threonine kinase (IGF1R/AKT) inhibitors, demonstrating that it is indeed an actionable target in ACC [&lt;span&gt;5&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;To identify more effective therapeutic options for ACC patients, we conducted an in vitro drug screen using carefully validated &lt;i&gt;MYB::NFIB&lt;/i&gt;-positive ACC cells and a custom-made library of more than 300 small-molecule inhibitors covering important druggable targets in precision oncology (Supplementary Materials). Notably, cyclin-dependent kinase (CDK) inhibitors emerged among the most effective agents that reduced the viability of ACC cells (Figure 1A, Supplementary Tables S1-S2). We further tested 8 different U.S. Food and Drug Administration (FDA)-approved/phase II–III CDK inhibitors, of which dinaciclib (a pan-CDK inhibitor) showed by far the highest potency (half maximal inhibitory concentration [IC50]: 10–13 nmol/L, &lt;i&gt;P&lt;/i&gt; &lt; 0.001) (Figure 1B, Supplementary Figure S1A). ACC cells were significantly less sensitive to U.S. FDA-approved CDK4/6 inhibitors, such as palbociclib and ribociclib, than to dinaciclib. The ACC cell line, UM-HACC-2A, showed similar sensitivity to dinaciclib as ACCX11 and ACC67 cells, whereas control pleomorphic adenoma (PA) cells were significantly less responsive (Supplementary Figure S1B). Additional top hits from our screen included histone deacetylase, proteasome, and IGF1R-phosphoinositide 3-kinase (PI3K)-AKT inhibitors, consistent with our previous findings [&lt;span&gt;5, 8&lt;/span&gt;] and thus validating our screening approach.&lt;/p&gt;&lt;p&gt;Dinaciclib caused a significant decrease in ACC spheroid formation at nanomolar concentrations (Figure 1C, Supplementary Figure S2A), suggesting that it inhibits cell division of immature stem-like ACC cells capable of tumor initiation. Flow cytometry analysis of dinaciclib-treated ACC cells revealed reduced S-phase entry and accumulation of cells in the G1 and G2/M phases, indicating cell cycle arrest at multiple checkpoints (Supplementary Figures S2B-C and S3). To test if CDK inhibition leads to apoptosis in ACC cells, we treated ACCX11 and ACC67 cells with CDK inhibitors at different concentrations for 24 h. Dinaciclib induced apoptosis at low concentrations, whereas Flavopiridol and AT7519 caused apoptosis at much higher concentrations; the other teste","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 12","pages":"1734-1738"},"PeriodicalIF":24.9,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12728483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145494756","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":"Unfolded protein response kinase PERK supports survival and metastasis of circulating tumor cell clusters via SAM synthesis and H3K4me3-dependent PDGFB signaling","authors":"Rui Tang,&nbsp;Yan Sun,&nbsp;Ao Deng,&nbsp;Jiahe Liu,&nbsp;Peijin Dai,&nbsp;Jing Chen,&nbsp;Chaoqun Deng,&nbsp;Hui Liu,&nbsp;Yuhang Hai,&nbsp;Yanran Tong,&nbsp;Yan-e Du,&nbsp;Manran Liu,&nbsp;Haojun Luo","doi":"10.1002/cac2.70072","DOIUrl":"10.1002/cac2.70072","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Metastasis is the leading cause of cancer-related mortality, with circulating tumor cell (CTC) clusters serving as highly efficient precursors of distant metastasis. Survival of CTC clusters in the bloodstream is the primary contributor to tumor metastasis. However, the underlying mechanisms of how CTC clusters respond to the blood environment and drive metastasis remain elusive. This study aimed to elucidate the potential mechanisms that enable CTC clusters to adapt and survive in the bloodstream.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;CTC clusters were detected using a microfluidic system in cancer patients, as well as in patient-derived xenograft (PDX), cell line-derived xenograft, and syngeneic models. The key molecules responsible for the adaptive survival of CTC clusters were characterized using RNA-sequencing (RNA-seq), gene interference, and flow cytometry. To investigate the underlying mechanisms of adaptive survival, RNA-seq, targeted metabolomics, isotope tracing experiments, chromatin immunoprecipitation (ChIP) sequencing, and immunofluorescence (IF) staining were employed. The therapeutic potential of survival pathway inhibitor combined with chemotherapy drug was evaluated in patient-derived CTCs and the PDX model.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;CTC clusters exhibited superior survival and metastatic capacity compared to single CTCs and were associated with adverse clinical outcomes. The unfolded protein response mediator protein kinase R-like endoplasmic reticulum kinase (PERK) was activated in CTC clusters and maintained S-adenosylmethionine (SAM) availability, facilitating their adaptive survival in the bloodstream. Mechanistically, PERK mediated the upregulation of activating transcription factor 4 (ATF4), which enhanced methionine adenosyltransferase 2A (MAT2A) expression, contributing to SAM synthesis. Increased SAM enhanced H3K4me3 modification of the platelet-derived growth factor B (&lt;i&gt;PDGFB&lt;/i&gt;) promoter, leading to elevated PDGFB secretion and its accumulation in the intercellular region within CTC clusters. PDGFB functioned as a shared survival signal, triggering the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway via platelet-derived growth factor receptor beta (PDGFRβ), supporting CTC cluster survival in the bloodstream. Inhibition of PERK and PDGFRβ profoundly impaired the survival signaling and suppressed the metastatic dissemination of CTC clusters.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Our findings revealed a PERK/MAT2A/PDGFB axi","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 12","pages":"1706-1733"},"PeriodicalIF":24.9,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12728491/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145487926","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":"HMGB3 promotes brain metastasis of lung adenocarcinoma by recruiting SSBP1 for nuclear translocation to remodel mitochondrial metabolism","authors":"Huanhuan Cui,&nbsp;Yuechao Yang,&nbsp;Sen Li,&nbsp;Yan Hao,&nbsp;Mingtao Feng,&nbsp;Changshuai Zhou,&nbsp;Xin Chen,&nbsp;Yang Gao,&nbsp;Lei Chen,&nbsp;Xiaojun Wu,&nbsp;Weiguo Hu,&nbsp;Liangdong Li,&nbsp;Yiqun Cao","doi":"10.1002/cac2.70075","DOIUrl":"10.1002/cac2.70075","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Brain metastasis, a leading cause of death in patients with lung adenocarcinoma (LUAD), arises from tumor cells adapting to the unique microenvironment of the brain through metabolic remodeling regulated by key oncogenes. Here, we aimed to determine the role of high mobility group protein box 3 (HMGB3) in regulating tumor cell metabolism to promote the progression and brain metastasis of LUAD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A LUAD cell model predisposed to brain metastasis was established, followed by differential gene expression analysis. HMGB3 expression was quantified via single-cell RNA sequencing (scRNA-seq) and immunohistochemistry, with clinical relevance assessed in two retrospective cohorts: the primary LUAD and the LUAD brain metastasis cohorts. Gene enrichment analysis of scRNA-seq and bulk RNA-seq data, along with Western blotting, were performed to identify HMGB3-associated pathways. Co-immunoprecipitation combined with mass spectrometry was used to detect HMGB3-interacting proteins. Gain-of-function, loss-of-function and rescue experiments targeting HMGB3 downstream pathways were conducted in vitro and in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>HMGB3 expression was significantly elevated in both primary LUAD lesions and brain metastatic foci, and its upregulation was strongly associated with poor prognosis in LUAD patients, as well as in those with concomitant brain metastasis. HMGB3 enhanced the migration, invasion, and epithelial-mesenchymal transition (EMT) capabilities of LUAD cells in vitro and promoted the development of brain metastasis in vivo. Mechanistically, HMGB3 recruited and interacted with single-stranded DNA-binding protein 1 (SSBP1), inducing its nuclear translocation and reprogramming mitochondrial metabolism. This process elevated cytoplasmic reactive oxygen species levels, which subsequently activated the phosphatidylinositol 3-kinase/protein kinase B (PI3K-Akt) signaling pathway through downregulating phosphatase and tensin homolog (PTEN), ultimately promoting tumor cell proliferation, migration, invasion, and EMT.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study demonstrated HMGB3 as a key regulator of the brain metastasis of LUAD, orchestrating tumor cells’ metabolic adaptation to the brain microenvironment through modulation of mitochondrial metabolism, thereby offering potential therapeutic targets for LUAD brain metastases.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 12","pages":"1676-1705"},"PeriodicalIF":24.9,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12728482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145451116","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":"In vivo intratumoral heterogeneity in a dish: scalable forebrain organoid models of embryonal brain tumors for high-throughput personalized drug discovery","authors":"Nicole C. Riedel,&nbsp;Carolin Walter,&nbsp;Flavia W. de Faria,&nbsp;Lea Altendorf,&nbsp;Paula Aust,&nbsp;Carolin Göbel,&nbsp;Archana Verma,&nbsp;Annika Ballast,&nbsp;Ivan Bedzhov,&nbsp;Rajanya Roy,&nbsp;Daniel Münter,&nbsp;Erik Schüftan,&nbsp;Thomas K. Albert,&nbsp;Claudia Rössig,&nbsp;Pascal Johann,&nbsp;Barbara von Zezschwitz,&nbsp;Sarah Sandmann,&nbsp;Julian Varghese,&nbsp;Christian Thomas,&nbsp;Ulrich Schüller,&nbsp;Jan M. Bruder,&nbsp;Kornelius Kerl","doi":"10.1002/cac2.70074","DOIUrl":"10.1002/cac2.70074","url":null,"abstract":"&lt;p&gt;Brain tumors are the most prevalent solid tumors in pediatrics, with atypical teratoid and rhabdoid tumor (ATRT) and embryonal tumor with multilayered rosettes (ETMR) presenting particularly poor prognoses.&lt;/p&gt;&lt;p&gt;The development of effective therapies is hampered by the lack of in vitro models that accurately reflect the complex tumor microenvironment (TME) and intratumoral heterogeneity observed in vivo. Traditional monolayer and tumorsphere/tumoroid cultures fail to capture these critical aspects [&lt;span&gt;1&lt;/span&gt;], biasing them towards proliferative cell populations that respond differently to drugs than the original tumor. Likewise, in vivo models have fundamental limitations: they lack the primate-specific chromosome 19 microRNA cluster (C19MC) driver central to ETMR [&lt;span&gt;2&lt;/span&gt;], cannot capture human-specific neurotoxicity, and are impractical for scalable drug screens [&lt;span&gt;1, 3&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;To address this, we developed a scalable and reproducible tumor-forebrain-organoid (TBO) model for ETMR and ATRT sonic hedgehog (ATRT-SHH) using a novel coaggregation method, which we characterized histologically and transcriptionally, and applied to drug screening, thereby identifying new candidate therapeutics for ETMR (Supplementary File of Methods). The automated workflow ensures high reproducibility and scalability, enabling the parallel generation of thousands of TBOs for high-throughput drug screening on tumor and TME.&lt;/p&gt;&lt;p&gt;To integrate central nervous system embryonal tumors into forebrain organoids (FBOs), which recapitulate key developmental trends and contain comparable cell populations found in first- and second-trimester fetal brains, we modified an automated FBO model [&lt;span&gt;4&lt;/span&gt;] (Supplementary Figures S1, S3). For this, we employed a coaggregation approach, which involved mixing tumor and human-induced pluripotent stem cells (hiPSCs), and subsequently allowing their aggregation and joint maturation to form TBOs (Figure 1A). Confocal microscopy of whole-mount immunostained and cleared organoids revealed a broad and uniform integration of green fluorescent protein (GFP)-tagged human ETMR and ATRT-SHH (hETMR and hATRT-SHH) cells throughout FBOs (Figure 1B). The automated workflow allowed for the parallel generation of highly uniform and reproducible TBOs in 96-well plates, with low-standard error of the mean for the GFP signal intensity, indicative for tumor content, across multiple TBOs for both hETMR-FBO and hATRT-SHH-FBO (Figure 1C).&lt;/p&gt;&lt;p&gt;To comprehensively characterize TBOs, we employed immunohistochemistry (IHC) to examine the phenotype of hETMR- and hATRT-SHH-FBOs, with age-matched FBOs as controls. hETMR tumor areas were identified based on lin-28 homolog A (LIN28A) positivity, multilayered rosettes, and C19MC alterations, along with GFP immunofluorescence (Figure 1D, Supplementary Figure S4A-D). Control 1-month aged FBOs exhibited a predominantly immature phenotype [LIN28A&lt;sup&gt;+&lt;/sup&gt;, SRY-box transcription factor 2 (","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 12","pages":"1670-1675"},"PeriodicalIF":24.9,"publicationDate":"2025-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12728470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145430387","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":"A practical overview and statistical analysis of interval-censored data in cancer","authors":"Tanujit Dey,&nbsp;Stuart Lipsitz,&nbsp;Zara Cooper,&nbsp;Debajyoti Sinha,&nbsp;Quoc-Dien Trinh,&nbsp;Alexander Cole,&nbsp;Timothy N. Clinton","doi":"10.1002/cac2.70073","DOIUrl":"10.1002/cac2.70073","url":null,"abstract":"&lt;p&gt;In many clinical, biomedical, and epidemiologic cancer studies, the outcome of interest is the time until an event (or failure) occurs, and “survival analysis” is performed to estimate the effect of covariates on survival. Most clinical investigators are familiar with the term “right censoring”. The type of censoring we focus on in this paper is “interval-censoring” [&lt;span&gt;1-3&lt;/span&gt;]. Interval-censoring occurs when the event of interest cannot be easily observed but is determined by imaging and/or blood biomarker tests at clinic visits. For example, suppose a patient comes in for imaging every 3 months, to detect the event (cancer recurrence). If recurrence is found at a visit, it occurred sometime between that visit and the previous visit where no recurrence was detected—this is “interval-censoring”. Researchers often code the event date as the visit when recurrence is detected, but this overestimates time to recurrence since it occurred earlier within the interval. Modern statistical software supports proper interval-censoring methods, making it unnecessary to use visit dates as event dates. Since most cancer recurrences are identified through imaging or biomarker tests at clinic visits, interval-censoring methods should be used, at least as a sensitivity analysis to assess the impact of coding the event date as the visit date when recurrence is detected .&lt;/p&gt;&lt;p&gt;Consider a study of biochemical recurrence in 260 patients with localized prostate cancer who underwent radical prostatectomy [&lt;span&gt;4&lt;/span&gt;]. After surgery, prostate-specific antigen (PSA) levels drop to 0 ng/mL, and recurrence is defined as the time PSA exceeds 0.1 ng/mL. Since PSA is measured only at regular intervals (every 3 or 6 months), the recurrence time is unknown and interval-censored between visits. Clinicians often use the first elevated PSA test as the recurrence date, though the true event occurred between the current and previous visit. An interval-censored Cox model assessed the impact of Gleason score, surgical margin, preoperative PSA, and pathologic stage on recurrence time.&lt;/p&gt;&lt;p&gt;Parameters of survival models are estimated by maximizing a “likelihood” (ML). A patient with an exact failure time &lt;i&gt;t&lt;/i&gt; contributes the probability of failure at &lt;i&gt;t&lt;/i&gt; to the likelihood. A patient right-censored at time &lt;i&gt;t&lt;/i&gt; contributes the probability of surviving beyond &lt;i&gt;t&lt;/i&gt;. An interval-censored patient whose event occurs in the interval (&lt;i&gt;L&lt;/i&gt;, &lt;i&gt;U&lt;/i&gt;), contributes the probability of failure within that interval. After assuming a survival model (e.g., proportional hazards), the probabilities of failure at a given time (no censoring), between two time points (interval-censoring), or greater than a time point (right-censoring), are easily calculated and used in ML.&lt;/p&gt;&lt;p&gt;Despite the long history of interval-censoring statistical methodology [&lt;span&gt;1-3&lt;/span&gt;], until recently, few software packages were available to analyze interval-censored data in a statistical","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 12","pages":"1666-1669"},"PeriodicalIF":24.9,"publicationDate":"2025-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12728475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145430321","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":"The INSPECTOR study: enhanced feasibility for clinical translation of a multi-cancer early detection method based on enzyme-assisted high signal-to-noise ratio sequencing of methylated circulating tumor DNA","authors":"Hui-Yan Luo,&nbsp;Wei Wei,&nbsp;Pansong Li,&nbsp;Qi-Hua Zhang,&nbsp;Zhipeng Zhou,&nbsp;Liang Cui,&nbsp;Yong-Bin Lin,&nbsp;Hong Yang,&nbsp;Xianyu Zhong,&nbsp;Qingfeng Liu,&nbsp;Han Yang,&nbsp;Kong-Jia Luo,&nbsp;Hai-Bo Qiu,&nbsp;Shu-Qiang Yuan,&nbsp;Yuan-Fang Li,&nbsp;Zhi-Wei Zhou,&nbsp;Xiao-Jun Lin,&nbsp;Bo-Kang Cui,&nbsp;Rong-Xin Zhang,&nbsp;Wen-Hua Fan,&nbsp;He Huang,&nbsp;Chun-Yan Lan,&nbsp;Jun-Dong Li,&nbsp;Zhi-Qiang Wang,&nbsp;Bin-Kui Li,&nbsp;Rong-Ping Guo,&nbsp;Jun Tang,&nbsp;Xin Huang,&nbsp;Mian Xi,&nbsp;Yuying Liu,&nbsp;Chuanbo Xie,&nbsp;Shi Chen,&nbsp;Zhi-Hu Li,&nbsp;Yu-Hua Liu,&nbsp;Xiao-Ting Zhang,&nbsp;Qiang Zeng,&nbsp;Xin Yi,&nbsp;Rui-Hua Xu","doi":"10.1002/cac2.70071","DOIUrl":"10.1002/cac2.70071","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Blood-based cell-free DNA (cfDNA) methylation testing has emerged as a promising approach for multi-cancer early detection (MCED), holding the potential to improve cancer survival rates. However, traditional bisulfite-based methods often encounter sensitivity limitations in detecting early-stage malignancies or certain cancer types. In the INSPECTOR study, we developed a MCED and cancer signal origin (CSO) system specifically designed for early-stage or hard-to-detect cancers, including those of the lung, breast, colorectum, liver, esophagus, stomach, pancreas, and ovary.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We established a comprehensive methylation marker discovery database (&lt;i&gt;n&lt;/i&gt; = 6,342) by integrating public datasets (&lt;i&gt;n&lt;/i&gt; = 4,699) and in-house samples (&lt;i&gt;n&lt;/i&gt; = 1,643), all processed using human TET (hTET) enzyme-assisted whole-methylome sequencing (GM-seq). This enabled the design of a targeted panel encompassing 155,362 methylated CpG sites. Leveraging hTET-assisted high-depth next-generation sequencing (NGS), our blood test achieved a median unique depth of 1,093×. Multicenter case-control cohorts, including various pathological subtypes, were used for training, validation, and independent validation of MCED and CSO models, and to verify the clinical feasibility.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Clinical validation was conducted across multi-center case-control cohorts, including 1,071 participants in the training set, 581 in the validation set, and 824 in the independent validation set. The MCED assay demonstrated robust performance with a specificity of 99.1% and sensitivity of 83.2% in the training set, 99.0% and 81.8% in the validation set, and comparable results in the independent validation set (99.0% specificity, 81.9% sensitivity). Notably, sensitivity reached 65.5% for stage I cancers, 79.7% for stage II, and 71.3% for stages I-II combined. The sensitivities for different cancer types were as follows: esophageal (79.2%), gastric (76.1%), colorectal (86.2%), pancreatic (66.7%), liver (100.0%), lung (72.9%), breast (88.9%), and ovarian (87.9%). The CSO model exhibited strong accuracy, with top-1 cancer origin prediction rates of 87.9% (validation) and 87.4% (independent validation), rising to 95.1% and 94.5% for top-2 predictions, respectively. For stage I cancers specifically, the top-1 accuracy was 85.5%.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;These findings underscore the efficacy of the hTET-assisted cfDNA methylation sequencing system across divers","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 12","pages":"1645-1665"},"PeriodicalIF":24.9,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12728497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145399604","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":"Intranuclear paraspeckle-circular RNA TACC3 assembly forms RNA-DNA hybrids to facilitate MASH-related hepatocellular carcinoma growth in an m6A-dependent manner","authors":"Jingbo Fu,&nbsp;Yanping Wei,&nbsp;Yun Yang,&nbsp;Xinwei Yang,&nbsp;Tao Ouyang,&nbsp;Xianming Wang,&nbsp;Shuzhen Chen,&nbsp;Zenglin Liu,&nbsp;Yu Su,&nbsp;Jing Fu,&nbsp;Miao Yu,&nbsp;Haihua Qian,&nbsp;Hao Song,&nbsp;Shuo Xu,&nbsp;Ru Zhao,&nbsp;Xue Jiang,&nbsp;Yunfei Huo,&nbsp;Man Zhang,&nbsp;Pinhua Yang,&nbsp;Zhao Yang,&nbsp;Kui Wang,&nbsp;Liang Li,&nbsp;Hongyang Wang","doi":"10.1002/cac2.70061","DOIUrl":"10.1002/cac2.70061","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Metabolic dysfunction-associated steatohepatitis (MASH) is anticipated to become the leading cause of hepatocellular carcinoma (HCC). Accumulating evidence indicates that N6-methyladenosine (m&lt;sup&gt;6&lt;/sup&gt;A)-modified circular RNAs (circRNAs) play key roles in tumor malignant progression. However, the precise molecular mechanisms by which circRNAs and their m&lt;sup&gt;6&lt;/sup&gt;A modification regulatory networks respond to metabolic reprogramming, such as lipid overload stress, to drive malignant tumor progression in the context of MASH-related HCC remain unclear. This study aimed to investigate the role and regulatory network of m&lt;sup&gt;6&lt;/sup&gt;A-modified circRNAs in MASH-related HCC.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Epitranscriptomic microarray and in situ hybridization assays were used to validate circTACC3 expression in MASH-related HCC specimens. Palmitic acid (PA) and oleic acid (OA) was applied to NAC-organ assembled three-dimensional-organoid and HCC cell lines to imitate pathological lipid overload. The circTACC3-paraspeckle interaction was studied utilizing fluorescence lifetime imaging microscopy-Forster resonance energy transfer. An integrative analysis combining DNA-RNA immunoprecipitation combined with chromatin isolation by RNA purification (DRIP-ChIRP), γH2AX cleavage under target and tagmentation, and high-throughput/resolution chromosome conformation capture sequencing were used to study chromatin remodeling induced by circTACC3-formed RNA-DNA hybrids (R loops) at DNA double-strand break (DSB) loci during lipid overload.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The most prevalent m&lt;sup&gt;6&lt;/sup&gt;A-modified circRNA in MASH-related HCC, circTACC3, had a substantial impact on the intracellular lipid accumulation, growth, and environmental adaptive survival of tumor cells. Under lipid overload conditions, circTACC3 interacted directly with non-POU domain-containing octamer-binding protein (NONO/p54&lt;sup&gt;nrb&lt;/sup&gt;) to assemble intranuclear paraspeckle. This process was dependent on the m&lt;sup&gt;6&lt;/sup&gt;A-modification sites of circTACC3 and facilitated its nuclear retention. Using DRIP-ChIRP-sequencing, we demonstrated that circTACC3-containing paraspeckles were recruited to DSB foci to form R loops (DSB-circTACC3-R loops). We discovered 4 highly enriched motifs of DSB-circTACC3-R loops. DSB-circTACC3-R loops further facilitated the contact and fusion of topologically associated domains (TADs) and selectively activated genes related to the malignant phenotype of MASH-related HCC. Interestingly, circTACC3-R loops exerted positive feedback control over the assembly of circTACC3 paraspeckle and clusteri","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 11","pages":"1583-1610"},"PeriodicalIF":24.9,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70061","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145306893","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":"RNA m1A methyltransferase TRMT61A promotes colorectal tumorigenesis by enhancing ONECUT2 mRNA stability and is a potential therapeutic target","authors":"Xiaoting Zhang,&nbsp;Na Qin,&nbsp;Fenfen Ji,&nbsp;Hao Su,&nbsp;Haiyun Shang,&nbsp;Hongyan Chen,&nbsp;Dan Huang,&nbsp;Qing Li,&nbsp;Jing Ren,&nbsp;Weixin Liu,&nbsp;Yifei Wang,&nbsp;Wei Kang,&nbsp;Jiabin Wu,&nbsp;Chi-Chun Wong,&nbsp;Zongwei Cai,&nbsp;Matthew Tak Vai Chan,&nbsp;William Ka Kei Wu,&nbsp;Jun Yu,&nbsp;Huarong Chen","doi":"10.1002/cac2.70070","DOIUrl":"10.1002/cac2.70070","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The role of N1-methyladenosine (m¹A) in cancer is poorly understood. Here we explored the function of RNA methyltransferase TRNA methyltransferase 61A (TRMT61A) in colorectal cancer (CRC) and its potential as a therapeutic target.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>RNA m¹A levels were assessed through liquid chromatography-mass spectrometry. The expression and clinical significance of TRMT61A were investigated across five human CRC cohorts. The function of TRMT61A was elucidated using CRC cell lines, patient-derived organoids, xenografts, and transgenic mouse models. Integrated analyses of m¹A-sequencing and RNA-sequencing revealed the underlying mechanisms of TRMT61A. A nanoparticle-based small interfering RNA (siRNA) delivery system and a specific inhibitor were developed to target TRMT61A. The efficacy and safety of targeting TRMT61A were assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our research revealed a consistent increase in TRMT61A expression and total RNA m¹A levels within primary CRCs. High TRMT61A expression was associated with poor prognosis of CRC patients. Through CRISPR/Cas9 screenings, we identified TRMT61A as the most essential gene among m¹A regulators. Furthermore, we established that TRMT61A promoted CRC tumorigenesis and progression by enhancing the mRNA stability of critical targets in an m¹A-dependent manner. In particular, TRMT61A boosted the mRNA stability of one cut homeobox 2 (ONECUT2), which in turn triggered son of sevenless homolog 1 (SOS1) transcription, leading to the induction of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling in CRC. Notably, our study underscored the safety and substantial anti-CRC effects achievable by inhibiting TRMT61A using nanoparticle-encapsulated siTRMT61A or our newly discovered small molecule compound, pentagalloylglucose.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study unveiled the tumor-promoting role of TRMT61A in CRC via the m¹A-ONECUT2-SOS1-MAPK/ERK pathway. Targeting TRMT61A showed promise as a therapeutic strategy for treating CRC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 12","pages":"1616-1644"},"PeriodicalIF":24.9,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12728496/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145306923","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}