Cancer letters最新文献_第3页

The Mechanisms and Countermeasures for CAR-T cell Expansion and Persistence Deficiency. CAR-T细胞扩增和持久性缺陷的机制及对策

IF 9.1 1区医学

Cancer letters Pub Date : 2025-05-02 DOI: 10.1016/j.canlet.2025.217771

Yu-Tong Bao, Meng Lv, Xiao-Jun Huang, Xiang-Yu Zhao

{"title":"The Mechanisms and Countermeasures for CAR-T cell Expansion and Persistence Deficiency.","authors":"Yu-Tong Bao, Meng Lv, Xiao-Jun Huang, Xiang-Yu Zhao","doi":"10.1016/j.canlet.2025.217771","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217771","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T cell therapy has emerged as a groundbreaking treatment for hematological malignancies, particularly B-cell malignancies. However, its high risk of relapse and low efficacy in malignancies such as chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) have limited its clinical utility. The expansion, infiltration and persistence of CAR-T cells are key determinants of their efficacy. It has been recognized that limited expansion and lack of persistence are major contributors to non-remission and early relapse, highlighting the need to elucidate their mechanisms and countermeasures. In this review, we described features of CAR-T cell expansion and persistence in various hematogenic malignancies and solid tumors. Then, current knowledge on the mechanisms underlying deficiency in CAR-T cell expansion and persistence is presented, focusing on the intrinsic deficiency of CAR-T cells as well as their interaction with the systemic and local immune environment. Finally, we summarize approaches to enhance CAR-T cell expansion and persistence by improving CAR-T cell quality and overcoming the immunosuppressive environment.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217771"},"PeriodicalIF":9.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954188","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}

引用次数: 0

SENP3 induced HADHA deSUMOylation enhances intrahepatic cholangiocarcinoma chemotherapy sensitivity via fatty acid oxidation SENP3诱导的HADHA去苏酰化通过脂肪酸氧化增强肝内胆管癌化疗敏感性

IF 9.1 1区医学

Cancer letters Pub Date : 2025-05-02 DOI: 10.1016/j.canlet.2025.217770

Jijun Shan , Zhiwen Chen , Mo Chen, Zong Wu, Hongxu Zhu, Xin Jin, Yixiu Wang, Yibin Wu, Zhiwen Ding, Zhen Xiang, Longrong Wang, Yiming Zhao, Zhenhai Lin, Lu Wang

{"title":"SENP3 induced HADHA deSUMOylation enhances intrahepatic cholangiocarcinoma chemotherapy sensitivity via fatty acid oxidation","authors":"Jijun Shan , Zhiwen Chen , Mo Chen, Zong Wu, Hongxu Zhu, Xin Jin, Yixiu Wang, Yibin Wu, Zhiwen Ding, Zhen Xiang, Longrong Wang, Yiming Zhao, Zhenhai Lin, Lu Wang","doi":"10.1016/j.canlet.2025.217770","DOIUrl":"10.1016/j.canlet.2025.217770","url":null,"abstract":"<div><div>Chemoresistance contributes to poor outcomes in patients with intrahepatic cholangiocarcinoma (ICC). This study aimed to explore the mechanisms underlying chemotherapy resistance and to develop strategies that can sensitize the chemotherapy. Patient derived organoids (PDOs) drug screening and Lipidomics profiling were performed to investigate the chemoresistance mechanism. Through multi-strategy analysis, we found that SENP3 enhanced chemotherapy sensitivity in a SUMO system dependent manner. Mechanistically, chemotherapy resistance increased METTL3 expression, which regulated SENP3 mRNA stability through YTHDF2-dependent m6A methylation modifications. SENP3 interacted with HADHA and catalyzed its deSUMOylation at two lysine residues. Specifically, SUMOylation and ubiquitination exhibited crosstalk at the same modification sites on HADHA, influencing its protein stability and, consequently, regulating fatty acid oxidation (FAO) levels. The physical interaction of SENP3, HADHA, and USP10 provides a novel molecular mechanism for the abnormal activation of FAO pathway. The lipid metabolism-targeting drug could be a promising therapeutic strategy for sensitizing ICC to chemotherapy.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"625 ","pages":"Article 217770"},"PeriodicalIF":9.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143906936","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}

引用次数: 0

Mutant p53 confers chemoresistance by activating KMT5B-mediated DNA repair pathway in nasopharyngeal carcinoma 突变型p53通过激活kmt5b介导的DNA修复途径在鼻咽癌中赋予化疗耐药。

IF 9.1 1区医学

Cancer letters Pub Date : 2025-04-30 DOI: 10.1016/j.canlet.2025.217736

Haidan Luo , Mo-Fan Huang , An Xu , Donghui Wang , Julian A. Gingold , Jian Tu , Ruoyu Wang , Zijun Huo , Yen-Ting Chiang , Kuang-Lei Tsai , Jie Su , Danielle A. Bazer , Mien-Chie Hung , Canmao Xie , Yubiao Guo , Dung-Fang Lee , Huiling Yang , Ruiying Zhao

{"title":"Mutant p53 confers chemoresistance by activating KMT5B-mediated DNA repair pathway in nasopharyngeal carcinoma","authors":"Haidan Luo , Mo-Fan Huang , An Xu , Donghui Wang , Julian A. Gingold , Jian Tu , Ruoyu Wang , Zijun Huo , Yen-Ting Chiang , Kuang-Lei Tsai , Jie Su , Danielle A. Bazer , Mien-Chie Hung , Canmao Xie , Yubiao Guo , Dung-Fang Lee , Huiling Yang , Ruiying Zhao","doi":"10.1016/j.canlet.2025.217736","DOIUrl":"10.1016/j.canlet.2025.217736","url":null,"abstract":"<div><div>Nasopharyngeal carcinoma (NPC), a malignancy arising from the nasopharyngeal epithelium, is common in the east and southeast area of Asia. Treatments for locally advanced and recurrent NPC include chemotherapy (usually combined with 5-Fluorouracil, 5-FU) and radiotherapy, but response is limited due to chemo-resistance. p53 mutation is a critical factor for 5-FU resistance in some cancers, but its role in NPC chemo-resistance remains unclear. Here, we demonstrate that p53(R280T), a common p53 somatic mutation found in multiple NPC tumor samples, induces gain-of-function upregulation of DNA repair genes which leads to 5-FU resistance in NPC. p53(R280T) specifically upregulates the expression of DNA repair-associated gene KMT5B by binding to its promoter, which leads to 5-FU resistance. Depletion of KMT5B in NPCs restores 5-FU induced DNA damages and improve the efficacy of 5-FU. By screening compounds affecting KMT5B expression, we identify curcumin as an effective down-regulator of KMT5B in NPC cells. We therefore evaluate the therapeutic potential of a 5-FU/curcumin combination to treat NPC and discover that curcumin enhances the efficacy of 5-FU to suppress NPC tumor growth. In summary, our findings indicate that mutant p53 and its regulated DNA repair genes serve as potential therapeutic targets to reverse 5-FU resistance for NPC patients.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"625 ","pages":"Article 217736"},"PeriodicalIF":9.1,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954703","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}

引用次数: 0

Exosomal Biglycan promotes gastric cancer progression via M2 polarization and CXCL10-mediated JAK/STAT1 activation

IF 9.1 1区医学

Cancer letters Pub Date : 2025-04-30 DOI: 10.1016/j.canlet.2025.217758

Wenchao Li , Hongfa Wei , Junjie Liu , Zidan Zhao , Fuhui Wang , Liang Qiao , Songcheng Yin , Changhua Zhang , Mingyu Huo

{"title":"Exosomal Biglycan promotes gastric cancer progression via M2 polarization and CXCL10-mediated JAK/STAT1 activation","authors":"Wenchao Li , Hongfa Wei , Junjie Liu , Zidan Zhao , Fuhui Wang , Liang Qiao , Songcheng Yin , Changhua Zhang , Mingyu Huo","doi":"10.1016/j.canlet.2025.217758","DOIUrl":"10.1016/j.canlet.2025.217758","url":null,"abstract":"<div><div>Recent advancements in tumor immunotherapy have highlighted the importance of the tumor microenvironment in modulating immune responses against cancer cells. Within the TME, macrophages - particularly the M2 phenotype - serve pivotal regulatory functions through cytokine/chemokine secretion to modulate tumor progression. Elucidating the molecular crosstalk between gastric cancer (GC) cells and tumor-associated macrophages (TAMs) remains imperative for developing targeted therapeutic interventions.</div><div>In this study, we identified Biglycan (BGN), a small leucine-rich proteoglycan, as a key mediator in GC progression. Exosomal BGN derived from GC cell is delivered to macrophages, where it binds to NONO protein, thereby driving M2 polarization and upregulating CXCL10 expression. Elevated CXCL10 levels activate the JAK/STAT1 signaling pathways, thereby potentiating GC cell proliferation, invasion, and metastatic dissemination. Clinically, elevated BGN expression correlates with advanced tumor stage and poor prognosis in GC patients, positioning it as a promising therapeutic target.</div><div>Our findings reveal a previously unrecognized mechanism of exosomal BGN-mediated M2 macrophage reprogramming and CXCL10-driven oncogenic signaling in the GC microenvironment. These insights establish a novel therapeutic paradigm for GC management through disruption of tumor-macrophage communication.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"626 ","pages":"Article 217758"},"PeriodicalIF":9.1,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143942905","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}

引用次数: 0

A necrosis inducer promotes an immunogenic response and destroys ovarian cancers in mouse xenografts and patient ascites organoids 坏死诱导剂促进免疫原性反应并破坏小鼠异种移植和患者腹水类器官中的卵巢癌

IF 9.1 1区医学

Cancer letters Pub Date : 2025-04-29 DOI: 10.1016/j.canlet.2025.217738

Darjan Duraki , Musarrat Jabeen , Chengjian Mao , Lawrence Wang , Santanu Ghosh , Xinyi Dai , Junyao Zhu , Matthew W. Boudreau , Erik R. Nelson , Paul J. Hergenrother , Georgina Cheng , David J. Shapiro

{"title":"A necrosis inducer promotes an immunogenic response and destroys ovarian cancers in mouse xenografts and patient ascites organoids","authors":"Darjan Duraki , Musarrat Jabeen , Chengjian Mao , Lawrence Wang , Santanu Ghosh , Xinyi Dai , Junyao Zhu , Matthew W. Boudreau , Erik R. Nelson , Paul J. Hergenrother , Georgina Cheng , David J. Shapiro","doi":"10.1016/j.canlet.2025.217738","DOIUrl":"10.1016/j.canlet.2025.217738","url":null,"abstract":"<div><div>Most ovarian cancer patients present with advanced disease and there are few targeted therapies; consequently, five-year survival for ovarian cancer remains below 50%. We described the anticipatory unfolded protein response (a-UPR) hyperactivator, ErSO, which induced profound and often complete regression of breast cancer in mouse models. Here we explore the effectiveness of ErSO against ovarian cancer. ErSO induced death of human PEO4 and Caov-3 ovarian cancer cells <em>in vitro</em>. In mouse xenografts, injected ErSO induced rapid complete, or near complete, regression of orthotopic metastatic PEO4 tumors and of Caov-3 ovarian tumors. Ovarian cancer patients often develop malignant ascites containing ovarian cancer organoids that drive metastasis. ErSO showed activity against 7/7 fresh patient derived ascites organoids (PDAOs). Low nanomolar ErSO destroyed 2/7 PDAOs. ErSO-mediated cell death in PDAOs occurred through the same a-UPR activation mechanism seen in cell culture. Moreover, ErSO family compound-induced a-UPR activation in ovarian cancer cells triggers necrotic cell death and release of damage associated molecular patterns (DAMPs), which strongly activated human macrophage and induced monocyte migration. These studies suggest ErSO has unusual potential for treatment of advanced ovarian cancer.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"625 ","pages":"Article 217738"},"PeriodicalIF":9.1,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143935651","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}

引用次数: 0

Sonrotoclax (BGB-11417) synergistically amplifies the radiotherapy-elicited anti-tumor immune response Sonrotoclax （BGB-11417）可协同增强放疗引发的抗肿瘤免疫反应

IF 9.1 1区医学

Cancer letters Pub Date : 2025-04-29 DOI: 10.1016/j.canlet.2025.217759

Mengmeng Ma , Zengfu Zhang , Chen Tian , Xu Liu , Meng Wu , Jinming Yu , Jupeng Yuan , Dawei Chen

{"title":"Sonrotoclax (BGB-11417) synergistically amplifies the radiotherapy-elicited anti-tumor immune response","authors":"Mengmeng Ma , Zengfu Zhang , Chen Tian , Xu Liu , Meng Wu , Jinming Yu , Jupeng Yuan , Dawei Chen","doi":"10.1016/j.canlet.2025.217759","DOIUrl":"10.1016/j.canlet.2025.217759","url":null,"abstract":"<div><div>Escape from apoptosis is one of the main hallmarks of cancer. The imbalance of BCL-2 family members is a key factor leading to radiotherapy resistance. Targeting BCL-2 can overcome radiotherapy resistance by promoting apoptosis. Nevertheless, the function of BCL-2 in regulating the tumor immune microenvironment (TIME) is still not well understood. Herein, we discovered that the specific BCL-2 inhibitor sonrotoclax (BGB-11417) boosted the effectiveness of radiotherapy in an immune-mediated manner. Using flow cytometry, we found that sonrotoclax combined with radiotherapy polarized tumor-associated macrophages (TAMs) toward the M1-type and promoted the infiltration of Gzmb<sup>+</sup> CD8<sup>+</sup> T cells into the tumor. Mechanistically, we demonstrated that the combination of sonrotoclax and radiotherapy induced immunogenic ferroptosis of cancer cells by inhibiting GPX4 expression, released tumor-associated damage-associated molecular patterns (DAMPs) and subsequently activated the NF-κB pathway in TAMs. Moreover, the combination therapy also led to aberrant cytosolic DNA abundance and activated the cGAS-STING pathway in cancer cells, leading to the release of type I interferons and enhanced activation of CD8<sup>+</sup> T cells. Meanwhile, the activation of cGAS-STING pathway also led to the upregulation of PD-L1 expression. Further combination of sonrotoclax and radiotherapy plus anti-PD-L1 exerted the most significant anti-tumor effects. Overall, our study indicated that sonrotoclax enhanced the anti-tumor immune response of radiotherapy through non-apoptotic roles of BCL-2, and shed light on the further clinical evaluation of the triple combination therapy of sonrotoclax, radiotherapy and immunotherapy.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"625 ","pages":"Article 217759"},"PeriodicalIF":9.1,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143912500","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}

引用次数: 0

Cancer mRNA vaccines: clinical application progress and challenges 肿瘤mRNA疫苗：临床应用进展与挑战

IF 9.1 1区医学

Cancer letters Pub Date : 2025-04-28 DOI: 10.1016/j.canlet.2025.217752

Hang Li , Lang Min , Haotian Du , Xiawei Wei , Aiping Tong

{"title":"Cancer mRNA vaccines: clinical application progress and challenges","authors":"Hang Li , Lang Min , Haotian Du , Xiawei Wei , Aiping Tong","doi":"10.1016/j.canlet.2025.217752","DOIUrl":"10.1016/j.canlet.2025.217752","url":null,"abstract":"<div><div>Messenger RNA (mRNA) vaccines have emerged as one of the most promising and rapidly evolving immunotherapeutic approaches due to their ease of production, demonstrated clinical efficacy, and high safety. The coronavirus disease 2019(COVID-19) pandemic has showcased the remarkable therapeutic potential of mRNA vaccines, prompting researchers to explore their use for cancer treatment. Preclinical studies and human clinical trials have indicated their substantial clinical applicability. However, current research faces several challenges, including the complexity of tumor antigen selection, vaccine stability, and the development of resistance. This review summarizes the optimization strategies for cancer mRNA vaccines in preclinical settings, the progress of clinical trials, and the challenges encountered while analyzing various delivery vehicle types, infusion methods, and application cases across different cancer types, highlighting key factors in vaccine design. The findings demonstrate that mRNA vaccines elicit specific immune responses and exhibit favorable safety and tolerability in clinical trials. Moreover, developing personalized neoantigen vaccines offers a novel direction for cancer immunotherapy. The unique contribution of this review lies in its comprehensive overview of the latest advancements in therapeutic mRNA vaccines for cancer treatment while identifying critical areas for future research to propel the field forward.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"625 ","pages":"Article 217752"},"PeriodicalIF":9.1,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143906937","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}

引用次数: 0

Cyst fluid proteins stratify malignant risk of intraductal papillary mucinous neoplasm of the pancreas 胰腺导管内乳头状黏液瘤的囊肿液蛋白分层恶性风险

IF 9.1 1区医学

Cancer letters Pub Date : 2025-04-27 DOI: 10.1016/j.canlet.2025.217753

Chunliang Liu , Amber Mosley , Ehsan Irajizad , Michele Yip-Schneider , Huangbing Wu , Whitney R. Smith-Kinnaman , Thoa Tran , James P. Long , Kim-Anh Do , Johannes Fahrmann , John M. DeWitt , Samir Hanash , C. Max Schmidt , Jianjun Zhang

{"title":"Cyst fluid proteins stratify malignant risk of intraductal papillary mucinous neoplasm of the pancreas","authors":"Chunliang Liu , Amber Mosley , Ehsan Irajizad , Michele Yip-Schneider , Huangbing Wu , Whitney R. Smith-Kinnaman , Thoa Tran , James P. Long , Kim-Anh Do , Johannes Fahrmann , John M. DeWitt , Samir Hanash , C. Max Schmidt , Jianjun Zhang","doi":"10.1016/j.canlet.2025.217753","DOIUrl":"10.1016/j.canlet.2025.217753","url":null,"abstract":"<div><div>Intraductal papillary mucinous neoplasm (IPMN) is the most common type of pancreatic cyst often incidentally detected in asymptomatic patients. The current consensus guidelines, largely based on imaging features, have high sensitivity but low specificity in differentiating benign from malignant IPMNs, leading to unnecessary surgeries. Discovering biomarkers is thus warranted to improve the preoperative risk stratification of IPMN. Pancreatic cyst fluid samples were obtained from patients with pathologically confirmed low-grade (n = 73) or high-grade/invasive (n = 18) IPMN. Global proteome quantitation was performed using liquid chromatography-tandem mass spectrometry. Differentially expressed proteins (DEPs) between the two groups were analyzed using Wilcoxon rank-sum test. 152 upregulated and 74 downregulated DEPs were discovered by comparing low-grade IPMN with high-grade/invasive IPMN (all p < 0.05). The enriched upstream regulators of these DEPs included let-7, miR-122, IL15, and FLT1 (p = 6.76 × 10<sup>−5</sup> - 5.97 × 10<sup>−3</sup>). Five discriminatory biomarkers with the largest LASSO coefficients and each with AUCs of >0.75 (FAHD2A, TCEAL3, TWF1, MMUT, and NTPCR) were identified. The combined five-protein model achieved a bootstrap-corrected AUC of 0.94. A combined analysis of TCGA and GTEx databases showed TWF1 overexpression in pancreatic cancer (p = 2.22 × 10<sup>−16</sup>) that was associated with poor prognosis (p = 0.0063). The present study identified several cyst fluid proteins (particularly TWF1) that are predictive of malignant pancreatic cyst lesions. If validated in other patient populations, these biomarkers may enhance the accuracy of the preoperative detection of high-risk IPMN and thereby improve patient outcomes.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"624 ","pages":"Article 217753"},"PeriodicalIF":9.1,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143887077","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}

引用次数: 0

Using a novel panel of drug-resistant triple-negative breast cancer cell lines to identify candidate therapeutic targets and biomarkers 使用一组新的耐药三阴性乳腺癌细胞系来确定候选治疗靶点和生物标志物

IF 9.1 1区医学

Cancer letters Pub Date : 2025-04-27 DOI: 10.1016/j.canlet.2025.217754

Helen E. Grimsley , Magdalena Antczak , Ian G. Reddin , Nicole Weiler , Katie-May McLaughlin , Florian Rothweiler , Johannes Haas , Andrea Nist , Marco Mernberger , Thorsten Stiewe , Tim R. Fenton , Daniel Speidel , Catherine Harper-Wynne , Karina Cox , Dirk Heckl , Jindrich Cinatl , Mark N. Wass , Michelle D. Garrett , Martin Michaelis

{"title":"Using a novel panel of drug-resistant triple-negative breast cancer cell lines to identify candidate therapeutic targets and biomarkers","authors":"Helen E. Grimsley , Magdalena Antczak , Ian G. Reddin , Nicole Weiler , Katie-May McLaughlin , Florian Rothweiler , Johannes Haas , Andrea Nist , Marco Mernberger , Thorsten Stiewe , Tim R. Fenton , Daniel Speidel , Catherine Harper-Wynne , Karina Cox , Dirk Heckl , Jindrich Cinatl , Mark N. Wass , Michelle D. Garrett , Martin Michaelis","doi":"10.1016/j.canlet.2025.217754","DOIUrl":"10.1016/j.canlet.2025.217754","url":null,"abstract":"<div><div>Here, we introduce a novel set of triple-negative breast cancer (TNBC) cell lines consisting of MDA-MB-468, HCC38, and HCC1806 and their sublines adapted to cisplatin, doxorubicin, eribulin, paclitaxel, gemcitabine, or 5-fluorouracil. Whole exome sequencing combined with TCGA-derived patient data resulted in the identification of 682 biomarker candidates in a pan-cancer analysis. Thirty-five genes were considered the most promising candidates because they harbored resistance-associated variants in at least two resistant sublines, and their expression correlated with TNBC patient survival. Exome sequencing and response profiles to cytotoxic drugs and DNA damage response inhibitors identified revealed remarkably little overlap between the resistant sublines, suggesting that each resistance formation process follows a unique route. This reflects recent findings on cancer cell evolution in patients, supporting the relevance of drug-adapted cancer cell lines as preclinical models of acquired resistance. Moreover, all of the drug-resistant TNBC sublines remained sensitive or even displayed collateral sensitivity to a range of tested compounds. Cross-resistance levels were lowest for the CHK2 inhibitor CCT241533, the PLK1 inhibitor SBE13, and the RAD51 recombinase inhibitor B02, suggesting that CHK2, PLK1, and RAD51 are potential drug targets for therapy-refractory TNBC. In conclusion, we present novel preclinical models of acquired drug resistance in TNBC and the identification of novel candidate therapeutic targets and biomarkers for this disease.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"624 ","pages":"Article 217754"},"PeriodicalIF":9.1,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143899870","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}

引用次数: 0

Decipher the single-cell level responses to chemotherapy in pancreatic ductal adenocarcinoma by a cross-time context graph model 通过跨时间上下文图模型解读胰腺导管腺癌对化疗的单细胞水平反应。

IF 9.1 1区医学

Cancer letters Pub Date : 2025-04-26 DOI: 10.1016/j.canlet.2025.217751

Xinqi Li , Yueze Liu , Feihan Zhou , Wenbo Guo , Guangyu Chen , Jinxin Tao , Jingmin Huang , Jiangdong Qiu , Hao Chen , Bo Ren , Lei You , Yanan Shi , Gang Yang , Taiping Zhang , Jin Gu , Yupei Zhao

{"title":"Decipher the single-cell level responses to chemotherapy in pancreatic ductal adenocarcinoma by a cross-time context graph model","authors":"Xinqi Li , Yueze Liu , Feihan Zhou , Wenbo Guo , Guangyu Chen , Jinxin Tao , Jingmin Huang , Jiangdong Qiu , Hao Chen , Bo Ren , Lei You , Yanan Shi , Gang Yang , Taiping Zhang , Jin Gu , Yupei Zhao","doi":"10.1016/j.canlet.2025.217751","DOIUrl":"10.1016/j.canlet.2025.217751","url":null,"abstract":"<div><div>Gemcitabine is commonly used for pancreatic ductal adenocarcinoma (PDAC), one of the most lethal cancer types. However, the drug resistance is a critical challenge for improving the PDAC chemotherapy. Here, we applied single-cell RNA sequencing (scRNA-seq) on PDAC patient-derived xenograft (PDX) models to study the complex cellular responses related to the gemcitabine resistances. To reconstruct dynamic tumor cell responses from these static scRNA-seq snapshots, we proposed scConGraph, a scalable bi-layer graph model that can efficiently integrate cross-time context information. Based on scConGraph, we observed that stemness and endoplasmic reticulum stress contribute to intrinsic resistance. As for acquired resistance, cancer cells may resist or evade gemcitabine treatment by activating the cell cycle, entering quiescence, or inducing epithelial-mesenchymal transition. Notably, <em>GDF15</em> exhibited recurrent and significant upregulations among acquired-resistance cell subpopulations. Experimental validation confirmed that inhibiting <em>GDF15</em> sensitizes tumor cells to gemcitabine, suggesting a potential target for gemcitabine-induced chemoresistance.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"626 ","pages":"Article 217751"},"PeriodicalIF":9.1,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983778","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}

引用次数: 0