Molecular Cancer最新文献

{"title":"Non-canonical ALK7 pathways promote pancreatic cancer metastasis through β-catenin/MMP-mediated basement membrane breakdown and intravasation.","authors":"Anna M Kolarzyk, Yujin Kwon, Elizabeth Oh, Keng-Jung Lee, Su-Yeon Cho, Issahy Cano, Renhao Lu, Tae Joon Kwak, Jaehyun Lee, Gigi Wong, Andrew H Kim, Omar Gandarilla, Manuel Hidalgo, Won Kyu Kim, Esak Lee","doi":"10.1186/s12943-025-02384-w","DOIUrl":"10.1186/s12943-025-02384-w","url":null,"abstract":"<p><p>Breaching the vascular barrier is a critical step in pancreatic ductal adenocarcinoma (PDAC) metastasis, yet the mechanisms enabling this process remain incompletely understood. Transforming growth factor beta (TGFβ) receptors have been extensively studied in many cancer types. However, activin receptor-like kinase 7 (ALK7), one of the TGFβ receptors, is under-investigated, and its roles in PDAC metastasis have been unclear. This study identifies two distinct but interconnected ALK7-driven non-canonical pathways that promote PDAC dissemination. The ALK7-β-catenin-EMT axis enhances intrinsic tumor cell motility, driving epithelial-mesenchymal transition (EMT). In parallel, the ALK7-β-catenin-MMP axis facilitates metastatic invasion by upregulating MMP production, leading to ECM degradation and invadosome formation, which promote vascular barrier breakdown and intravasation. An orthotopic PDAC metastasis model reveals that both pharmacological and genetic ALK7 inhibition suppresses metastasis. 3D microfluidic vessel-on-chip platforms further demonstrate that ALK7 inhibition preserves basement membrane (BM) integrity, limiting intravasation. While MMP inhibition effectively blocks BM breakdown and intravasation, extravasation remains unaffected, highlighting distinct molecular requirements for different metastatic stages. These findings establish ALK7 as a dual-function pro-metastatic regulator that orchestrates both tumor cell plasticity and ECM remodeling, positioning ALK7 inhibition as a promising strategy to target early metastatic dissemination in PDAC.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"24 1","pages":"188"},"PeriodicalIF":27.7,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564979","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":"IFITM3 enhances immunosensitivity via MHC-I regulation and is associated with the efficacy of anti-PD-1/-L1 therapy in SCLC","authors":"Yanan Cui, Tianyu Qiu, Jiale Wang, Xinyu Liu, Libo Luo, Jizhong Yin, Xinxin Zhi, Wanying Wang, Gaohua Feng, Chunyan Wu, Zhikai Zhao, Hua Zhang, Fei Li, Fengying Wu, Shengxiang Ren","doi":"10.1186/s12943-025-02383-x","DOIUrl":"https://doi.org/10.1186/s12943-025-02383-x","url":null,"abstract":"Most small cell lung cancer (SCLC) patients exhibit resistance to immune checkpoint inhibitors (ICIs) and demonstrate downregulation of major histocompatibility complex class I (MHC-I) molecules. This study aimed to elucidate the regulatory mechanisms underlying MHC-I expression and potential combination strategies. Single-cell and bulk RNA sequencing data from SCLC patients were analyzed. Clinical data from SCLC patients treated with PD-1/PD-L1 inhibitors were used to investigate the associations between treatment efficacy and IFITM3 expression. In vitro and in vivo functional studies were conducted to evaluate the role and mechanisms of IFITM3 in modulating tumor sensitivity to PD-1 inhibitors. Integrative analysis of multiple real-world SCLC cohorts confirmed a significant positive association between IFITM3 expression and MHCI. IFITM3 overexpression upregulated MHC-I-related genes, enriched antigen presentation pathways, and increased CD8+ T-cell infiltration and cytotoxicity. Elevated IFITM3 expression was significantly associated with prolonged progression-free survival (PFS) in patients receiving chemoimmunotherapy but not in those treated with chemotherapy alone. Additionally, patients with high H-scores for IFITM3, as determined by immunohistochemistry, demonstrated better clinical outcomes with chemoimmunotherapy. Inducing IFITM3 expression directly or through treatment with ethyl gallate (EG), an IFITM3 inducer, effectively sensitized tumors to PD-1 blockade in SCLC mouse models. Mechanistic studies revealed that IFITM3 upregulates NLRC5, a key transcriptional activator of MHC-I, facilitating its nuclear translocation and thereby increasing MHC-I levels. IFITM3 is associated with MHC-I expression and can predict the efficacy of anti-PD-1/-L1 therapy in SCLC patients. IFITM3 inducers potently improved the efficacy of anti-PD1 monotherapy in SCLC.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"07 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CircERC1 facilitates chemoresistance through inhibiting pyroptosis and remodeling extracellular matrix in pancreatic cancer","authors":"Jian Zhang, Shengnan Lv, Xinyu Peng, Huan Liu, Jianxiong Guo, Ziyu Liu, Tongjia Chu, Han Liu, Kehang Duan, Fengxiang Lou, Yubo Chi, Bing Gao, Yan Liu, Feng Wei","doi":"10.1186/s12943-025-02385-9","DOIUrl":"https://doi.org/10.1186/s12943-025-02385-9","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) resists to neoadjuvant treatment even though overall survival (OS) is transiently prolonged while the underlying mechanism of this drug resistance remains elusive. Gemcitabine combined with Nab-paclitaxel (GEM-NabP) treated PDAC tissues-derived EVs were isolated and underwent circRNA sequencing. CircERC1 was identified as an EVs-packaged circRNA that regulates PDAC progression and tumor microenvironment (TME) in vitro and in vivo with the help of EdU, colony formation, SRB viability assays, transwell assays and PET-CT analysis. The underlying mechanism was substantiated by qRT-PCR, Western blot, RNA pull-down, mass spectrometry, RNA immunoprecipitation and Co-immunoprecipitation. In addition, single-cell RNA sequencing was adopted to analyze the TME and immunohistochemistry, dual luciferase reporter assay were performed to validate the results. CircERC1 biogenesis is activated by QKI after GEM-NabP treatment. It interacts with hnRNPA1 and promotes its ubiquitination degradation by blocking its SUMOylation at K183. The degraded hnRNPA1 fails to upregulate PKM2, a crucial activator of NLRP3 inflammasome, thereby inhibiting Caspase1-GSDMD mediated pyroptosis. Furthermore, EVs-packaged circERC1 enhances extracellular matrix (ECM) deposition and hindering drug and immune cells infiltration in cancer associated fibroblasts (CAFs) in PDAC microenvironment. Our findings reveal a novel circERC1 as a key regulator in PDAC-secreted EVs following paclitaxel (PTX) treatment, thereby inhibiting gemcitabine/Nab-paclitaxel (GEM-NabP) induced pyroptosis. Our results highlight a potential therapeutic target for overcoming chemoresistance and remodeling pancreatic TME.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"20 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"STK3 is a transcriptional target of YAP1 and a hub component in the crosstalk between Hippo and Wnt signaling pathways during gastric carcinogenesis","authors":"Fuda Xie, Yang Lyu, Bonan Chen, Hoi Wing Leung, Peiyao Yu, Tiejun Feng, Canbin Fang, Alvin H.K. Cheung, Bin Zhou, Jianhui Jiang, Ge Zhang, Dazhi Xu, Liang Li, Chen Jiang, Jianwu Chen, Zhaocai Zhou, Liwei An, Bing Huang, Kangmin Zhuang, Xiaobei Luo, Kam Tong Leung, Ching Hei To, Brigette BY Ma, Chi Chun Wong, William KK Wu, Jun Yu, Ka Fai To, Wei Kang","doi":"10.1186/s12943-025-02391-x","DOIUrl":"https://doi.org/10.1186/s12943-025-02391-x","url":null,"abstract":"Serine/threonine kinase 3 (STK3) is recognized as a key regulator in Hippo pathway and a tumor-suppressing gene in various cancer types. However, its non-canonical role has been gradually revealed in cancer development. Our objective is to elucidate the upregulation pattern and molecular mechanisms of STK3 in advancing gastric cancer (GC) progression. The regulation of YAP1 on STK3 was assessed through a combination of bulk and single-cell RNA-sequencing, Western blot, ChIP-qPCR, gene knockout mouse models, and functional rescue assays. The oncogenic roles of STK3 were confirmed through subcutaneous xenograft formation models and functional assays including spheroid formation and organoid growth. The phosphorylated target of STK3 was revealed by co-immunoprecipitation and in vitro kinase assays. STK3-targeted drugs were screened out by molecular docking and cellular thermal shift assay (CETSA). Reduction of YAP1 significantly impaired STK3 expression at both mRNA and protein levels, and deletion of STK3 partially attenuated the oncogenic activity of YAP1. Notably, MNNG-induced tumors in Yap1−/−Taz−/− mice exhibited decreased STK3 expression. Knockdown of STK3 led to reduced expression of stemness markers and xenograft growth, while sensitizing GC organoids and xenografts to 5-fluorouracil treatment. Mechanistically, the direct interaction between STK3 and GSK-3β promoted GSK-3β phosphorylation and β-catenin nuclear accumulation, and thus the activation of Wnt signaling. Furthermore, aminopterin demonstrates as a promising STK3-targeted small molecule with remarkable effectiveness in inhibiting GC cell malignance and xenograft growth. STK3 was identified as a transcriptional target of YAP1, leading to enhanced DNA repair ability and stemness acquisition during GC progression by activating Wnt/β-catenin activity through GSK-3β degradation. Moreover, STK3-targeted therapy offered a novel approach to concur acquired chemo-resistance in GC patients. ","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"104 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: THBS2 + cancer-associated fibroblasts promote EMT leading to oxaliplatin resistance via COL8A1-mediated PI3K/AKT activation in colorectal cancer","authors":"Xing Zhou, Jiashu Han, Anning Zuo, Yuhao Ba, Shutong Liu, Hui Xu, Yuyuan Zhang, Siyuan Weng, Zhaokai Zhou, Long Liu, Peng Luo, Quan Cheng, Chuhan Zhang, Yukang Chen, Dan Shan, Benyu Liu, Shuaixi Yang, Xinwei Han, Jinhai Deng, Zaoqu Liu","doi":"10.1186/s12943-025-02388-6","DOIUrl":"https://doi.org/10.1186/s12943-025-02388-6","url":null,"abstract":"&lt;p&gt;&lt;b&gt;Correction: Mol Cancer 23, 282 (2024)&lt;/b&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;https://doi.org/10.1186/s12943-024-02180-y&lt;/b&gt;&lt;/p&gt;&lt;p&gt;Following the publication of the original article [1], the authors reported that they identified an inadvertent duplication of images labeled GDSC and CTRP in the Fig. 2O, and wish to formally request an erratum to rectify this issue. In the correct Fig. 2, they have replaced the correct Fig. 2O. They are confident that the inadvertent panel duplication did not have any effect on their analyses or on any conclusions drawn from the paper, and they apologize for the error.&lt;/p&gt;&lt;p&gt;Incorrect Fig. 2:&lt;/p&gt;&lt;figure&gt;&lt;picture&gt;&lt;source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12943-025-02388-6/MediaObjects/12943_2025_2388_Figa_HTML.png?as=webp\" type=\"image/webp\"/&gt;&lt;img alt=\"figure a\" aria-describedby=\"Figa\" height=\"805\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12943-025-02388-6/MediaObjects/12943_2025_2388_Figa_HTML.png\" width=\"685\"/&gt;&lt;/picture&gt;&lt;/figure&gt;&lt;p&gt;Correct Fig. 2:&lt;/p&gt;&lt;figure&gt;&lt;picture&gt;&lt;source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12943-025-02388-6/MediaObjects/12943_2025_2388_Figb_HTML.png?as=webp\" type=\"image/webp\"/&gt;&lt;img alt=\"figure b\" aria-describedby=\"Figb\" height=\"807\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12943-025-02388-6/MediaObjects/12943_2025_2388_Figb_HTML.png\" width=\"685\"/&gt;&lt;/picture&gt;&lt;/figure&gt;&lt;ol data-track-component=\"outbound reference\" data-track-context=\"references section\"&gt;&lt;li data-counter=\"1.\"&gt;&lt;p&gt;Zhou X, Han J, Zuo A, et al. THBS2 + cancer-associated fibroblasts promote EMT leading to oxaliplatin resistance via COL8A1-mediated PI3K/AKT activation in colorectal cancer. Mol Cancer. 2024;23:282. https://doi.org/10.1186/s12943-024-02180-y.&lt;/p&gt;&lt;p&gt;Article CAS PubMed PubMed Central Google Scholar &lt;/p&gt;&lt;/li&gt;&lt;/ol&gt;&lt;p&gt;Download references&lt;svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"&gt;&lt;use xlink:href=\"#icon-eds-i-download-medium\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"&gt;&lt;/use&gt;&lt;/svg&gt;&lt;/p&gt;&lt;span&gt;Author notes&lt;/span&gt;&lt;ol&gt;&lt;li&gt;&lt;p&gt;Xing Zhou, Jiashu Han, Anning Zuo, Yuhao Ba and Shutong Liu contributed equally to this work and share first authorship.&lt;/p&gt;&lt;/li&gt;&lt;/ol&gt;&lt;h3&gt;Authors and Affiliations&lt;/h3&gt;&lt;ol&gt;&lt;li&gt;&lt;p&gt;Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China&lt;/p&gt;&lt;p&gt;Xing Zhou, Anning Zuo, Yuhao Ba, Shutong Liu, Hui Xu, Yuyuan Zhang, Siyuan Weng, Yukang Chen, Xinwei Han &amp; Zaoqu Liu&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Interventional Institute of Zhengzhou University, Zhengzhou, Henan, 450052, China&lt;/p&gt;&lt;p&gt;Xing Zhou, Xinwei Han &amp; Zaoqu Liu&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, Henan, 450052, China&lt;/p&gt;&lt;p&gt;Xing Zhou, Xinwei Han &amp; Zaoqu Liu&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou ","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"648 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144488523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular vesicles: the “Trojan Horse” within breast cancer host microenvironments","authors":"Yue Kang, Ling’ao Meng, Shi Bai, Shenglong Li","doi":"10.1186/s12943-025-02358-y","DOIUrl":"https://doi.org/10.1186/s12943-025-02358-y","url":null,"abstract":"Breast cancer represents a significant global health concern among women. The intricate processes and pathways underlying metastasis contribute to the challenging prognoses experienced by some patients. Extracellular vesicles (EVs) are membrane-bound structures characterized by phospholipid bilayers, capable of secretion by a multitude of cell types. The contents of these vesicles encompass a diverse assortment of lipids, proteins, nucleic acids, and cellular metabolites. The tumor microenvironment (TME) comprises a complex network involving tumor cells, non-cancerous cells, and an array of molecules they generate and release. Components include the extracellular matrix, cancer-associated fibroblasts, inflammatory immune cells, tumor-associated vasculature, and EVs discharged by these cellular entities. Within the TME, EVs serve as a mechanism akin to the “Trojan Horse,” exerting significant influence in tumor initiation, progression, metastasis, and responses to therapeutic interventions. EVs originating from tumor cells and associated entities within the TME bolster processes such as stimulating angiogenesis adjacent to tumor sites, establishing pre-metastatic niches in distant anatomical regions, and inducing transformative changes in cancer cells to acquire characteristics promoting invasion, angiogenesis, immune evasion, distant metastasis, and resistance to chemotherapy. Noteworthy is the unique capacity of EVs to traverse biological barriers due to their inherent biocompatibility, rendering them promising candidates for innovative drug delivery systems. This attribute presents an avenue to surmount the constraints of traditional cancer treatments. This scholarly inquiry delves into the pathogenic mechanisms of EVs in breast cancer and delves into prospective therapeutic interventions, offering a groundwork for forthcoming precision-guided therapies tailored to breast cancer.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"38 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144341220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Targeting BATF2-RGS2 axis reduces T-cell exhaustion and restores anti-tumor immunity","authors":"Xuyu Gu, Chanchan Gao, Xiangyu Su, Yaoyao Zhu, Qiyu Fang, Jia Yu, Ziming Wang, Deping Zhao, Wentian Zhang","doi":"10.1186/s12943-025-02387-7","DOIUrl":"https://doi.org/10.1186/s12943-025-02387-7","url":null,"abstract":"&lt;p&gt;&lt;b&gt;Correction: Mol Cancer 24&lt;/b&gt;,&lt;b&gt; 157 (2025)&lt;/b&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;https://doi.org/10.1186/s12943-025-02351-5&lt;/b&gt;&lt;/p&gt;&lt;p&gt;Following the publication of the original article [1], the authors identified an error in page 13 at line 8–9 within the sentences “Additionally, we generated BATF2-/- mice (Fig. 5E).” and that they requested a publication of an erratum so that the correct version of the sentences will be noted as shown below.&lt;/p&gt;&lt;p&gt; Correct Version:&lt;/p&gt;&lt;p&gt;“Additionally, BATF2-/- mice (Purchased from Cyagen Biosciences, #S-KO-20232) were used…”.&lt;/p&gt;&lt;p&gt;“generated” should be revised as “used”.&lt;/p&gt;&lt;ol data-track-component=\"outbound reference\" data-track-context=\"references section\"&gt;&lt;li data-counter=\"1.\"&gt;&lt;p&gt;Gu X, Gao C, Su X, et al. Targeting BATF2-RGS2 axis reduces T-cell exhaustion and restores anti-tumor immunity. Mol Cancer. 2025;24:157. https://doi.org/10.1186/s12943-025-02351-5.&lt;/p&gt;&lt;p&gt;Article PubMed PubMed Central Google Scholar &lt;/p&gt;&lt;/li&gt;&lt;/ol&gt;&lt;p&gt;Download references&lt;svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"&gt;&lt;use xlink:href=\"#icon-eds-i-download-medium\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"&gt;&lt;/use&gt;&lt;/svg&gt;&lt;/p&gt;&lt;h3&gt;Authors and Affiliations&lt;/h3&gt;&lt;ol&gt;&lt;li&gt;&lt;p&gt;Department of Oncology, School of Medicine, Shanghai Pulmonary Hospital, Tongji University, Shanghai, 200433, China&lt;/p&gt;&lt;p&gt;Xuyu Gu, Qiyu Fang &amp; Jia Yu&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Department of Oncology, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China&lt;/p&gt;&lt;p&gt;Chanchan Gao &amp; Xiangyu Su&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Department of Radiation Oncology, School of Medicine, Shanghai Pulmonary Hospital, Tongji University, Shanghai, 200433, China&lt;/p&gt;&lt;p&gt;Yaoyao Zhu&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Department of Thoracic Surgery, School of Medicine, Shanghai Pulmonary Hospital, Tongji University, Shanghai, 200433, China&lt;/p&gt;&lt;p&gt;Ziming Wang, Deping Zhao &amp; Wentian Zhang&lt;/p&gt;&lt;/li&gt;&lt;/ol&gt;&lt;span&gt;Authors&lt;/span&gt;&lt;ol&gt;&lt;li&gt;&lt;span&gt;Xuyu Gu&lt;/span&gt;View author publications&lt;p&gt;&lt;span&gt;Search author on:&lt;/span&gt;&lt;span&gt;PubMed&lt;span&gt; &lt;/span&gt;Google Scholar&lt;/span&gt;&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;span&gt;Chanchan Gao&lt;/span&gt;View author publications&lt;p&gt;&lt;span&gt;Search author on:&lt;/span&gt;&lt;span&gt;PubMed&lt;span&gt; &lt;/span&gt;Google Scholar&lt;/span&gt;&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;span&gt;Xiangyu Su&lt;/span&gt;View author publications&lt;p&gt;&lt;span&gt;Search author on:&lt;/span&gt;&lt;span&gt;PubMed&lt;span&gt; &lt;/span&gt;Google Scholar&lt;/span&gt;&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;span&gt;Yaoyao Zhu&lt;/span&gt;View author publications&lt;p&gt;&lt;span&gt;Search author on:&lt;/span&gt;&lt;span&gt;PubMed&lt;span&gt; &lt;/span&gt;Google Scholar&lt;/span&gt;&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;span&gt;Qiyu Fang&lt;/span&gt;View author publications&lt;p&gt;&lt;span&gt;Search author on:&lt;/span&gt;&lt;span&gt;PubMed&lt;span&gt; &lt;/span&gt;Google Scholar&lt;/span&gt;&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;span&gt;Jia Yu&lt;/span&gt;View author publications&lt;p&gt;&lt;span&gt;Search author on:&lt;/span&gt;&lt;span&gt;PubMed&lt;span&gt; &lt;/span&gt;Google Scholar&lt;/span&gt;&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;span&gt;Ziming Wang&lt;/span&gt;View author publications&lt;p&gt;&lt;span&gt;Search author on:&lt;/span&gt;&lt;span&gt;PubMed&lt;span&gt; &lt;/span&gt;Google Scholar&lt;/span&gt;&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;span&gt;Deping Zhao&lt;/span&gt;View author publications&lt;p&gt;&lt;span&gt;Search author on:&lt;/span&gt;&lt;span&gt;PubMed&lt;span&gt; &lt;/span&gt;Google Schola","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"18 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144341355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aurora kinases signaling in cancer: from molecular perception to targeted therapies","authors":"Prerna Vats, Chainsee Saini, Bhavika Baweja, Sandeep K. Srivastava, Ashok Kumar, Atar Singh Kushwah, Rajeev Nema","doi":"10.1186/s12943-025-02353-3","DOIUrl":"https://doi.org/10.1186/s12943-025-02353-3","url":null,"abstract":"Aurora kinases, AURKA, AURKB, and AURKC, are serine/threonine kinases that play a vital role in regulating cell division and mitosis, particularly in the separation of chromosomes. These kinases are often overexpressed in human tumor cell lines, indicating their potential involvement in tumorigenesis. Preliminary evidence supports the use of Aurora kinase inhibitors for certain types of tumors, several AURKs inhibitors are currently under phase I and II trials. As a result, there is a growing interest in identifying small-molecule Aurora kinase inhibitors to develop as anti-cancer agents. The regulation of the cell cycle, including mitosis, is increasingly recognized as a key target in the fight against various forms of cancer. Novel drugs are being designed to inhibit the function of regulatory proteins, such as Aurora kinases, with the goal of creating personalized treatments. This review summarizes the biology of Aurora kinases in the context of cancer, integrating both preclinical and clinical data. It discusses the challenges and opportunities associated with using Aurora kinases to enhance cancer treatment. Future directions for Aurora kinase-based therapies include developing more selective inhibitors that minimize off-target effects and improve therapeutic efficacy. Researchers are also exploring combination therapies that use Aurora kinase inhibitors alongside other targeted treatments to overcome resistance and improve patient outcomes. Additionally, advancements in biomarker discovery are expected to facilitate the identification of patients most likely to benefit from Aurora kinase-targeted therapies, paving the way for more personalized approaches to cancer treatment.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"1 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biologically targeted dual adaptive and innate nano-Immunotherapy for clear cell renal cell carcinoma treatment","authors":"Kin Man Au, Siqing Li, Tian Zhang, Andrew Z. Wang","doi":"10.1186/s12943-025-02382-y","DOIUrl":"https://doi.org/10.1186/s12943-025-02382-y","url":null,"abstract":"Immunotherapy treatments have significantly improved metastatic renal cell carcinoma (RCC) treatment outcomes. Despite recent advancements, the rates of durable response to immunotherapy remain low, and the toxicity profiles of treatment continue to be high. To address these challenges, we report the development of a human carbonic anhydrase-IX (hCA-9)-targeted multifunctional immunotherapy nanoparticles (MINPs) aimed at improving treatment efficacy and reducing toxicity. We hypothesized that these MINPs will facilitate the recognition and elimination of hCA-9-expressing tumor cells by both adaptive immune cells (cytotoxic CD8+ T cells) and innate immune cells (natural killer (NK) cells). Non-targeted and hCA-9-targeted MINPs were prepared by conjugating anti-CA-9, anti-4-1BB, and anti-CD27 antibodies to poly(ethylene glycol)-block-poly(lactic-co-glycolic acid) diblock copolymer NPs. The abilities of different MINPs in activating CD8+ T cells, NK cells, and human peripheral blood mononuclear cells (hPBMCs) were assessed. In vivo efficacy and mechanistic studies were conducted to evaluate the anticancer activities of different MINPs in immunocompetent hCA-9-transfected mouse RCC tumor models and human ccRCC xenograft models using humanized mice. We also investigated the impact of aging on anticancer efficacy of hCA-9-targeted MINPs in humanized mice. The immune-related side effects associated with the systemic administration of hCA-9-targeted MINPs were characterized. Human CA-9-targeted multifunctionalized immunotherapy NPs (MINPs) functionalized with anti-CA-9, anti-4-1BB, and anti-CD27 antibodies outperformed hCA-9-targeted bifunctionalized immunotherapy NPs (BINPs), non-targeted BINPs, and the combination of free antibodies in activating mouse CD8+ T cells and NK cells to kill hCA-9-expressing RCC cells in vitro. In vivo correlative study confirmed that tumor targeting and effective spatiotemporal coactivation of the 4-1BB and CD27 pathways in CD8+ T cells and NK cells are essential for robust antitumor activity. Furthermore, hCA-9-targeted MINPs, but not the combination of free antibodies, inhibited the growth of human ccRCC in hPBMC-humanized mouse models. The anticancer activity of MINPs in mice humanized with hPBMCs from older donors was slightly weaker than in those humanized with younger donors. More importantly, the MINP formulation effectively prevented the hepatotoxicity associated with the systemic administration of immune checkpoint agonistic antibodies. This study demonstrates that MINPs are a versatile platform capable of facilitating immune cell engagement and the eradication of targeted ccRCC without causing systemic immune-related side effects.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"21 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell multi-omics reveals that FABP1 + renal cell carcinoma drive tumor angiogenesis through the PLG-PLAT axis under fatty acid reprogramming.","authors":"Yiqiu Wang,Yingchun Liang,Min Li,Jiayi Lu,Sian Zhou,Yaoyu Yu,Changwei Yang,Xinhuang Hou","doi":"10.1186/s12943-025-02377-9","DOIUrl":"https://doi.org/10.1186/s12943-025-02377-9","url":null,"abstract":"Renal cell carcinoma is characterized by a poor prognosis. Recently, renal cell carcinoma has been recognized as a metabolic disease associated with fatty acid metabolic reprogramming, although in-depth studies on this topic are still lacking. We found that fatty acid metabolism reprogramming in renal cell carcinoma is primarily characterized by high expression of FABP1. FABP1 + tumors significantly impact survival and display distinct differentiation trajectories compared to other tumor subclusters. They show elevated expression of angiogenesis and cell migration signals, with PLG-PLAT-mediated interactions with endothelial cells notably enhanced. Spatial transcriptomics show a prominent co-localization of FABP1 + tumors with endothelial cells, and their spatial distribution closely aligns with that of PLAT + endothelial cells. FABP1 + tumors exhibit a unique pattern in spatial transcriptomics, enriched in Extracellular Matrix and angiogenesis-related pathways. Through receptor-ligand interaction analysis, a novel PLG-PLAT functional axis was found between tumor epithelial cells and endothelial cells. Based on results of experiments, we infer that FABP1 + tumors can promote plasmin-related tumor angiogenesis by triggering the PLG-PLAT signaling axis. Finally, utilizing preclinical models, we suggest that targeting the FABP1-PLG-PLAT axis may serve as promising strategy enhancing the sensitivity of Tyrosine Kinase Inhibitor therapy.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"91 1","pages":"179"},"PeriodicalIF":37.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}