Cancer Science最新文献

{"title":"BCL-2 Inhibitor Regulates Number, Function, and Antitumor Immunity of T Cells by Influencing Glycolysis in AML","authors":"Xiaohuan Peng,&nbsp;Yanhong Li,&nbsp;Futian Tang,&nbsp;Yanling Ma,&nbsp;Jun Bai,&nbsp;Lijuan Li,&nbsp;Liansheng Zhang","doi":"10.1111/cas.70139","DOIUrl":"10.1111/cas.70139","url":null,"abstract":"<p><i>BCL-2</i> is one of the key genes in the mitochondrial apoptotic pathway, and BCL-2 inhibitor Venetoclax (VEN) is the preferred targeted drug for acute myeloid leukemia (AML) patients. However, the effects of VEN on immune cells and antitumor immune responses in AML patients are poorly understood. We first tested the influence of VEN on AML cells and immune cells. Subsequently, we sorted CD4+ T cells and CD8+ T cells from newly diagnosed AML patients in vitro and constructed a peripheral blood mononuclear cell (PBMC)-humanized AML mouse model to explore the effects of VEN on the T cell number, function, and antitumor immune responses, while actively seeking potential mechanisms. VEN could effectively induce leukemia cell apoptosis and affect the lymphocyte proportion and cytokine levels in the tumor immune microenvironment of AML. T cells of AML patients had apoptosis resistance to VEN, possibly due to their relatively low expression levels of BCL-2 protein. VEN could regulate the secretory function and activation status of T cells in AML, which mainly manifested in promoting IFN-γ and Perforin and Granzyme B secretion, upregulating PD-1 expression, promoting T cell activation, and increasing the proportion of memory T cells. Finally, it was also observed that VEN could enhance T cell-mediated antitumor immune responses in AML. Mechanistically, VEN modulates the glycolysis pathway of T cells to regulate their number, function, and antitumor immune responses. This research provided a new perspective that molecular-targeted drugs can promote tumor cell death through a unique immune-dependent mechanism.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 10","pages":"2657-2676"},"PeriodicalIF":4.3,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70139","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144795837","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":"Allelic Imbalance and Chromothripsis Lead to Diversity in Japanese Tumor Genomes With Whole-Genome Duplication","authors":"Keiichi Hatakeyama,&nbsp;Takeshi Nagashima,&nbsp;Sumiko Ohnami,&nbsp;Shumpei Ohnami,&nbsp;Koji Maruyama,&nbsp;Keiichi Ohshima,&nbsp;Yuji Shimoda,&nbsp;Akane Naruoka,&nbsp;Hirotsugu Kenmotsu,&nbsp;Kenichi Urakami,&nbsp;Yasuto Akiyama,&nbsp;Ken Yamaguchi","doi":"10.1111/cas.70159","DOIUrl":"10.1111/cas.70159","url":null,"abstract":"<p>Whole-genome analyses have revealed that large-scale structural variations (SVs) such as whole-genome duplication (WGD) occur early in the development of many cancers. However, the diversity of chromosomal abnormalities within tumors before and after WGD remains poorly understood. Here, we analyzed various types of Japanese tumor genomes via whole-genome sequencing and examined the diversity of WGD by focusing on large SVs at the chromosomal level. WGD was detected in 52% of cases, while the frequency of chromothripsis (CT) was 20%. Although aneuploidy via deletion of chromosome arms was common in many cancers, in rare ovarian cancers, all chromosomes were near-haploidy before WGD. Minor allele analysis revealed that many non-mutated ohnolog genes drifted down chromosome arms after WGD and returned to normal ploidy, but only 17p, including <i>TP53</i>, which is also an ohnolog, underwent loss of heterozygosity due to arm deletion before WGD in most cancers. <i>TP53</i> mutations were frequently detected in WGD and CT-positive tumors, and these SVs strongly correlated with homologous recombination deficiency scores. Furthermore, these tumors had many mutations that continued to generate neoantigens and resulted in worse survival outcomes. Diversity analysis of tumors with WGD will provide a new perspective on structural abnormalities in tumor genomes.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 10","pages":"2882-2892"},"PeriodicalIF":4.3,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70159","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144795836","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":"Discovery-Replication Strategy Identifies Serum Metabolite Biomarkers for Colorectal Cancer in a Chinese Cohort","authors":"Lugen Zuo,&nbsp;Bowen Song,&nbsp;Xuening Jiang,&nbsp;Jing Li,&nbsp;Xiaofeng Zhang,&nbsp;Lian Wang,&nbsp;Yueyue Wang,&nbsp;Zhijun Geng,&nbsp;Xue Song,&nbsp;Sitang Ge,&nbsp;Jianguo Hu","doi":"10.1111/cas.70166","DOIUrl":"10.1111/cas.70166","url":null,"abstract":"<p>Early diagnosis of colorectal cancer (CRC) is difficult to achieve. The use of serum metabolites may be a noninvasive diagnostic method for CRC; however, few studies have examined this method in China. This study aimed to analyze serum metabolite alterations and their diagnostic value for CRC in a Chinese cohort. Serum metabolomics analysis was performed via liquid chromatography–mass spectrometry in a discovery cohort of 20 CRC patients and 20 healthy controls. The diagnostic value of differential serum metabolites was verified by LASSO regression and receiver operating characteristic (ROC) curve analysis. Furthermore, an independent validation cohort of 80 CRC patients and 80 controls was established. A total of 1299 serum metabolites, including 311 differentially abundant metabolites, were detected in the discovery cohort. LASSO regression revealed that 8 metabolites could distinguish CRC patients from controls: among which 2-hydroxyhexadecanoic acid, 3-hydroxypentadecanoic acid, 5(S)-HETE, glutamine pyruvate, lactic acid, and lysoPC (0:0/16:0) were elevated in CRC patients, whereas DG (8:0/10:0/0:0) and cis-muconic acid were decreased. Each of the elevated metabolites had a high diagnostic value for CRC, with an AUC exceeding 0.80. The panel of 8 metabolites was superior for diagnosing CRC, with an AUC of 0.968, a sensitivity of 0.95, and a specificity of 1.00. The validation cohort replicated the results of the discovery cohort and further confirmed that the metabolite panel was valuable for the early diagnosis and assessment of lymph node metastasis. In conclusion, our study revealed that serum metabolites could be used for CRC detection.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 10","pages":"2808-2818"},"PeriodicalIF":4.3,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70166","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144790504","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":"Mechanisms Involved in Focal Adhesion Signaling Regulating Tumor Anoikis Resistance","authors":"Bin Liu,&nbsp;Qingqing Wu,&nbsp;Zuodong Xuan,&nbsp;Zeyuan Zheng,&nbsp;Yifan Du,&nbsp;Xiuyuan Sui,&nbsp;Haodong Wu,&nbsp;Zeyi Zhang,&nbsp;Zhengying Zhang,&nbsp;Min Zhong,&nbsp;Yue Zhao,&nbsp;Huimin Sun,&nbsp;Chen Shao","doi":"10.1111/cas.70154","DOIUrl":"10.1111/cas.70154","url":null,"abstract":"<p>Among the numerous malignant behaviors of tumors, metastasis plays a critical role in contributing to poor prognosis. Anoikis is a distinct form of apoptosis induced when cells detach from the extracellular matrix (ECM) or adhere to an improper ECM. It is a physiological obstacle to tumor cell metastasis. Anoikis resistance is considered to be a critical initial step in cancer cell metastasis. However, the mechanism by which tumor cells develop anoikis resistance is still unclear, in which the focal adhesion signaling pathway plays an important role. This review first outlines the composition of focal adhesion (FAs) multi-protein signaling complexes and then discusses the following three aspects: integrin expression changes of tumor cells, intracellular oxidative stress response, and FAs multi-protein signaling complex members activating downstream survival signaling pathways. The specific mechanisms of focal adhesion signaling pathways in tumor cell anoikis resistance and molecular characteristics of the anoikis resistance state are reviewed.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 10","pages":"2640-2648"},"PeriodicalIF":4.3,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70154","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144785738","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":"Potential of Platelet-Based Drug Delivery System for Treating Peritoneal Metastasis of Gastric Cancer","authors":"Takashi Nakayama,&nbsp;Katsutoshi Shoda,&nbsp;Yudai Higuchi,&nbsp;Takaomi Ozawa,&nbsp;Hiroto Tanaka,&nbsp;Ryo Saito,&nbsp;Suguru Maruyama,&nbsp;Koichi Takiguchi,&nbsp;Wataru Izumo,&nbsp;Shinji Furuya,&nbsp;Kensuke Shiraishi,&nbsp;Yoshihiko Kawaguchi,&nbsp;Hidetake Amemiya,&nbsp;Hiromichi Kawaida,&nbsp;Kentaro Yoshimura,&nbsp;Nagaharu Tsukiji,&nbsp;Katsue Suzuki-Inoue,&nbsp;Daisuke Ichikawa","doi":"10.1111/cas.70167","DOIUrl":"10.1111/cas.70167","url":null,"abstract":"<p>Peritoneal metastasis is a lethal manifestation of gastric cancer, with poor prognosis and limited treatment options. A targeted drug delivery system minimizing systemic toxicity is urgently needed. Given that platelets form stable aggregates with gastric cancer cells, we explored their feasibility as a drug carrier. We engineered paclitaxel-loaded platelets and assessed their antitumor efficacy using human gastric cancer cell lines. To evaluate therapeutic performance in vivo, a murine model of peritoneal metastasis was established with BALB/c-Slc-nu/nu mice. Paclitaxel was administered intraperitoneally at 25 mg/kg per week in both the free paclitaxel and paclitaxel-loaded platelets groups, via injection every 7 days for a total of 8 times. Paclitaxel-loaded platelets exhibited strong adhesion to gastric cancer cells, efficiently delivering paclitaxel intracellularly. Functional assays confirmed platelet activation capacity was preserved post drug loading. In vitro, paclitaxel-loaded platelets significantly inhibited tumor cell viability (<i>p</i> &lt; 0.001). In vivo, they markedly reduced systemic drug exposure (<i>p</i> &lt; 0.047) and significantly improved antitumor efficacy and survival versus free paclitaxel (<i>p</i> &lt; 0.001). Our findings highlight platelets as a novel drug delivery system for peritoneal metastasis in gastric cancer. Leveraging their tumor-homing properties and biocompatibility, this approach enables targeted intraperitoneal chemotherapy, representing a promising strategy for this treatment-refractory disease.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 10","pages":"2858-2867"},"PeriodicalIF":4.3,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70167","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144790505","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":"Clinical Application of In-House Comprehensive Genomic Profiling for Thoracic Cancer: Insights From a Japanese Hospital","authors":"Hatsuyo Takaoka,&nbsp;Hideki Terai,&nbsp;Kohei Nakamura,&nbsp;Takaaki Mizuno,&nbsp;Ryutaro Kawano,&nbsp;Katsura Emoto,&nbsp;Yutaka Kurebayashi,&nbsp;Nao Takada,&nbsp;Kenta Hamabe,&nbsp;Kazuhito Horie,&nbsp;Akihiko Ogata,&nbsp;Katsuhito Kinoshita,&nbsp;Lisa Shigematsu,&nbsp;Fumimaro Ito,&nbsp;Masahiko Okada,&nbsp;Takahiro Fukushima,&nbsp;Shigenari Nukaga,&nbsp;Testuo Tani,&nbsp;Keiko Ohgino,&nbsp;Kaoru Kaseda,&nbsp;Shinnosuke Ikemura,&nbsp;Hiroyuki Yasuda,&nbsp;Keisuke Asakura,&nbsp;Hajime Okita,&nbsp;Hiroshi Nishihara,&nbsp;Koichi Fukunaga","doi":"10.1111/cas.70168","DOIUrl":"10.1111/cas.70168","url":null,"abstract":"<p>Comprehensive genomic profiling (CGP) is useful for optimizing targeted therapy and immunotherapy strategies for thoracic malignancies. This study aimed to evaluate the clinical utility and diagnostic complementarity of the in-house sequencing platform Rapid-Neo. We retrospectively analyzed 110 patients with thoracic malignancies who underwent Rapid-Neo testing. The baseline characteristics, sequencing results, concordance with companion diagnostics (CDx), and clinical outcomes were assessed. Of 110 patients, 100 (90.9%) had primary lung cancer. Rapid-Neo identified at least one genomic alteration in 99.1% of cases and well-established driver alterations in 66.0% of lung cancer cases. TMB-high and MSI-high statuses were observed in 9.0% and 2.0% of cases, respectively. Among the 90 cases with prior CDx, Rapid-Neo identified driver alterations in 10.0% of the cases, including <i>EGFR</i>, <i>KRAS</i>, <i>MET</i>, <i>RET</i>, and <i>ERBB2</i>, suggesting its potential to overcome the limitations of conventional CDx tests. High concordance (96.8%) was observed between the Rapid-Neo and CDx results, finally. In EGFR-mutant lung adenocarcinoma, high tumor mutation burden (TMB) was associated with a significantly shorter progression-free survival (PFS) after EGFR-TKI therapy (HR = 2.58, <i>p</i> = 0.018) and remained an independent prognostic factor in multivariate analysis. Furthermore, among patients receiving immune checkpoint inhibitors (ICIs), favorable genomic markers such as TMB-high or MSI-high were associated with prolonged PFS. Rapid-Neo demonstrated high sensitivity and concordance with CDx, while also identifying actionable driver alterations missed by the initial CDx. Moreover, the genomic markers identified by Rapid-Neo may provide predictive values for both targeted therapy and immunotherapy responses, supporting their integration into routine clinical decision-making.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 10","pages":"2819-2830"},"PeriodicalIF":4.3,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70168","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144776713","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":"Resident Memory T Cell in Metastatic Lymph Nodes Is Associated With Favorable Prognosis in Gastric Cancer Patients","authors":"Masaki Nishiyama,&nbsp;Yuichiro Miki,&nbsp;Hiroaki Tanaka,&nbsp;Seiji Natsuki,&nbsp;Kenji Kuroda,&nbsp;Mami Yoshii,&nbsp;Tatsuro Tamura,&nbsp;Takahiro Toyokawa,&nbsp;Shigeru Lee,&nbsp;Kiyoshi Maeda","doi":"10.1111/cas.70163","DOIUrl":"10.1111/cas.70163","url":null,"abstract":"<p>Infiltration of resident memory T cells (TRMs) in the main tumor has been reported as a favorable prognostic factor. However, the role of TRMs in the lymph nodes (LNs) remains unclear. Thus, we examined the prognostic impact of TRMs infiltration within LNs of patients with gastric cancer (GC). Among 151 patients with metastasis to LN station No. 3, we classified them into two groups (CD103^hi and CD103^lo) based on the number of CD103⁺ T cells using immunohistochemical staining and analyzed the association between these groups and survival outcomes. We also examined the phenotype of CD8⁺ CD103⁺ T cells in the metastatic LNs using flow cytometry. Among patients with LN metastasis, metastasis to LN station No. 3 was significantly associated with a poor prognosis. There was a significant correlation between the number of CD8⁺ CD103⁺ T cells between the main lesion and the metastatic LNs. CD103^hi was associated with a favorable prognosis (5-year overall survival [OS], log-rank <i>p</i> = 0.001; 5-year recurrence free survival [RFS], log-rank <i>p</i> = 0.001). Among adjuvant chemotherapy cases, patients with CD103^hi exhibited significantly better OS and RFS than those with CD103^lo (OS, log-rank <i>p</i> &lt; 0.001; RFS, log-rank <i>p</i> &lt; 0.001). Flow cytometry revealed that PD-1 expression in CD8⁺ CD103⁺ T cells was higher in metastatic than in normal LNs. Among patients with CD103^hi, those with high PD-1 expression exhibited significantly better OS than those with low PD-1 expression. In conclusion, the infiltration of TRMs into LNs is a critical prognostic factor in GC.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 10","pages":"2688-2698"},"PeriodicalIF":4.3,"publicationDate":"2025-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70163","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144776714","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":"Discovery of Novel RASGRF2 Fusions as a Therapeutic Target in Lung Adenocarcinoma of Never or Light Smokers","authors":"Yuki Terashima,&nbsp;Soohwan Park,&nbsp;Hiroshi Ikeuchi,&nbsp;Takuo Hayashi,&nbsp;Shinya Kojima,&nbsp;Toshihide Ueno,&nbsp;Masachika Ikegami,&nbsp;Rina Kitada,&nbsp;Yoshiyuki Suehara,&nbsp;Shinya Tanaka,&nbsp;Kenji Suzuki,&nbsp;Hiroyuki Mano,&nbsp;Kazuya Takamochi,&nbsp;Shinji Kohsaka","doi":"10.1111/cas.70142","DOIUrl":"10.1111/cas.70142","url":null,"abstract":"<p>Lung adenocarcinomas (LUADs) in never-smokers exhibit distinct molecular profiles from those of smokers, and their driver mutations are quite divergent. We aimed to evaluate the utility of RNA-seq for the molecular profiling of LUAD in Japanese never or light smokers. A hybridization capture-based RNA panel (TOP2-RNA) was used to confirm the validity of mutational and expression analyses of the panel in 122 Japanese LUAD cases. For the discovery cohort, 270 primary LUADs were molecularly profiled using TOP2-RNA. Whole transcriptome sequencing (WTS) was conducted for the samples without any oncogenic driver mutations. A risk score was developed using TOP2-RNA expression data to predict the prognosis of surgically resected LUAD. Driver oncogenes were identified in 180 cases (66.7%) of the discovery cohort. The frequency of <i>MET</i> ex14 skipping was high (12.6%) among cases without <i>EGFR</i> mutations. Actionable novel fusions of <i>RDX-RASGRF1</i>, <i>PRKCI-RASGRF2,</i> and <i>OCLN-RASGRF2</i> were identified in three never-smoker cases by WTS. A functional assay identified that the expression of <i>RASGRF</i> fusions transformed the cells through phosphorylation of MEK, which was inhibited by cobimetinib treatment. High-risk patients defined by the risk score based on the four-gene signature had significantly worse RFS and OS for all stages and stage I patients in the discovery and validation cohorts. This study identified novel <i>RASGRF1/2</i> fusions that might be targetable by MEK inhibitors. RNA-based molecular profiling could identify actionable mutations and assess the prognostic biomarkers for patient stratification to determine the optimal treatment based on the molecular profiling of individual LUAD cases.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 10","pages":"2868-2881"},"PeriodicalIF":4.3,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70142","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144745613","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":"Nucleolar Organization in Response to Transcriptional Stress","authors":"Rikiya Imamura,&nbsp;Takaaki Yasuhara","doi":"10.1111/cas.70164","DOIUrl":"10.1111/cas.70164","url":null,"abstract":"<p>The nucleolus, a prominent membrane-less nuclear compartment, is organized around ribosomal RNA (rRNA) gene (rDNA) clusters, known as nucleolar organizing regions (NORs), located on the short arms of acrocentric chromosomes. It serves as the primary site for ribosome biogenesis, an energy-intensive process crucial for cell growth and proliferation. This involves RNA polymerase I (Pol I)-mediated transcription of 47S precursor rRNA (pre-rRNA), pre-rRNA processing, and ribosomal subunit assembly, reflected in its tripartite structure maintained by liquid–liquid phase separation. Recent evidence indicates that only about 30% of nucleolar proteins are exclusively involved in ribosome production. The remaining proteome participates in diverse cellular functions, establishing the nucleolus as a multifunctional organelle. It functions as a critical stress sensor and signaling hub, responding to various intracellular insults such as nutrient starvation, DNA damage, and viral infection. Many chemotherapeutic agents also induce the response called nucleolar stress via disruption of the nucleolar structure or function, potentially leading to rDNA instability. Nucleolar stress frequently leads to dynamic transition of nucleolar proteins, inducing nucleolar reorganization. Of these, the stress induced by transcriptional changes leads to the unique nucleolar structures termed nucleolar caps and nucleolar necklaces. In this review, we summarize the recent findings about the molecular mechanism of nucleolar changes upon stresses and discuss the possible relationship between rDNA instability and cancer.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 10","pages":"2649-2656"},"PeriodicalIF":4.3,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70164","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144734525","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":"TP-0903 Suppresses Aurora A–PLK1 Signaling to Inhibit Proliferation of a Myelodysplastic Syndrome-Derived Cell Line","authors":"Tomoko Kimura-Hyoda,&nbsp;Mikuri Ryu,&nbsp;Ryosuke Yuta,&nbsp;Saori Fukumoto,&nbsp;Kentaro Hosokawa,&nbsp;Hisayuki Yao,&nbsp;Yoko Yasuda,&nbsp;Koichi Miura,&nbsp;Kaoru Tohyama,&nbsp;Fumio Arai,&nbsp;Takeshi Uchiumi","doi":"10.1111/cas.70151","DOIUrl":"10.1111/cas.70151","url":null,"abstract":"<p>A low molecular compound originally developed as an anexelekto inhibitor, TP-0903, has been highlighted as a promising therapeutic agent for treating chronic lymphocytic leukemia, solid tumors, and drug-resistant AML. We investigated the in vitro effects of TP-0903 on a myelodysplastic syndrome (MDS)-derived cell line (MDS-L) and two myeloid leukemia cell lines. TP-0903 effectively inhibited cell proliferation and induced apoptosis in all three cell lines. In MDS-L cells, the PI3K/AKT and JAK/STAT3 pathways were inhibited, suggesting that this may be partly due to decreased direct interactions with hepatocyte growth factor receptor, commonly known as MET. Regarding its effect on the cell cycle, TP-0903 was found to impact the DNA damage response and cell cycle-related factors, particularly those centered around Aurora kinases. In MDS-L cells, inhibition of Aurora A phosphorylation led to decreased levels of BORA, which in turn suppressed polo-like kinase 1 activation. This suppression hindered mitosis initiation, resulting in cell cycle arrest at the G2/M phase. Additionally, chromosomal misregulation caused by Aurora A inhibition appeared to impair cell division and contribute to cell death. Gene expression profiling of MDS-L revealed changes in the ferroptosis-related genes, including <i>HMOX1</i> and <i>transferrin</i>, along with elevated levels of reactive oxygen species and intracellular iron accumulation. These findings suggest the activation of an atypical ferroptosis pathway mediated through the TGF-β1/SMAD3 signaling pathway. Overall, these data indicate that TP-0903 may offer a novel therapeutic strategy for the treatment of refractory hematological malignancies.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 10","pages":"2831-2845"},"PeriodicalIF":4.3,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70151","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144734526","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}