Journal of Experimental & Clinical Cancer Research最新文献

{"title":"A perspective review on the systematic implementation of ctDNA in phase I clinical trial drug development.","authors":"Nolwen Guigal-Stephan, Brian Lockhart, Tina Moser, Ellen Heitzer","doi":"10.1186/s13046-025-03328-4","DOIUrl":"10.1186/s13046-025-03328-4","url":null,"abstract":"<p><p>Circulating tumour DNA (ctDNA) represents an increasingly important biomarker for the screening, diagnosis and management of patients in clinical practice in advanced/metastatic disease across multiple cancer types. In this context, ctDNA-based comprehensive genomic profiling is now available for patient management decisions, and several ctDNA-based companion diagnostic assays have been approved by regulatory agencies. However, although the assessment of ctDNA levels in Phase II-III drug development is now gathering momentum, it remains somewhat surprisingly limited in the early Phase I phases in light of the potential opportunities provided by such analysis. In this perspective review, we investigate the potential and hurdles of applying ctDNA testing for the inclusion and monitoring of patients in phase 1 clinical trials. This will enable more informed decisions regarding patient inclusion, dose optimization, and proof-of-mechanism of drug biological activity and molecular response, thereby supporting the evolving oncology drug development paradigm. Furthermore, we will highlight the use of cost-efficient, agnostic genome-wide techniques (such as low-pass whole genome sequencing and fragmentomics) and methylation-based methods to facilitate a more systematic integration of ctDNA in early clinical trial settings.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"79"},"PeriodicalIF":11.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11871688/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531844","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":"Retraction Note: Pancreatic cancer-initiating cell exosome message transfer into noncancer-initiating cells: the importance of CD44v6 in reprogramming.","authors":"Zhe Wang, Hanxue Sun, Jan Provaznik, Thilo Hackert, Margot Zöller","doi":"10.1186/s13046-025-03339-1","DOIUrl":"10.1186/s13046-025-03339-1","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"78"},"PeriodicalIF":11.4,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11869581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532051","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":"Decoding chromosomal instability insights in CRC by integrating omics and patient-derived organoids.","authors":"Federica Papaccio, Manuel Cabeza-Segura, Blanca García-Micó, Francisco Gimeno-Valiente, Sheila Zúñiga-Trejos, Valentina Gambardella, María Fernanda Gutiérrez-Bravo, Carolina Martinez-Ciarpaglini, Pilar Rentero-Garrido, Tania Fleitas, Susana Roselló, Juan Antonio Carbonell-Asins, Marisol Huerta, David Moro-Valdezate, Desamparados Roda, Noelia Tarazona, Manuel M Sánchez Del Pino, Andrés Cervantes, Josefa Castillo","doi":"10.1186/s13046-025-03308-8","DOIUrl":"10.1186/s13046-025-03308-8","url":null,"abstract":"<p><strong>Background: </strong>Chromosomal instability (CIN) is involved in about 70% of colorectal cancers (CRCs) and is associated with poor prognosis and drug resistance. From a clinical perspective, a better knowledge of these tumour's biology will help to guide therapeutic strategies more effectively.</p><p><strong>Methods: </strong>We used high-density chromosomal microarray analysis to evaluate CIN level of patient-derived organoids (PDOs) and their original mCRC tissues. We integrated the RNA-seq and mass spectrometry-based proteomics data from PDOs in a functional interaction network to identify the significantly dysregulated processes in CIN. This was followed by a proteome-wGII Pearson correlation analysis and an in silico validation of main findings using functional genomic databases and patient-tissues datasets to prioritize the high-confidence CIN features.</p><p><strong>Results: </strong>By applying the weighted Genome Instability Index (wGII) to identify CIN, we classified PDOs and demonstrated a good correlation with tissues. Multi-omics analysis showed that our organoids recapitulated genomic, transcriptomic and proteomic CIN features of independent tissues cohorts. Thanks to proteotranscriptomics, we uncovered significant associations between mitochondrial metabolism and epithelial-mesenchymal transition in CIN CRC PDOs. Correlating PDOs wGII with protein abundance, we identified a subset of proteins significantly correlated with CIN. Co-localisation analysis in PDOs strengthened the putative role of IPO7 and YAP, and, through in silico analysis, we found that some of the targets give significant dependencies in cell lines with CIN compatible status.</p><p><strong>Conclusions: </strong>We first demonstrated that PDO models are a faithful reflection of CIN tissues at the genetic and phenotypic level. Our new findings prioritize a subset of genes and molecular processes putatively required to cope with the burden on cellular fitness imposed by CIN and associated with disease aggressiveness.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"77"},"PeriodicalIF":11.4,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11869439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531846","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":"Retraction Note: Kindlin-2 promotes hepatocellular carcinoma invasion and metastasis by increasing Wnt/β-catenin signaling.","authors":"Jie Lin, Wansong Lin, Yunbin Ye, Liping Wang, Xiaoyan Chen, Shengbing Zang, Aimin Huang","doi":"10.1186/s13046-025-03333-7","DOIUrl":"10.1186/s13046-025-03333-7","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"76"},"PeriodicalIF":11.4,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11869669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143525036","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":"Comprehensive genetic variant analysis reveals combination of KRAS and LRP1B as a predictive biomarker of response to immunotherapy in patients with non-small cell lung cancer.","authors":"Ella A Eklund, Johanna Svensson, Louise Stauber Näslund, Maria Yhr, Sama I Sayin, Clotilde Wiel, Levent M Akyürek, Per Torstensson, Volkan I Sayin, Andreas Hallqvist, Sukanya Raghavan, Anna Rohlin","doi":"10.1186/s13046-025-03342-6","DOIUrl":"10.1186/s13046-025-03342-6","url":null,"abstract":"<p><strong>Background: </strong>In non-small cell lung cancer (NSCLC), the rapid advancement of predictive genetic testing of tumors by identifying specific pathogenic driver variants has significantly improved treatment guidance. However, immune checkpoint blockade (ICB) is typically administered to patients with tumors in the absence of such driver variants. Since only about 30% of patients will respond to ICB treatment, identifying novel genetic biomarkers of clinical response is crucial and will improve treatment decisions. This prospective clinical study aims to combine molecular biology, advanced bioinformatics and clinical data on response to treatment with ICB from a prospective cohort of NSCLC patients to identify single or combination of genetic variants in the tumor that can serve as predictive biomarkers of clinical response.</p><p><strong>Methods: </strong>In this prospective bi-center clinical study, we performed next-generation sequencing (NGS) of 597 cancer-associated genes in a prospective cohort of 49 patients as the final cohort analyzed, with stage III or IV NSCLC, followed by establishment of an in-house developed bioinformatics-based molecular classification method that integrates, interprets and evaluates data from multiple databases and variant prediction tools. Overall survival (OS) and progression-free survival (PFS) were analyzed for selected candidate genes and variants identified using our novel methodology including molecular tools, databases and clinical information.</p><p><strong>Results: </strong>Our novel molecular interpretation and classification method identified high impact variants in frequently altered genes KRAS, LRP1B, and TP53. Analysis of these genes as single predictive biomarkers in ICB-treated patients revealed that the presence of likely pathogenic variants and variants of unclear significance in LRP1B was associated with improved OS (p = 0.041). Importantly, further analysis of variant combinations in the tumor showed that co-occurrence of KRAS and LRP1B variants significantly improved OS (p = 0.003) and merged PFS (p = 0.008). Notably, the triple combination of variants in KRAS, LRP1B, and TP53 positively impacted both OS (p = 0.026) and merged PFS (p = 0.003).</p><p><strong>Conclusions: </strong>This study suggests that combination of the LRP1B and KRAS variants identified through our novel molecular classification scheme leads to better outcomes following ICB treatment in NSCLC. The addition of TP53 improves the outcome even further. To our knowledge, this is the first report indicating that harboring a combination of KRAS, LRP1B, and TP53 variants can significantly enhance the response to ICB, suggesting a novel predictive biomarker combination for NSCLC patients.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"75"},"PeriodicalIF":11.4,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866712/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517093","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":"Retraction Note: Metformin-repressed miR-381-YAP-snail axis activity disrupts NSCLC growth and metastasis.","authors":"Dan Jin, Jiwei Guo, Yan Wu, Weiwei Chen, Jing Du, Lijuan Yang, Xiaohong Wang, Kaikai Gong, Juanjuan Dai, Shuang Miao, Xuelin Li, Guoming Su","doi":"10.1186/s13046-025-03331-9","DOIUrl":"10.1186/s13046-025-03331-9","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"73"},"PeriodicalIF":11.4,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517137","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":"Radiotherapy resistance driven by Asparagine endopeptidase through ATR pathway modulation in breast cancer.","authors":"Macarena Morillo-Huesca, Ignacio G López-Cepero, Ryan Conesa-Bakkali, Mercedes Tomé, Colin Watts, Pablo Huertas, Gema Moreno-Bueno, Raúl V Durán, Jonathan Martínez-Fábregas","doi":"10.1186/s13046-025-03334-6","DOIUrl":"10.1186/s13046-025-03334-6","url":null,"abstract":"<p><strong>Background: </strong>Tumor resistance represents a major challenge in the current oncology landscape. Asparagine endopeptidase (AEP) overexpression correlates with worse prognosis and reduced overall survival in most human solid tumors. However, the underlying mechanisms of the connection between AEP and reduced overall survival in cancer patients remain unclear.</p><p><strong>Methods: </strong>High-throughput proteomics, cellular and molecular biology approaches and clinical data from breast cancer (BC) patients were used to identify novel, biologically relevant AEP targets. Immunoblotting and qPCR analyses were used to quantify protein and mRNA levels. Flow cytometry, confocal microscopy, chemical inhibitors, siRNA- and shRNA-silencing and DNA repair assays were used as functional assays. In-silico analyses using the TCGA BC dataset and immunofluorescence assays in an independent cohort of invasive ductal (ID) BC patients were used to validate the clinical relevance of our findings.</p><p><strong>Results: </strong>Here we showed a dual role for AEP in genomic stability and radiotherapy resistance in BC patients by suppressing ATR and PPP1R10 levels. Reduced ATR and PPP1R10 levels were found in BC patients expressing high AEP levels and correlated with worst prognosis. Mechanistically, AEP suppresses ATR levels, reducing DNA damage-induced cell death, and PPP1R10 levels, promoting Chek1/P53 cell cycle checkpoint activation, allowing BC cells to efficiently repair DNA. Functional studies revealed AEP-deficiency results in genomic instability, increased DNA damage signaling, reduced Chek1/P53 activation, impaired DNA repair and cell death, with phosphatase inhibitors restoring the DNA damage response in AEP-deficient BC cells. Furthermore, AEP inhibition sensitized BC cells to the chemotherapeutic reagents cisplatin and etoposide. Immunofluorescence assays in an independent cohort of IDBC patients showed increased AEP levels in ductal cells. These analyses showed that higher AEP levels in radioresistant IDBC patients resulted in ATR nuclear eviction, revealing AEPhigh/ATRlow protein levels as an efficient predictive biomarker for the stratification of radioresistant patients.</p><p><strong>Conclusion: </strong>The newly identified AEP/ATR/PPP1R10 axis plays a dual role in genomic stability and radiotherapy resistance in BC. Our work provides new clues to the underlying mechanisms of tumor resistance and strong evidence validating the AEP/ATR axis as a novel predictive biomarker and therapeutic target for the stratification and treatment of radioresistant BC patients.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"74"},"PeriodicalIF":11.4,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517099","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":"Combining molecular characteristics and therapeutic analysis of PDOs predict clinical responses and guide PDAC personalized treatment.","authors":"Peng Li, Minli Huang, Mengyao Li, Gen Li, Yifan Ma, Yong Zhao, Xiaowu Wang, Yongbin Zhang, Changhong Shi","doi":"10.1186/s13046-025-03332-8","DOIUrl":"10.1186/s13046-025-03332-8","url":null,"abstract":"<p><strong>Background: </strong>The emergence of targeted therapies and immunotherapy has broadened treatment options for patients with pancreatic ductal adenocarcinoma (PDAC). Despite this, traditional drug selection, predominantly relies on tumor markers and clinical staging, has underutilized these drugs due to ignoring patient genomic diversity. Patient-derived organoids (PDOs) and corresponding patient-derived organoid xenograft (PDOX) models offer a way to better understand and address this.</p><p><strong>Methods: </strong>In this study, we established PDOs and PDOX models from PDAC clinical samples. These models were analyzed using immunohistochemistry, H&E staining, and genomic profiling. Drug screening with 111 FDA-approved drugs was performed on PDOs, and drug responses in PDOs and PDOX models were compared to assess consistency with clinical treatment outcomes. Gene analysis was conducted to explore the molecular mechanisms underlying variations in drug responses. Additionally, by analyzing the sequencing results from various drug-sensitive groups, the identified differential gene-drug metabolism gene UGT1A10 were modulated in PDOs to evaluate its impact on drug efficacy. A co-culture system of PDOs with immune cells was developed to study the efficacy of immunotherapies.</p><p><strong>Results: </strong>PDOs and matched PDOX models retain the morphological, biological, and genomic characteristics of the primary tumor. Exome sequencing and RNA sequencing confirmed both the consistency and heterogeneity among the PDOs. High-throughput drug screening revealed significant variability in drug sensitivity across different organoids, yet PDOs and PDOX derived from the same patient exhibited a high degree of concordance in response to clinical chemotherapy agents. The gene expression analysis of PDOs with significant differences in drug sensitivity revealed UGT1A10 as a crucial regulator. The knockdown of UGT1A10 notably increased drug sensitivity. Furthermore, immune cells demonstrated specific cytotoxicity towards the organoids, underscoring the potential of the co-culture system for application in tumor immunotherapy.</p><p><strong>Conclusion: </strong>Our results highlight the necessity for personalized treatment strategies that consider genomic diversity beyond tumor markers, thus validating the utility of PDOs and PDOX models in advancing PDAC research and personalized medicine.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"72"},"PeriodicalIF":11.4,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11863571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143505779","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":"Retraction Note: The oncogenic Golgi phosphoprotein 3 like overexpression is associated with cisplatin resistance in ovarian carcinoma and activating the NF-κB signaling pathway.","authors":"Shanyang He, Gang Niu, Jianhong Shang, Yalan Deng, Zhiyong Wan, Cai Zhang, Zeshan You, Hongwei Shen","doi":"10.1186/s13046-025-03344-4","DOIUrl":"10.1186/s13046-025-03344-4","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"71"},"PeriodicalIF":11.4,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11863398/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143505781","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":"Retraction Note: Long noncoding RNA MIR31HG inhibits hepatocellular carcinoma proliferation and metastasis by sponging microRNA-575 to modulate ST7L expression.","authors":"Shaoying Yan, Zhenrong Tang, Ke Chen, Yuyang Liu, Gangfeng Yu, Qiuxu Chen, Hao Dang, Fengjiao Chen, Jiaji Ling, Liying Zhu, Ailong Huang, Hua Tang","doi":"10.1186/s13046-025-03340-8","DOIUrl":"10.1186/s13046-025-03340-8","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"69"},"PeriodicalIF":11.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11852547/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143494344","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}