Cancer letters最新文献

{"title":"Targeted inhibition of CHKα and mTOR in models of pancreatic ductal adenocarcinoma: A novel regimen for metastasis","authors":"Jianzhou Liu ,&nbsp;Bolun Jiang ,&nbsp;Wenchao Xu ,&nbsp;Qiaofei Liu ,&nbsp;Haoran Huang ,&nbsp;Xiaoyan Chang ,&nbsp;Guoxu Ma ,&nbsp;Xudong Xu ,&nbsp;Li Zhou ,&nbsp;Gary Guishan Xiao ,&nbsp;Junchao Guo","doi":"10.1016/j.canlet.2024.217280","DOIUrl":"10.1016/j.canlet.2024.217280","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic malignancy for which there are currently no effective anti-metastatic therapies. Herein, we employed single-cell RNA sequencing and metabolomics analysis to demonstrate that metastatic cells highly express focal adhesion kinase (FAK), which promotes metastasis by remodeling choline kinase α (CHKα)-dependent choline metabolism. We designed a novel CHKα inhibitor, CHKI-03, and verified its efficacy in inhibiting metastasis in multiple preclinical models. Classical and newly synthesized small-molecule inhibitors have previously been used to assess the therapeutic potential of targeting mTOR and CHKα in various animal models. Mechanistically, FAK activated mTOR and its downstream HIF-1α, thereby elevating CHKα expression and promoting the proliferation, migration, and invasion of PDAC cells, as well as tumor growth and metastasis. Consistently, high expression levels of both FAK and CHKα are correlated with poor prognosis in patients with PDAC. Notably, CHK1-03 inhibited CHKα expression and also suppressed mTORC1 phosphorylation, disrupting the mTORC1-CHKα positive feedback loop. In addition, the combination of CHKI-03 and the mTORC1 inhibitor rapamycin synergistically inhibited tumor growth and metastasis in PDX models. The combination of CHKI-03 and rapamycin demonstrates considerable therapeutic efficacy in PDO models resistant to gemcitabine. Our findings reveal a pivotal mechanism underlying PDAC metastasis regulated by mTORC1-CHKα loop-dependent choline metabolism reprogramming, highlighting the therapeutic potential of this novel regimen for treating PDAC metastasis.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"605 ","pages":"Article 217280"},"PeriodicalIF":9.1,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342212","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":"Corrigendum to “Pin1 inhibition reverses the acquired resistance of human hepatocellular carcinoma cells to Regorafenib via the Gli1/Snail/E-cadherin pathway” [Cancer Lett. 444 (2019) 82–93]","authors":"Jichuang Wang ,&nbsp;Nan Zhang ,&nbsp;Qi Han ,&nbsp;Wenxian Lu ,&nbsp;Long Wang ,&nbsp;Dayun Yang ,&nbsp;Min Zheng ,&nbsp;Zhenzhen Zhang ,&nbsp;Hekun Liu ,&nbsp;Tae Ho Lee ,&nbsp;Xiao Zhen Zhou ,&nbsp;Kun Ping Lu","doi":"10.1016/j.canlet.2024.217257","DOIUrl":"10.1016/j.canlet.2024.217257","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"604 ","pages":"Article 217257"},"PeriodicalIF":9.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342205","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":"NSUN4-mediated m5C modification of circERI3 promotes lung cancer development by altering mitochondrial energy metabolism","authors":"Jiaxi Wu ,&nbsp;Qingyun Zhao ,&nbsp;Sixian Chen ,&nbsp;Haotian Xu ,&nbsp;Ruirui Zhang ,&nbsp;Dunyu Cai ,&nbsp;Yihong Gao ,&nbsp;Wenyi Peng ,&nbsp;Xingcai Chen ,&nbsp;Shengyi Yuan ,&nbsp;Deqing Li ,&nbsp;Gang Li ,&nbsp;Aruo Nan","doi":"10.1016/j.canlet.2024.217266","DOIUrl":"10.1016/j.canlet.2024.217266","url":null,"abstract":"<div><div>As a highly important methylation modification, the 5-methyladenosine (m5C) modification can profoundly affect RNAs by regulating their transcription, structure and stability. With the continuous development of high-throughput technology, differentially expressed circular RNAs (circRNAs) have been increasingly discovered, and circRNAs play unique roles in tumorigenesis and development. However, the regulatory mechanism of the m5C modification of circRNAs has not yet been revealed. In this study, circERI3, which is highly expressed in lung cancer tissue and significantly correlated with the clinical progression of lung cancer, was initially identified through differential expression profiling of circRNAs. A combined m5C microarray analysis revealed that circERI3 contains the m5C modification and that the NSUN4-mediated m5C modification of circERI3 can increase its nuclear export. The important function of circERI3 in promoting lung cancer progression <em>in vitro</em> and <em>in vivo</em> was clarified. Moreover, we elucidated the novel mechanism by which circERI3 targets DNA binding protein 1 (DDB1), regulates its ubiquitination, enhances its stability, and in turn promotes the transcription of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) through DDB1 to affect mitochondrial function and energy metabolism, which ultimately promotes the development of lung cancer. This study not only revealed the reasons for the abnormal distribution of circERI3 in lung cancer tissues from the perspective of methylation and clarified the important role of circERI3 in lung cancer progression but also described a novel mechanism by which circERI3 promotes lung cancer development through mitochondrial energy metabolism, providing new insights for the study of circRNAs in lung cancer.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"605 ","pages":"Article 217266"},"PeriodicalIF":9.1,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342209","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":"Unravelling the biological and clinical challenges of circulating tumour cells in epithelial ovarian carcinoma","authors":"Faye Lewis ,&nbsp;James Beirne ,&nbsp;Brian Henderson ,&nbsp;Lucy Norris ,&nbsp;Karen Cadoo ,&nbsp;Tanya Kelly ,&nbsp;Cara Martin ,&nbsp;Sinéad Hurley ,&nbsp;Marika Kanjuga ,&nbsp;Lorraine O'Driscoll ,&nbsp;Kathy Gately ,&nbsp;Ezgi Oner ,&nbsp;Volga M. Saini ,&nbsp;Doug Brooks ,&nbsp;Stavros Selemidis ,&nbsp;Waseem Kamran ,&nbsp;Niamh Haughey ,&nbsp;Patrick Maguire ,&nbsp;Catherine O'Gorman ,&nbsp;Feras Abu Saadeh ,&nbsp;Sharon A. O'Toole","doi":"10.1016/j.canlet.2024.217279","DOIUrl":"10.1016/j.canlet.2024.217279","url":null,"abstract":"<div><div>Epithelial ovarian carcinoma (EOC) is the eighth most common cancer in women and the leading cause of gynaecological cancer death, predominantly due to the absence of effective screening tools, advanced stage at diagnosis, and high rates of recurrence. Circulating tumour cells (CTCs), a rare subset of tumour cells that disseminate from a tumour and migrate into the circulation, play a pivotal role in the metastatic cascade, and therefore hold promise as biomarkers for disease monitoring and prognostication. Exploring CTCs from liquid biopsies is an appealing approach for research and clinical practice, given it is minimally invasive, facilitates serial sampling and enables the capture of the entire spectrum of cancer cells circulating in the blood. The prognostic utility of CTC enumeration has been FDA-approved for clinical use in metastatic breast, prostate, and colorectal cancers. However, the unique biology of EOC, discussed herein, compounds the detection and characterisation complexities already inherent in CTC research, consequently hindering progress towards clinical applications. The aim of this review is to provide an overview of both the biological and clinical challenges encountered in harnessing the power of CTCs in EOC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"605 ","pages":"Article 217279"},"PeriodicalIF":9.1,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342214","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":"Integrated proteomic and glycoproteomic analysis reveals heterogeneity and molecular signatures of brain metastases from lung adenocarcinomas","authors":"Yang Zhao ,&nbsp;Dainan Zhang ,&nbsp;Bo Meng ,&nbsp;Yong Zhang ,&nbsp;Shunchang Ma ,&nbsp;Jiaming Zeng ,&nbsp;Xi Wang ,&nbsp;Tao Peng ,&nbsp;Xiaoyun Gong ,&nbsp;Rui Zhai ,&nbsp;Lianhua Dong ,&nbsp;You Jiang ,&nbsp;Xinhua Dai ,&nbsp;Xiang Fang ,&nbsp;Wang Jia","doi":"10.1016/j.canlet.2024.217262","DOIUrl":"10.1016/j.canlet.2024.217262","url":null,"abstract":"<div><div>Brain metastasis is a major cause of poor prognosis and death in lung adenocarcinoma (LUAD); however, the understanding of therapeutic strategies and mechanisms for brain metastases from LUAD (BM-LUAD) remains notably limited, especially at the proteomics levels. To address this issue, we conducted integrated proteomic and glycoproteomic analyses on 49 BM-LUAD tumors, revealing two distinct subtypes of the disease: BM-S1 and BM-S2. Whole exome sequencing analysis revealed that somatic mutations in STK11 and KEAP1, as well as copy number deletions on chr19p13.3, such as STK11, UQCR11, and SLC25A23, were more frequently detected in BM-S2. In BM-S1 tumors, we observed significant infiltration of GFAP + astrocytes, as evidenced by elevated levels of GFAP, GABRA2, GABRG1 and GAP43 proteins and an enrichment of astrocytic signatures in both our proteomic data and external spatial transcriptomic data. Conversely, BM-S2 tumors demonstrated higher levels of PD-1 immune cell infiltration, supported by the upregulation of PD-1 and LAG-3 genes. These findings suggest distinct microenvironmental adaptations required by the different BM-LUAD subtypes. Additionally, we observed unique glycosylation patterns between the subtypes, with increased fucosylation in BM-S1 and enhanced sialylation in BM-S2, primarily affected by glycosylation enzymes such as FUT9, B4GALT1, and ST6GAL1. Specifically, in BM-S2, these sialylation modifications are predominantly localized to the lysosomes, underscoring the critical role of N-glycosylation in the tumor progression of BM-LUAD. Overall, our study not only provides a comprehensive multi-omic data resource but also offers valuable biological insights into BM-LUAD, highlighting potential mechanisms and therapeutic targets for further investigation.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"605 ","pages":"Article 217262"},"PeriodicalIF":9.1,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342207","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":"Revisiting the CXCL13/CXCR5 axis in the tumor microenvironment in the era of single-cell omics: Implications for immunotherapy","authors":"Xuanyu Gu ,&nbsp;Dongyu Li ,&nbsp;Peng Wu ,&nbsp;Chaoqi Zhang ,&nbsp;Xinyu Cui ,&nbsp;Dexin Shang ,&nbsp;Ruijie Ma ,&nbsp;Jingjing Liu ,&nbsp;Nan Sun ,&nbsp;Jie He","doi":"10.1016/j.canlet.2024.217278","DOIUrl":"10.1016/j.canlet.2024.217278","url":null,"abstract":"<div><div>As one of the important members of the family of chemokines and their receptors, the CXCL13/CXCR5 axis is involved in follicle formation in normal lymphoid tissues and the establishment of somatic cavity immunity under physiological conditions, as well as being associated with a wide range of infectious, autoimmune, and tumoral diseases. Here in this review, we focus on its role in tumors. Traditional studies have found the axis to be both pro- and anti-tumorigenic, involving a variety of immune cells, including the tumor cells themselves and those in the tumor microenvironment (TME), and the prognostic significance of this axis is clinical context-dependent. With the development of techniques at the single-cell level, we were able to explain in detail the status of the CXCL13/CXCR5 axis in the TME based on real clinical samples and found that it involves a range of crucial intrinsic anti-tumor immune processes in the TME and is therefore important in tumor immunotherapy. We summarize the cellular subsets, physiological functions, and prognostic significance associated with this axis in the most promising immune checkpoint inhibitor (ICI) therapies of the day and summarize possible therapeutic ideas based on this axis. As with any TME study, the most important takeaway is that the complexity of the CXCL13/CXCR5 axis in TME suggests the importance of personalized therapy in tumor therapy.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"605 ","pages":"Article 217278"},"PeriodicalIF":9.1,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342210","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":"Consensus on the monitoring, treatment, and prevention of leukaemia relapse after allogeneic haematopoietic stem cell transplantation in China: 2024 update","authors":"Yu Wang ,&nbsp;Ying-Jun Chang ,&nbsp;Jing Chen ,&nbsp;Mingzhe Han ,&nbsp;JianDa Hu ,&nbsp;Jiong Hu ,&nbsp;He Huang ,&nbsp;Yongrong Lai ,&nbsp;Daihong Liu ,&nbsp;Qifa Liu ,&nbsp;Yi Luo ,&nbsp;Er-lie Jiang ,&nbsp;Ming Jiang ,&nbsp;Yongping Song ,&nbsp;Xiao-Wen Tang ,&nbsp;Depei Wu ,&nbsp;Ling-Hui Xia ,&nbsp;Kailin Xu ,&nbsp;Xi Zhang ,&nbsp;Xiao-Hui Zhang ,&nbsp;Xiaojun Huang","doi":"10.1016/j.canlet.2024.217264","DOIUrl":"10.1016/j.canlet.2024.217264","url":null,"abstract":"<div><div>The consensus in 2018 from The Chinese Society of Haematology (CSH) on the monitoring, treatment, and prevention of leukaemia relapse after allogeneic haematopoietic stem cell transplantation (HSCT) facilitated the standardization of clinical practices in China and progressive integration with the world. To integrate recent developments and further improve the consensus, a panel of experts from the CSH recently updated the following consensus: (1) integrate risk-adapted, measurable residual disease (MRD)-guided strategy on modified donor lymphocyte infusion (DLI) and interferon-α into total therapy, which was pioneered and refined by Chinese researchers; (2) provide additional evidence of the superiority of haploidentical HSCT (the dominant donor source in China) to matched HSCT for high-risk populations, especially for pre-HSCT MRD-positive patients; (3) support the rapid progress of techniques for MRD detection, such as next-generation sequencing (NGS) and leukaemia stem cell-based MRD detection; and (4) address the role of new targeted options in transplant settings. In conclusion, the establishment of a “total therapy” strategy represents a great step forward. We hope that the consensus updated by Chinese scholars will include the latest cutting-edge developments and inspire progress in post-HSCT relapse management.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"605 ","pages":"Article 217264"},"PeriodicalIF":9.1,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342203","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":"Integration of transcriptomics, proteomics and loss-of-function screening reveals WEE1 as a target for combination with dasatinib against proneural glioblastoma","authors":"Obada T. Alhalabi ,&nbsp;Mona Göttmann ,&nbsp;Maxwell P. Gold ,&nbsp;Silja Schlue ,&nbsp;Thomas Hielscher ,&nbsp;Murat Iskar ,&nbsp;Tobias Kessler ,&nbsp;Ling Hai ,&nbsp;Tolga Lokumcu ,&nbsp;Clara C. Cousins ,&nbsp;Christel Herold-Mende ,&nbsp;Bernd Heßling ,&nbsp;Sandra Horschitz ,&nbsp;Ammar Jabali ,&nbsp;Philipp Koch ,&nbsp;Ulrich Baumgartner ,&nbsp;Bryan W. Day ,&nbsp;Wolfgang Wick ,&nbsp;Felix Sahm ,&nbsp;Sandro M. Krieg ,&nbsp;Violaine Goidts","doi":"10.1016/j.canlet.2024.217265","DOIUrl":"10.1016/j.canlet.2024.217265","url":null,"abstract":"<div><div>Glioblastoma is characterized by a pronounced resistance to therapy with dismal prognosis. Transcriptomics classify glioblastoma into proneural (PN), mesenchymal (MES) and classical (CL) subtypes that show differential resistance to targeted therapies. The aim of this study was to provide a viable approach for identifying combination therapies in glioblastoma subtypes. Proteomics and phosphoproteomics were performed on dasatinib inhibited glioblastoma stem cells (GSCs) and complemented by an shRNA loss-of-function screen to identify genes whose knockdown sensitizes GSCs to dasatinib. Proteomics and screen data were computationally integrated with transcriptomic data using the SamNet 2.0 algorithm for network flow learning to reveal potential combination therapies in PN GSCs. <em>In vitro</em> viability assays and tumor spheroid models were used to verify the synergy of identified therapy. Further <em>in vitro</em> and TCGA RNA-Seq data analyses were utilized to provide a mechanistic explanation of these effects. Integration of data revealed the cell cycle protein WEE1 as a potential combination therapy target for PN GSCs. Validation experiments showed a robust synergistic effect through combination of dasatinib and the WEE1 inhibitor, MK-1775, in PN GSCs. Combined inhibition using dasatinib and MK-1775 propagated DNA damage in PN GCSs, with GCSs showing a differential subtype-driven pattern of expression of cell cycle genes in TCGA RNA-Seq data. The integration of proteomics, loss-of-function screens and transcriptomics confirmed WEE1 as a target for combination with dasatinib against PN GSCs. Utilizing this integrative approach could be of interest for studying resistance mechanisms and revealing combination therapy targets in further tumor entities.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"605 ","pages":"Article 217265"},"PeriodicalIF":9.1,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The incidence and risk of cardiovascular events associated with pembrolizumab in patients with breast cancer.","authors":"Cho-Han Chiang, Xiaocao Haze Xu, Junmin Song, Nutchapon Xanthavanij, Kuan-Yu Chi, Yu-Cheng Chang, Yu Chang, Chieh-Lien Hsiao, Yuan Ping Hsia, Cho-Hung Chiang, Shuwen Lin","doi":"10.1016/j.canlet.2024.217277","DOIUrl":"https://doi.org/10.1016/j.canlet.2024.217277","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217277"},"PeriodicalIF":9.1,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342213","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":"RCC1 regulation of subcellular protein localization via Ran GTPase drives pancreatic ductal adenocarcinoma growth","authors":"Sahar F. Bannoura ,&nbsp;Amro Aboukameel ,&nbsp;Husain Yar Khan ,&nbsp;Md Hafiz Uddin ,&nbsp;Hyejeong Jang ,&nbsp;Eliza W Beal ,&nbsp;Amalraj Thangasamy ,&nbsp;Yang Shi ,&nbsp;Seongho Kim ,&nbsp;Kay-Uwe Wagner ,&nbsp;Rafic Beydoun ,&nbsp;Bassel F. El-Rayes ,&nbsp;Philip A. Philip ,&nbsp;Ramzi M. Mohammad ,&nbsp;Muhammad Wasif Saif ,&nbsp;Mohammed Najeeb Al-Hallak ,&nbsp;Boris C. Pasche ,&nbsp;Asfar S. Azmi","doi":"10.1016/j.canlet.2024.217275","DOIUrl":"10.1016/j.canlet.2024.217275","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, with limited therapeutic options. Here, we evaluated the role of regulator of chromosome condensation 1 (<em>RCC1</em>) in PDAC. RCC1 functions as a guanine exchange factor for GTP-binding nuclear protein Ran (Ran) GTPase and is involved in nucleocytoplasmic transport. <em>RCC1</em> RNA expression is elevated in PDAC tissues compared to normal pancreatic tissues and correlates with poor prognosis. <em>RCC1</em> silencing by RNAi and CRISPR-Cas9 knockout (KO) results in reduced proliferation in 2-D and 3-D cell cultures. <em>RCC1</em> knockdown (KD) reduced migration and clonogenicity, enhanced apoptosis, and altered cell cycle progression in human PDAC and murine cells from LSL-Kras^G12D/+; LSL-Trp53^R172H/+; Pdx1-Cre (KPC) tumors. Mechanistically, <em>RCC1</em> KO shows widespread transcriptomic alterations including regulation of PTK7, a co-receptor of the Wnt signaling pathway. <em>RCC1</em> KD disrupted subcellular Ran localization and the Ran gradient. Nuclear and cytosolic proteomics revealed altered subcellular proteome localization in <em>Rcc1</em> KD KPC-tumor-derived cells and several altered metabolic biosynthesis pathways. In vivo, <em>RCC1</em> KO cells show reduced tumor growth potential when injected as sub-cutaneous xenografts. Finally, <em>RCC1</em> KD sensitized PDAC cells to gemcitabine chemotherapy treatment. This study reveals the role of <em>RCC1</em> in pancreatic cancer as a novel molecular vulnerability that could be exploited to enhance therapeutic response.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"604 ","pages":"Article 217275"},"PeriodicalIF":9.1,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328075","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}