Cancer research最新文献

{"title":"The Genetic Footprint of Tobacco Smoking: Unraveling the Mutational Signatures in Head and Neck Cancer","authors":"Kaito Mimura, Kenichi Yoshida","doi":"10.1158/0008-5472.can-25-1990","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-1990","url":null,"abstract":"Tobacco smoking and alcohol consumption are among the most significant, yet preventable, behavioral risk factors for cancer. In a recent paper in Nature Genetics, Torrens and colleagues performed whole-genome sequencing of 265 head and neck cancer (HNC) samples collected from eight countries across Europe and South America. They investigated the mechanisms underlying HNC development using mutational signature analysis and driver mutation analysis, complemented by regression analysis with epidemiological data. While the analyses confirmed the established roles of tobacco smoking and alcohol consumption as the primary causes of HNC, key findings included the synergistic effect of tobacco smoke and alcohol consumption, and that alcohol-induced mutational burden was significantly higher when combined with tobacco smoking. Additionally, the difference in smoking habits between countries was identified as a direct contributor to regional differences in HNC incidence. Furthermore, a novel smoking-related mutational signature SBS_I was discovered, awaiting further investigation into the underlying mutational process. This genomics-driven work by Torrens and colleagues evokes further research interest regarding the precise mechanisms of tumor initiation and promotion, and in the field of public health measures. In the end, Torrens and colleagues conclude with a call for anti-smoking measures, emphasizing the need to combat this major cancer risk factor.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"146 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143940661","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":"Targeting Innate Immune Checkpoint TREX1 is a Safe and Effective Immunotherapeutic Strategy in Cancer.","authors":"Cong Xing,Xintao Tu,Wanwan Huai,Zhen Tang,Kun Song,Devon Jeltema,Kennady Knox,Nicole Dobbs,Kun Yang,Nan Yan","doi":"10.1158/0008-5472.can-24-2747","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2747","url":null,"abstract":"Three-prime repair exonuclease 1 (TREX1) is the major DNase in mammalian cells that degrades cytosolic DNA to prevent activation of the cGAS-STING pathway. Genotoxic stress, DNA damage, and radiotherapy induce TREX1 expression in cancer cells, allowing them to evade innate immune activation of type I interferon (IFN-I)-mediated antitumor response. Therefore, targeting TREX1 could represent a potential approach to stimulate antitumor immunity and enhance therapeutic efficacy. Here, we conducted a high-throughput small-molecule inhibitor (SMI) screen of TREX1 using a cell-free DNase assay. Compound 296 specifically inhibited TREX1 DNase activity at low micromolar concentrations, induced IFN-I signaling in cancer cells, and inhibited tumor growth in mice in an IFNAR-dependent manner. Treatment with compound 296 also stimulated T cell infiltration into tumors and synergized with immune checkpoint blockade. Trex1 knockout cancer cells elicited robust systemic antitumor immunity through tumor-intrinsic cGAS-STING activation and functioned as autologous cancer vaccines that protected against tumor challenge and metastasis. An inducible whole-body Trex1 knockout mouse model was established to simulate \"on-demand\" systemic TREX1 inactivation in adult mice. Sustained TREX1 loss suppressed a broad range of solid and metastatic tumors in adult mice without incurring severe immune toxicity, even when combined with immune checkpoint blockade, demonstrating the feasibility of an immune-safe therapeutic window. Together, these data demonstrate the antitumor efficacy and immune safety of multiple therapeutic modalities, including targeting TREX1 using SMIs and employing TREX1 knockout tumor cells as an autologous cancer vaccine, which should pave the way for developing TREX1-targeted cancer immunotherapies.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"101 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915032","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":"Combining Multiplexed CRISPR/Cas9-Nickase and PARP Inhibitors Efficiently and Precisely Targets Cancer Cells.","authors":"Soyoung Lee,Kyunghwan Kim,Hye-Jin Jeong,Subin Choi,Himchan Cheng,Dayoung Kim,Soomin Heo,Jinhee Mun,Minjong Kim,Eunjin Lee,Yoon Ji Choi,Seon-Gyeong Lee,Eun A Lee,Yewon Jang,Kayeong Lim,Heon Seok Kim,Euihwan Jeong,Seung-Jae Myung,Deok-Beom Jung,Chang Sik Yu,In Ho Song,M Ryan Corces,Joo H Kang,Kyungjae Myung,Taejoon Kwon,Tae-Eun Park,Jinmyoung Joo,Seung Woo Cho","doi":"10.1158/0008-5472.can-24-2938","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2938","url":null,"abstract":"Triggering cancer cell death by inducing DNA damage is the primary aim of radiation therapy; however, normal cells are also damaged. Here, we showed that delivery of only four synthetic guide RNAs (sgRNAs) with Cas9 endonuclease efficiently induced simultaneous DNA double-strand breaks, resulting in efficient cell death in a cell type-specific manner. Off-target effects of Cas9 endonuclease were prevented by using Cas9-nickase to induce DNA single-strand breaks and blocking their repair with poly ADP-ribose polymerase (PARP) inhibitors. When recombinant Cas9-nickase protein and multiple sgRNAs were delivered with PARP inhibitors into cultured cells, in vivo xenografts, and patient-derived cancer organoids via lipid nanoparticles, cancer cells were unable to tolerate the induced DNA damage, even in the presence of a functional BRCA2 gene. This approach has the potential to expand the use of PARP inhibitors with verified safety and thus is a potentially powerful tool for personalized genome-based anti-cancer therapy.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"47 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915033","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":"The Integrated Stress Response Pathway Coordinates Translational Control of Multiple Immune Checkpoints in Lung Cancer.","authors":"Shayna Thomas-Jardin,Shruthy Suresh,Ariana Arce,Nicole Novaresi,Qing Deng,Emily Stein,Lisa Thomas,Cheryl Lewis,Chul Ahn,Bret M Evers,Esra A Akbay,Maria E Salvatierra,Wei Lu,Khaja Khan,Luisa M Solis Soto,Ignacio I Wistuba,John D Minna,Kathryn A O'Donnell","doi":"10.1158/0008-5472.can-24-3844","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-3844","url":null,"abstract":"The integrated stress response (ISR) is an adaptive pathway hijacked by cancer cells to survive cellular stresses in the tumor microenvironment. ISR activation potently induces PD-L1, leading to suppression of anti-tumor immunity. Here, we sought to uncover additional immune checkpoint proteins regulated by the ISR to elucidate mechanisms of tumor immune escape. ISR coordinately induced CD155 and PD-L1, enhancing translation of both immune checkpoint proteins through bypass of inhibitory upstream open reading frames in their 5' UTRs. Analysis of primary human lung tumors identified a significant correlation between expression of PD-L1 and CD155. ISR activation accelerated tumorigenesis and inhibited T cell function, which could be overcome by combining PD-1 and TIGIT blockade with the ISR inhibitor ISRIB. This study uncovers a mechanism by which two immune checkpoint proteins are coordinately regulated and suggests a therapeutic strategy for lung cancer patients.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"115 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915034","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":"HRProfiler Detects Homologous Recombination Deficiency in Breast and Ovarian Cancers Using Whole-Genome and Whole-Exome Sequencing Data.","authors":"Ammal Abbasi,Christopher D Steele,Erik N Bergstrom,Azhar Khandekar,Akanksha Farswan,Rana R McKay,Nischalan Pillay,Ludmil B Alexandrov","doi":"10.1158/0008-5472.can-24-2639","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2639","url":null,"abstract":"Breast and ovarian cancers harboring homologous recombination deficiency (HRD) are sensitive to PARP inhibitors and platinum chemotherapy. Conventionally, detecting HRD involves screening for defects in BRCA1, BRCA2, and other relevant genes. Recent analyses have shown that HRD cancers exhibit characteristic mutational signatures due to the activities of HRD-associated mutational processes. At least three machine learning tools exist for detecting HRD based on mutational patterns. Here, using sequencing data from 1,043 breast and 182 ovarian cancers, we trained Homologous Recombination Proficiency Profiler (HRProfiler), a machine learning method for detecting HRD using six mutational features. The performance of HRProfiler was assessed against prior approaches using additional independent datasets of 417 breast and 115 ovarian cancers, including retrospective data from a clinical trial involving patients treated with PARP inhibitors. Individual HRD-associated mutational signatures alone did not consistently detect HRD or predict clinical response across datasets. Notably, while all tools performed comparably for whole-genome sequenced cancers, HRProfiler was the only approach that consistently identified HRD in whole-exome sequenced breast and ovarian cancers, offering clinically relevant insights. Retrospective analyses provided strong evidence that HRProfiler could serve as a valuable tool for predicting HRD and clinical response in breast and ovarian cancers. This study provides the rational for large-scale prospective clinical trials to validate the potential of HRProfiler as a routine predictive and/or prognostic HRD biomarker to guide clinical decision-making.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"31 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915030","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":"Stabilization of RUNX1 Induced by O-GlcNAcylation Promotes PDGF-BB-Mediated Resistance to CDK4/6 Inhibitors in Breast Cancer.","authors":"Shuyan Zhou, Yi Zhang, Julie Belmar, Chunyan Hou, Yaqin Zhang, Changmin Peng, Yunxiao Meng, Zhuqing Li, Muhammad Jameel Mughal, Yanjun Gao, Edward Seto, Min Shen, Matthew D Hall, Junfeng Ma, Cynthia X Ma, Shunqiang Li, Wenge Zhu","doi":"10.1158/0008-5472.CAN-24-2492","DOIUrl":"10.1158/0008-5472.CAN-24-2492","url":null,"abstract":"<p><p>Cyclin-dependent kinases 4 and 6 (CDK4/6) are crucial in regulating cell-cycle progression and cancer development. Targeting CDK4/6 has shown considerable promise in treating various cancers, including breast cancer. Despite significant therapeutic efficacy, resistance to CDK4/6 inhibitors (CDK4/6i), such as palbociclib, remains a substantial hurdle in clinical practice. Using a coculture system, cytokine array, and quantitative high-throughput combinatorial screening, we discovered a mechanism by which the Runt-related transcription factor (RUNX) 1-platelet-derived growth factor (PDGF)-BB axis regulates palbociclib resistance in breast cancer cells. Specifically, RUNX1 functioned as a transcription factor to drive expression of PDGFB, leading to resistance to palbociclib by enhancing the Akt pathway and suppressing senescence. Furthermore, in resistant cells, RUNX1 was O-GlcNAcylated at serine 252 by O-GlcNAc transferase, resulting in the stabilization of RUNX1 by preventing ubiquitin-mediated degradation. Inhibition of the RUNX1-PDGF-BB axis by specific inhibitors overcame palbociclib resistance both in vitro and in vivo. Notably, the RUNX1-PDGF-BB axis was upregulated in resistant patient-derived xenograft lines and in patients with breast cancer following treatment with CDK4/6i. These findings not only unveil O-GlcNAcylation-mediated activation of a RUNX1-PDGF-BB pathway as a driver of palbociclib resistance but also provide clinical evidence supporting the repurposing of FDA-approved PDGFR inhibitors as a therapeutic strategy to treat patients with CDK4/6i-resistant breast cancer. Significance: RUNX1-PDGF-BB signaling drives resistance to CDK4/6 inhibition in breast cancer, providing the foundation to develop approaches to target the RUNX1-PDGF-BB axis to overcome CDK4/6 inhibitor resistance in breast cancer patients.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"1708-1724"},"PeriodicalIF":12.5,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Alternative Lengthening of Telomeres in Cancer Confers a Vulnerability to Reactivation of p53 Function.","authors":"Shawn J Macha, Balakrishna Koneru, Trevor A Burrow, Charles Zhu, Dzmitry Savitski, Rakshandra L Rahman, Catherine A Ronaghan, Jonas Nance, Kristyn McCoy, Cody Eslinger, C Patrick Reynolds","doi":"10.1158/0008-5472.CAN-25-0818","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-25-0818","url":null,"abstract":"","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"85 9","pages":"1738"},"PeriodicalIF":12.5,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954871","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":"Tumorigenesis Driven by BRAFV600E Requires Secondary Mutations That Overcome Its Feedback Inhibition of RAC1 and Migration.","authors":"Sunyana Gadal, Jacob A Boyer, Simon F Roy, Noah A Outmezguine, Malvika Sharma, Hongyan Li, Ning Fan, Eric Chan, Yevgeniy Romin, Afsar Barlas, Qing Chang, Priya Pancholi, Neilawattie Merna Timaul, Michael Overholtzer, Rona Yaeger, Katia Manova-Todorova, Elisa de Stanchina, Marcus W Bosenberg, Neal Rosen","doi":"10.1158/0008-5472.CAN-24-2220","DOIUrl":"10.1158/0008-5472.CAN-24-2220","url":null,"abstract":"<p><p>BRAF V600E mutations occur in 46% of melanomas and drive high levels of ERK activity and ERK-dependent proliferation. However, BRAFV600E is insufficient to drive melanoma in genetically engineered mouse models, and 82% of human benign nevi harbor BRAFV600E mutations. We found that BRAFV600E inhibited mesenchymal migration by causing feedback inhibition of RAC1 activity. ERK pathway inhibition induced RAC1 activation and restored migration and invasion. In cells with BRAFV600E, mutant RAC1 or PTEN inactivation restored RAC1 activity and cell motility. Together, these lesions occurred in 26% of melanomas with BRAFV600E mutations. Thus, although BRAFV600E activation of ERK deregulates cell proliferation, it prevents full malignant transformation by causing feedback inhibition of RAC1. Secondary mutations are, therefore, required for tumorigenesis. One mechanism underlying tumor evolution may be the selection of lesions that rescue the deleterious effects of oncogenic drivers. Significance: Secondary genetic lesions that rescue BRAFV600E/ERK-induced feedback inhibition on cell migration are required for tumorigenesis, indicating that oncogenic feedback may shape the genetic landscape and select for mutations that are therapeutic targets.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"1611-1627"},"PeriodicalIF":12.5,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12046322/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482354","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":"Launching SMART 3D Cancer Models","authors":"Sam Ernst, Olivier De Wever","doi":"10.1158/0008-5472.can-25-1050","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-1050","url":null,"abstract":"The tumor microenvironment plays a crucial role in shaping the tumor phenotype, yet replicating its complexity in vitro remains challenging. Traditional two-dimensional culture models lack physiologic relevance, and three-dimensional models often fail to fully capture native extracellular matrix (ECM) composition and cellular heterogeneity. In this issue of Cancer Research, Buckenmeyer and colleagues bridged this gap by integrating decellularized porcine-derived small intestinal submucosa ECM into monocellular spheroids, resulting in the formation of “MatriSpheres” with in vivo–like cancer cell heterogeneity. Although small intestinal submucosa ECM proved to be beneficial, several routes remain unexplored, such as incorporating other cell types (immune cells and cancer-associated fibroblasts) or species-, organ- or pathology-specific ECM or leveraging patient-derived tumor material. Pursuing these avenues of investigation to further develop Self-Matrix-Assembly to Recapitulate a Tumor (SMART) three-dimensional models could provide a powerful tool for cancer research, drug discovery, and personalized medicine. See related article by Buckenmeyer et al., p. 1577","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"97 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901250","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":"Integrating Plasma Cell-Free DNA Fragment End Motif and Size with Genomic Features Enables Lung Cancer Detection.","authors":"Tae-Rim Lee, Jin Mo Ahn, Junnam Lee, Dasom Kim, Juntae Park, Byeong-Ho Jeong, Dongryul Oh, Sang Man Kim, Gyou-Chul Jung, Beom Hee Choi, Min-Jung Kwon, Mengchi Wang, Michael Salmans, Andrew Carson, Bryan Leatham, Kristin Fathe, Byung In Lee, Byoungsok Jung, Chang-Seok Ki, Young Sik Park, Eun-Hae Cho","doi":"10.1158/0008-5472.CAN-24-1517","DOIUrl":"10.1158/0008-5472.CAN-24-1517","url":null,"abstract":"<p><p>Early detection of lung cancer is important for improving patient survival rates. Liquid biopsy using whole-genome sequencing of cell-free DNA (cfDNA) offers a promising avenue for lung cancer screening, providing a potential alternative or complementary approach to current screening modalities. Here, we aimed to develop and validate an approach by integrating fragment and genomic features of cfDNA to enhance lung cancer detection accuracy across diverse populations. Deep learning-based classifiers were trained using comprehensive cfDNA fragmentomic features from participants in multi-institutional studies, including a Korean discovery dataset (218 patients with lung cancer and 2,559 controls), a Korean validation dataset (111 patients with lung cancer and 1,136 controls), and an independent Caucasian validation cohort (50 patients with lung cancer and 50 controls). In the discovery dataset, classifiers using fragment end motif by size, a feature that captures both fragment end motif and size profiles, outperformed standalone fragment end motif and fragment size classifiers, achieving an area under the curve (AUC) of 0.917. The ensemble classifier integrating fragment end motif by size and genomic coverage achieved an improved performance, with an AUC of 0.937. This performance extended to the Korean validation dataset and demonstrated ethnic generalizability in the Caucasian validation cohort. Overall, the development of a deep learning-based classifier integrating cfDNA fragmentomic and genomic features in this study highlights the potential for accurate lung cancer detection across diverse populations. Significance: Evaluating fragment-based features and genomic coverage in cell-free DNA offers an accurate lung cancer screening method, promising improvements in early cancer detection and addressing challenges associated with current screening methods.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"1696-1707"},"PeriodicalIF":12.5,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708704","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}