NPJ Precision Oncology最新文献

{"title":"Anti-EGFR aptamer exhibits direct anti-cancer effects in NSCLC cells harboring EGFR L858R mutations","authors":"Brian J. Thomas, Sania Z. Awan, Trupti Joshi, Mark A. Daniels, David Porciani, Donald H. Burke","doi":"10.1038/s41698-024-00758-9","DOIUrl":"10.1038/s41698-024-00758-9","url":null,"abstract":"Non-small cell lung cancer (NSCLC) adenocarcinoma (LUAD) is a leading cause of death worldwide. Activating mutations in the tyrosine kinase domain of the oncogene epidermal growth factor receptor (EGFR) are responsible for ~10–50% of all LUAD cases. Although tyrosine kinase inhibitors (TKIs) have been effective in prolonging patient survival and quality of life, acquired resistance and disease progression are inevitable, presenting a clear unmet need for alternative or adjuvant therapeutics. Here we show that an anti-EGFR aptamer (EGFRapt) decreases viability and tumor growth of LUAD cell lines harboring the L858R ± T790M mutation in EGFR. Additionally, we elucidate the mechanism by which EGFRapt exerts these effects by monitoring cellular processes associated with kinase-dependent and kinase-independent mechanisms. Overall, these data establish that EGFRapt has direct anti-cancer activity in mutant EGFR positive LUAD via targetable mechanisms that are independent of existing approaches, and they provide a foundation for further development of nucleic acid-based therapies that target EGFR.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":" ","pages":"1-17"},"PeriodicalIF":6.8,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41698-024-00758-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687854","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":"Multi-omics analysis deciphers intercellular communication regulating oxidative stress to promote oral squamous cell carcinoma progression","authors":"Hongrong Zhang, Yemei Qian, Yang Zhang, Xue Zhou, Shiying Shen, Jingyi Li, Zheyi Sun, Weihong Wang","doi":"10.1038/s41698-024-00764-x","DOIUrl":"10.1038/s41698-024-00764-x","url":null,"abstract":"Oral squamous cell carcinoma (OSCC) is a common malignant tumor in the head and neck, associated with high recurrence and poor prognosis. We performed an integrated analysis of single-cell RNA and spatial transcriptomic data from cancerous and normal tissues to create a comprehensive atlas of epithelial cells and cancer-associated fibroblasts (CAFs). Our findings show that AKR1C3+ epithelial cells, located at the tumor’s stromal front, exhibit significant copy number variation and poor prognostic indicators, suggesting a role in tumor invasion. We also identified a distinct group of early-stage CAFs (named OSCC_Normal, characterized by ADH1B+, MFAP4+, and PLA2G2A+) that interact with AKR1C3+ cells, where OSCC_Normal may inhibit the FOXO1 redox switch in these epithelial cells via the IGF1/IGF1R pathway, causing oxidative stress overload. Conversely, AKR1C3+ cells use ITGA6/ITGB4 receptor to counteract the effects of OSCC_Normal, promoting cancer invasion. This study unveils complex interactions within the OSCC tumor microenvironment.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":" ","pages":"1-18"},"PeriodicalIF":6.8,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41698-024-00764-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687856","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":"Pediatric brain tumor patients display altered immune activation and reduced lymphopoiesis at the onset of disease","authors":"Marco Rosichini, Giada Del Baldo, Carmen Dolores De Luca, Francesca Benini, Shirley Genah, Maria Vinci, Alfredo Cerimele, Marianna Coccetti, Sara Flamini, Rita Carsetti, Antonella Cacchione, Andrea Carai, Angela Mastronuzzi, Franco Locatelli, Enrico Velardi","doi":"10.1038/s41698-024-00755-y","DOIUrl":"10.1038/s41698-024-00755-y","url":null,"abstract":"Optimal immune function is crucial in preventing cancer development and growth and for the success of anti-cancer therapies. Here, we characterized the peripheral immunological status of 83 steroids-naïve pediatric patients with central nervous system neoplasia at the disease onset. Tumors were classified into low-grade gliomas (LGG), high-grade gliomas (HGG), medulloblastoma, and other tumors. We revealed that glioma patients showed an altered lymphocyte pool. T-cells of HGG patients shifted from naïve to effector memory phenotype. LGG patients exhibited T-cell central memory expansion and higher T-cell activation. Interestingly, HGG patients displayed reduced thymic function. Furthermore, LGG and HGG patients showed reduced activated B-cells and suboptimal B-cell formation. Our data demonstrate that glioma patients have reduced lymphopoiesis at the disease onset, which could contribute to the systemic lymphopenia characterizing these patients. This study offers novel insights into the immunological status of brain tumor patients which may help in designing more effective treatments.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":" ","pages":"1-10"},"PeriodicalIF":6.8,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41698-024-00755-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681898","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":"Delta-like ligand 3 (DLL3) landscape in pulmonary and extra-pulmonary neuroendocrine neoplasms","authors":"Alejandra G. Serrano, Pedro Rocha, Cibelle Freitas Lima, Allison Stewart, Bingnan Zhang, Lixia Diao, Junya Fujimoto, Robert J. Cardnell, Wei Lu, Khaja Khan, Beate Sable, Aaron R. Ellison, Ignacio I. Wistuba, Kyle F. Concannon, Daniel M. Halperin, Czerniak Bogdan, Kanishka Sircar, Miao Zhang, Kasey Cargill, Qi Wang, Ana Aparicio, Alexander Lazar, Sharia Hernandez, Jeannelyn Estrella, Preetha Ramalingam, Adel El-Naggar, Neda Kalhor, Carl M. Gay, Lauren Averett Byers, Luisa M. Solis Soto","doi":"10.1038/s41698-024-00739-y","DOIUrl":"10.1038/s41698-024-00739-y","url":null,"abstract":"Delta-like Ligand 3 (DLL3) targeting therapies are promising in small cell lung cancer (SCLC) treatment. However, DLL3 expression in SCLC and other neuroendocrine neoplasms (NEN) is heterogeneous and not well characterized. We describe the landscape of DLL3 at the mRNA and protein levels across SCLC, large cell neuroendocrine carcinoma (LCNEC), and non-small cell lung cancer. Additionally, we explore its expression in extra-pulmonary NEN (EP-NEN) using a standardized DLL3 IHC assay. DLL3 expression is enriched in SCLC, LCNEC along with combined histology lung cancers. Moreover, we find a wide range of DLL3 expression in high-grade EP-NEN. We describe heterogenous DLL3 expression not only in SCLC but also in different NEN types. This comprehensive characterization of DLL3 can help guide future clinical trial design targeting DLL3 in NEN including LCNEC and EP-NEN that are lacking standard of care treatment options.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":" ","pages":"1-13"},"PeriodicalIF":6.8,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574146/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668221","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":"Methylation cytometric pretreatment blood immune profiles with tumor mutation burden as prognostic indicators for survival outcomes in head and neck cancer patients on anti-PD-1 therapy","authors":"Ze Zhang, Kartik Sehgal, Keisuke Shirai, Rondi A. Butler, John K. Wiencke, Devin C. Koestler, Geat Ramush, Min Kyung Lee, Annette M. Molinaro, Hannah G. Stolrow, Ariel Birnbaum, Lucas A. Salas, Robert I. Haddad, Karl T. Kelsey, Brock C. Christensen","doi":"10.1038/s41698-024-00759-8","DOIUrl":"10.1038/s41698-024-00759-8","url":null,"abstract":"Tissue biomarkers for immune checkpoint inhibitor (ICI) response are limited by tumor sample heterogeneity and availability. This study identifies clinically actionable pretreatment blood biomarkers that are associated with ICI treatment response and survival in recurrent/metastatic head and neck squamous cell carcinoma. A prospective multi-center study enrolled 100 patients before standard-of-care immunotherapy. Blood immune profiles, measured by methylation cytometry, were assessed alongside tumor mutational burden (TMB) and PD-L1 combined proportion score (CPS). TMB and PD-L1 CPS were available for 56 and 91 patients, respectively. High neutrophils, monocytes, and neutrophil-to-lymphocyte ratio were associated with worse survival, while high CD4T cells, especially naïve CD4T cells, and lymphocyte-to-monocyte ratio were associated with better survival. Significant interactions between TMB and peripheral immune profiles for both progression-free and overall survival were found. Clinically relevant pretreatment peripheral immune biomarkers were identified, demonstrating the potential of DNA-based immune profiling to predict ICI response before treatment.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":" ","pages":"1-10"},"PeriodicalIF":6.8,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11573993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668343","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":"Genomic and transcriptomic analyses identify distinctive features of triple-negative inflammatory breast cancer","authors":"Xiaoping Wang, Li Zhao, Xingzhi Song, Xiaogang Wu, Savitri Krishnamurthy, Takashi Semba, Shan Shao, Mark Knafl, Larry W. Coffer II, Angela Alexander, Anita Vines, Swetha Bopparaju, Wendy A. Woodward, Randy Chu, Jianhua Zhang, Clinton Yam, Lenora W. M. Loo, Azadeh Nasrazadani, Le-Petross Huong, Scott E. Woodman, Andrew Futreal, Rare Tumor Initiative Team, Debu Tripathy, Naoto T. Ueno","doi":"10.1038/s41698-024-00729-0","DOIUrl":"10.1038/s41698-024-00729-0","url":null,"abstract":"Triple-negative inflammatory breast cancer (TN-IBC) is the most aggressive type of breast cancer, yet its defining genomic, molecular, and immunological features remain largely unknown. In this study, we performed the largest and most comprehensive genomic and transcriptomic analyses of prospectively collected TN-IBC patient samples from a phase II clinical trial (ClinicalTrials.gov, NCT02876107, registered on August 22, 2016) and compared them to similarly analyzed stage III TN-non-IBC patient samples (ClinicalTrials.gov, NCT02276443, registered on October 21, 2014). We found that TN-IBC tumors have distinctive genomic, molecular, and immunological characteristics, including a lower tumor mutation load than TN-non-IBC, and an association of immunosuppressive tumor-infiltrating immune components with an unfavorable response to neoadjuvant chemotherapy. To our knowledge, this is the only study in which TN-IBC and TN-non-IBC samples were collected prospectively. Our analysis improves the understanding of the molecular landscape of the most aggressive subtype of breast cancer. Further studies are needed to discover novel prognostic biomarkers and druggable targets for TN-IBC.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":" ","pages":"1-14"},"PeriodicalIF":6.8,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668255","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":"Understanding tumour growth variability in breast cancer xenograft models identifies PARP inhibition resistance biomarkers","authors":"D. Voulgarelis, J. V. Forment, A. Herencia Ropero, D. Polychronopoulos, J. Cohen-Setton, A. Bender, V. Serra, M. J. O’Connor, J. W. T. Yates, K. C. Bulusu","doi":"10.1038/s41698-024-00702-x","DOIUrl":"10.1038/s41698-024-00702-x","url":null,"abstract":"Understanding the mechanisms of resistance to PARP inhibitors (PARPi) is a clinical priority, especially in breast cancer. We developed a novel mathematical framework accounting for intrinsic resistance to olaparib, identified by fitting the model to tumour growth metrics from breast cancer patient-derived xenograft (PDX) data. Pre-treatment transcriptomic profiles were used with the calculated resistance to identify baseline biomarkers of resistance, including potential combination targets. The model provided both a classification of responses, as well as a continuous description of resistance, allowing for more robust biomarker associations and capturing the observed variability. Thirty-six resistance gene markers were identified, including multiple homologous recombination repair (HRR) pathway genes. High WEE1 expression was also linked to resistance, highlighting an opportunity for combining PARP and WEE1 inhibitors. This framework facilitates a fully automated way of capturing intrinsic resistance, and accounts for the pharmacological response variability captured within PDX studies and hence provides a precision medicine approach.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":" ","pages":"1-12"},"PeriodicalIF":6.8,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574300/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668346","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":"Deep learning for oncologic treatment outcomes and endpoints evaluation from CT scans in liver cancer","authors":"Yujia Xia, Jie Zhou, Xiaolei Xun, Luke Johnston, Ting Wei, Ruitian Gao, Yufei Zhang, Bobby Reddy, Chao Liu, Geoffrey Kim, Jin Zhang, Shuai Zhao, Zhangsheng Yu","doi":"10.1038/s41698-024-00754-z","DOIUrl":"10.1038/s41698-024-00754-z","url":null,"abstract":"Accurate treatment response assessment using serial CT scans is essential in oncological clinical trials. However, oncologists’ assessment following the Response Evaluation Criteria in Solid Tumors (RECIST) guideline is subjective, time-consuming, and sometimes fallible. Advanced liver cancer often presents multifocal hepatic lesions on CT imaging, making accurate characterization more challenging than with other malignancies. In this work, we developed a tumor volume guided comprehensive objective response evaluation based on deep learning (RECORD) for liver cancer. RECORD performs liver tumor segmentation, followed by sum of the volume (SOV)-based treatment response classification and new lesion assessment. Then, it can provide treatment evaluations of response, stability, and progression, and calculates progression-free survival (PFS) and response time. The RECORD pipeline was developed with both CNN and ViT backbones. Its performance was evaluated in three longitudinal cohorts involving 60 multi-national centers, 206 patients, 891 CT scans, using internal five-fold cross-validation and external validations. RECORD with the most effective backbone achieved an average AUC-response of 0.981, AUC-stable of 0.929, and AUC-progression of 0.969 for SOV-based disease status classification, F1-score of 0.887 for new lesion identification, and accuracy of 0.889 for final treatment outcome assessments across all cohorts. RECORD’s PFS and response time predictions strongly correlated with clinician’s assessments (P < 0.001). Moreover, RECORD can better stratify high-risk versus low-risk patients for overall survival compared to the human-assessed RECIST results. In conclusion, RECORD demonstrates efficiency and objectivity in analyzing liver lesions for treatment response evaluation. Further research should extend the pipeline to other metastatic organ sites.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":" ","pages":"1-17"},"PeriodicalIF":6.8,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41698-024-00754-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142645801","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":"Targeting ErbB and tankyrase1/2 prevent the emergence of drug-tolerant persister cells in ALK-positive lung cancer","authors":"Takaaki Fujimura, Koh Furugaki, Hayato Mizuta, Satoshi Muraoka, Makoto Nishio, Jun Adachi, Ken Uchibori, Eisaku Miyauchi, Hidetoshi Hayashi, Ryohei Katayama, Shigeki Yoshiura","doi":"10.1038/s41698-024-00757-w","DOIUrl":"10.1038/s41698-024-00757-w","url":null,"abstract":"Targeting the drug tolerant persister (DTP) state in cancer cells should prevent further development of resistance mechanisms. This study explored combination therapies to inhibit alectinib-induced DTP cell formation from anaplastic lymphoma kinase–positive non-small cell lung cancer (ALK + NSCLC) patient–derived cells. After drug-screening 3114 compounds, pan-HER inhibitors (ErbB pathway) and tankyrase1/2 inhibitors (Wnt/β-catenin signaling) emerged as top candidates to inhibit alectinib-induced DTP cells growth. We confirmed knockdown of both TNKS1/2 in DTP cells recovered the sensitivity to alectinib. Further, our study suggested knockdown of TNKS1/2 increased stability of Axin1/2, which induced β-catenin degradation and decreased its nuclear translocation, thereby suppressing transcription of antiapoptotic and proliferation-related genes (survivin, c-MYC). Targeting both pathways with alectinib+pan-HER inhibitor and alectinib+TNKS1/2 inhibitor suppressed alectinib-induced DTP cells, and the triple combination almost completely prevented the appearance of DTP cells. In conclusion, combination with ALK-TKI, pan-HER and TNKS1/2 inhibitors has the potential to prevent the emergence of DTP in ALK + NSCLC.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":" ","pages":"1-16"},"PeriodicalIF":6.8,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41698-024-00757-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142645807","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":"Single cell-spatial transcriptomics and bulk multi-omics analysis of heterogeneity and ecosystems in hepatocellular carcinoma","authors":"Jiazhou Ye, Yan Lin, Zhiling Liao, Xing Gao, Cheng Lu, Lu Lu, Julu Huang, Xi Huang, Shilin Huang, Hongping Yu, Tao Bai, Jie Chen, Xiaobo Wang, Mingzhi Xie, Min Luo, Jinyan Zhang, Feixiang Wu, Guobin Wu, Liang Ma, Bangde Xiang, Lequn Li, Yongqiang Li, Xiaoling Luo, Rong Liang","doi":"10.1038/s41698-024-00752-1","DOIUrl":"10.1038/s41698-024-00752-1","url":null,"abstract":"This study profiled global single cell-spatial-bulk transcriptome landscapes of hepatocellular carcinoma (HCC) ecosystem from six HCC cases and a non-carcinoma liver control donor. We discovered that intratumoral heterogeneity mainly derived from HCC cells diversity and pervaded the genome-transcriptome-proteome-metabolome network. HCC cells are the core driving force of taming tumor-associated macrophages (TAMs) with pro-tumorigenic phenotypes for favor its dominant growth. Remarkably, M1-types TAMs had been characterized by disturbance of metabolism, poor antigen-presentation and immune-killing abilities. Besides, we found simultaneous cirrhotic and HCC lesions in an individual patient shared common origin and displayed parallel clone evolution via driving disparate immune reprograms for better environmental adaptation. Moreover, endothelial cells exhibited phenotypically conserved but executed differential functions in a space-dependent manner. Further, the spatiotemporal traits of rapid recurrence niche genes were identified and validated by immunohistochemistry. Our data unravels the great significance of HCC cells in shaping vibrant tumor ecosystems corresponding to clinical scenarios.","PeriodicalId":19433,"journal":{"name":"NPJ Precision Oncology","volume":" ","pages":"1-18"},"PeriodicalIF":6.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41698-024-00752-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639437","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}