Cancer research最新文献

{"title":"Multidimensional Fragmentomics Enables Early and Accurate Detection of Colorectal Cancer.","authors":"Yuepeng Cao, Nannan Wang, Xuxiaochen Wu, Wanxiangfu Tang, Hua Bao, Chengshuai Si, Peng Shao, Dongzheng Li, Xin Zhou, Dongqin Zhu, Shanshan Yang, Fufeng Wang, Guoqing Su, Ke Wang, Qifan Wang, Yao Zhang, Qiangcheng Wang, Dongsheng Yu, Qian Jiang, Jun Bao, Liu Yang","doi":"10.1158/0008-5472.CAN-23-3486","DOIUrl":"10.1158/0008-5472.CAN-23-3486","url":null,"abstract":"<p><p>Colorectal cancer is frequently diagnosed in advanced stages, highlighting the need for developing approaches for early detection. Liquid biopsy using cell-free DNA (cfDNA) fragmentomics is a promising approach, but the clinical application is hindered by complexity and cost. This study aimed to develop an integrated model using cfDNA fragmentomics for accurate, cost-effective early-stage colorectal cancer detection. Plasma cfDNA was extracted and sequenced from a training cohort of 360 participants, including 176 patients with colorectal cancer and 184 healthy controls. An ensemble stacked model comprising five machine learning models was employed to distinguish patients with colorectal cancer from healthy controls using five cfDNA fragmentomic features. The model was validated in an independent cohort of 236 participants (117 patients with colorectal cancer and 119 controls) and a prospective cohort of 242 participants (129 patients with colorectal cancer and 113 controls). The ensemble stacked model showed remarkable discriminatory power between patients with colorectal cancer and controls, outperforming all base models and achieving a high area under the receiver operating characteristic curve of 0.986 in the validation cohort. It reached 94.88% sensitivity and 98% specificity for detecting colorectal cancer in the validation cohort, with sensitivity increasing as the cancer progressed. The model also demonstrated consistently high accuracy in within-run and between-run tests and across various conditions in healthy individuals. In the prospective cohort, it achieved 91.47% sensitivity and 95.58% specificity. This integrated model capitalizes on the multiplex nature of cfDNA fragmentomics to achieve high sensitivity and robustness, offering significant promise for early colorectal cancer detection and broad patient benefit.  Significance: The development of a minimally invasive, efficient approach for early colorectal cancer detection using advanced machine learning to analyze cfDNA fragment patterns could expedite diagnosis and improve treatment outcomes for patients. See related commentary by Rolfo and Russo, p. 3128.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"3286-3295"},"PeriodicalIF":12.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787264","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 Next Frontier for Colorectal Cancer Screening: Blood-Based Tests.","authors":"Christian Rolfo, Alessandro Russo","doi":"10.1158/0008-5472.CAN-24-1620","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-1620","url":null,"abstract":"<p><p>Colorectal cancer is associated with substantial morbidity and mortality worldwide. Detection of early colorectal cancer is possible through approved screening tests but overall adherence is quite low. Implementation of effective noninvasive options could increase screening uptake and prevent a significant number of deaths. Noninvasive early cancer detection can potentially be achieved using a liquid biopsy. In this issue of Cancer Research, Cao and colleagues report on a novel multidimensional fragmentomics assay, named FRAGTECT, for colorectal cancer detection in circulating cell-free DNA with promising results. See related article by Cao et al., p. 3286.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"84 19","pages":"3128-3129"},"PeriodicalIF":12.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342176","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 Cholesterol Biosynthesis with Statins Synergizes with AKT Inhibitors in Triple-Negative Breast Cancer.","authors":"Alissandra L Hillis, Timothy D Martin, Haley E Manchester, Jenny Högström, Na Zhang, Emmalyn Lecky, Nina Kozlova, Jonah Lee, Nicole S Persky, David E Root, Myles Brown, Karen Cichowski, Stephen J Elledge, Taru Muranen, David A Fruman, Simon T Barry, John G Clohessy, Ralitsa R Madsen, Alex Toker","doi":"10.1158/0008-5472.CAN-24-0970","DOIUrl":"10.1158/0008-5472.CAN-24-0970","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is responsible for a disproportionate number of breast cancer patient deaths due to extensive molecular heterogeneity, high recurrence rates, and lack of targeted therapies. Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT pathway occurs in approximately 50% of TNBC patients. Here, we performed a genome-wide CRISPR/Cas9 screen with PI3Kα and AKT inhibitors to find targetable synthetic lethalities in TNBC. Cholesterol homeostasis was identified as a collateral vulnerability with AKT inhibition. Disruption of cholesterol homeostasis with pitavastatin synergized with AKT inhibition to induce TNBC cytotoxicity in vitro in mouse TNBC xenografts and in patient-derived estrogen receptor (ER)-negative breast cancer organoids. Neither ER-positive breast cancer cell lines nor ER-positive organoids were sensitive to combined AKT inhibitor and pitavastatin. Mechanistically, TNBC cells showed impaired sterol regulatory element-binding protein 2 (SREBP-2) activation in response to single-agent or combination treatment with AKT inhibitor and pitavastatin, which was rescued by inhibition of the cholesterol-trafficking protein Niemann-Pick C1 (NPC1). NPC1 loss caused lysosomal cholesterol accumulation, decreased endoplasmic reticulum cholesterol levels, and promoted SREBP-2 activation. Taken together, these data identify a TNBC-specific vulnerability to the combination of AKT inhibitors and pitavastatin mediated by dysregulated cholesterol trafficking. These findings support combining AKT inhibitors with pitavastatin as a therapeutic modality in TNBC. Significance: Two FDA-approved compounds, AKT inhibitors and pitavastatin, synergize to induce cell death in triple-negative breast cancer, motivating evaluation of the efficacy of this combination in clinical trials.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"3250-3266"},"PeriodicalIF":12.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11443248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723192","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":"Editor's Note: Inhibition of Phosphatidylinositol 3-Kinase Destabilizes Mycn Protein and Blocks Malignant Progression in Neuroblastoma.","authors":"Louis Chesler, Chris Schlieve, David D Goldenberg, Anna Kenney, Grace Kim, Alex McMillan, Katherine K Matthay, David Rowitch, William A Weiss","doi":"10.1158/0008-5472.CAN-24-2888","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-2888","url":null,"abstract":"","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"84 19","pages":"3311"},"PeriodicalIF":12.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342172","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":"Therapeutic Targeting of the GLS1-c-Myc Positive Feedback Loop Suppresses Glutaminolysis and Inhibits Progression of Head and Neck Cancer.","authors":"Jianqiang Yang, Fanghui Chen, Liwei Lang, Fan Yang, Zhenzhen Fu, Juan Martinez, Amber Cho, Nabil F Saba, Yong Teng","doi":"10.1158/0008-5472.CAN-24-0254","DOIUrl":"10.1158/0008-5472.CAN-24-0254","url":null,"abstract":"<p><p>Head and neck squamous cell carcinoma (HNSCC) is addicted to glutaminolysis. Targeting this metabolic dependency has emerged as a potential therapeutic approach for HNSCC. In this study, we conducted a bioinformatic analysis of The Cancer Genome Atlas HNSCC cohort that revealed a robust correlation between expression of MYC (encoding the protein c-Myc) and glutaminase 1 (GLS1), which catalyzes the first step in glutaminolysis. Intriguingly, disruption of GLS1 signaling in HNSCC cells by genetic depletion or CB-839 treatment resulted in a reduction in c-Myc protein stability via a ubiquitin-specific peptidase 1-dependent ubiquitin-proteasome pathway. On the other hand, c-Myc directly binds to the promoter region of GLS1 and upregulates its transcription. Notably, the GLS1-c-Myc pathway enhanced acetyl-coenzyme A carboxylase-dependent Slug acetylation, prompting cancer cell invasion and metastasis. Thus, the GLS1-c-Myc axis emerged as a positive feedback loop critical for driving the aggressiveness of HNSCC. Therapeutically, combining CB-839 with the c-Myc inhibitor MYCi975 strongly suppressed GLS1-c-Myc signaling, resulting in a superior antitumor effect compared with either single agent in an orthotopic mouse model of HNSCC. These findings hold promise for the development of effective therapies for patients with HNSCC, addressing an urgent need arising from the significant incidence and high metastatic rate of the disease. Significance: GLS1 and c-Myc form a positive feedback loop that promotes head and neck cancer metastasis and can be targeted as a promising therapeutic strategy for this disease.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"3223-3234"},"PeriodicalIF":12.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11444885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723119","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":"Hyperactive Dendritc Cells Redirect Aged Antitumor Immunity.","authors":"Alex C Y Chen, Debattama R Sen","doi":"10.1158/0008-5472.CAN-24-2650","DOIUrl":"10.1158/0008-5472.CAN-24-2650","url":null,"abstract":"<p><p>Aging is one of the biggest risk factors for cancer development. More than 85% of all cancers occur in individuals above 55 years old, often accompanied by age-associated immune defects. Previous studies on the tumor microenvironment during aging have identified several factors, such as the roles of fibroblasts, immunosuppression, and metastasis. However, the aging-associated defects in antitumor immunity, particularly with regard to T cells, remain underexplored. Recent findings by Zhivaki and colleagues suggest that age-related immune defects affecting antitumor responses involve reduced levels of CD8+ T cells and compromised dendritic cell (DC) functions such as antigen presentation and migration. Their study demonstrates that a hyperactive DC vaccine can restore DC functions in older mice. Furthermore, these hyperactive DCs, characterized by increased IL1β production and better migratory capability to the lymph node, promote the development of cytolytic CD4+ T cells exhibiting Th1-like phenotypes. This research reveals mechanisms underlying the response to hyperactive DC vaccines in older mice and highlights the critical role of cytolytic CD4+ T cells as substitutes for CD8+ T cells in driving antitumor immunity and achieving long-term tumor control in older mice.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"3130-3131"},"PeriodicalIF":12.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792019","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":"Retraction: mda-9/Syntenin Regulates the Metastatic Phenotype in Human Melanoma Cells by Activating Nuclear Factor-κB.","authors":"Habib Boukerche, Zao-Zhong Su, Luni Emdad, Devanand Sarkar, Paul B Fisher","doi":"10.1158/0008-5472.CAN-24-2216","DOIUrl":"10.1158/0008-5472.CAN-24-2216","url":null,"abstract":"","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"84 19","pages":"3312"},"PeriodicalIF":12.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342175","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":"TCTN1 Induces Fatty Acid Oxidation to Promote Melanoma Metastasis","authors":"Yinlam Li, Ren Ming, Tianyi Zhang, Zixu Gao, Lu Wang, Yang Yang, Kangjie Shen, Chenlu Wei, Yu Zhu, Jianrui Li, Shaoluan Zheng, Zucheng Luo, Yiteng Ding, Jiangying Xuan, Qianrong Hu, Yanwen Yang, Jianying Gu, Chuanyuan Wei","doi":"10.1158/0008-5472.can-24-0158","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0158","url":null,"abstract":"Metabolic reprogramming promotes and sustains multiple steps of melanoma metastasis. Identification of key regulators of metabolic reprogramming could lead to the development of treatments for preventing and treating metastatic melanoma. Here, we identified that the tectonic family member TCTN1 promotes melanoma metastasis by increasing fatty acid oxidation (FAO). In clinical melanoma samples, high expression of TCTN1 correlated with increased metastasis and shorter patient survival. Functionally, TCTN1 promoted melanoma invasion and migration in vitro and distant metastasis in vivo, and TCTN1 induced a mesenchymal-like phenotype switch. Mechanistically, TCTN1 acted as a protein scaffold to promote the binding of HADHA and HADHB, subunits of the mitochondrial trifunctional protein complex, thus leading to FAO activation. TCTN1-mediated FAO activated the p38/MAPK signaling pathway in melanoma cells, promoting tumor EMT and stemness. Molecular docking indicated that the prostaglandin F receptor agonist fluprostenol can block HADHA/HADHB binding, which was confirmed experimentally. Treatment with fluprostenol was able to inhibit TCTN1-induced melanoma invasion and metastasis. Taken together, these findings elucidate the mechanism of TCTN1-mediated promotion of melanoma metastasis and support the potential application of fluprostenol for targeted therapy of metastatic melanoma.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"4 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325302","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 Genomic Landscape of Benign and Malignant Thyroid Tumors from Individuals Carrying Germline PTEN Variants Is Distinct from Sporadic Thyroid Cancers","authors":"Gilman Plitt, Takae Brewer, Lamis Yehia, Laura Rabinowitz, Christopher C. Griffith, Charis Eng","doi":"10.1158/0008-5472.can-23-2216","DOIUrl":"https://doi.org/10.1158/0008-5472.can-23-2216","url":null,"abstract":"Patients with PTEN hamartoma tumor syndrome (PHTS), a molecular diagnosis for those carrying germline PTEN pathogenic variants, have a high prevalence of benign and malignant thyroid disease. Characterizing the genomic landscape in PHTS thyroid tumors could provide insights into malignant potential and tumor progression to help optimize diagnosis, surveillance, and treatment in this population. To reveal the somatic alterations in PHTS-associated thyroid tumors, we conducted exome sequencing on 58 thyroid tumors (28 cancers, 30 benign nodules) from 19 patients with PHTS. A control cohort of 447 sporadic papillary thyroid cancers (PTC) from The Cancer Genome Atlas was used for comparison. PHTS-associated thyroid tumors had a unique genomic landscape in the setting of a pathogenic germline PTEN mutation, when compared with the general population. PHTS-associated thyroid tumors demonstrated a high frequency of second-hit somatic PTEN alterations, including variants and loss-of-heterozygosity events. Second-hit somatic PTEN alterations were more prevalent in PHTS-associated PTC than sporadic PTC (65.2% vs. 0.067%), occurring frequently in PHTS-associated follicular thyroid cancer (100%) and benign follicular nodules (90%). PHTS-associated PTC additionally harbored somatic alterations in BRAF, RAS family members, and genes associated with DNA double-stranded break repair, as well as somatic arm-level copy-number variations. Together, these findings suggest that biallelic PTEN alterations may function as foundational mutations in PHTS thyroid tissue, promoting benign growth and increasing potential for malignant transformation through impaired DNA double-stranded break repair and increased genomic instability. The unique genomic landscape of PHTS-associated thyroid tumors carries implications for molecular-targeted therapies for patients. Significance: Exome sequencing reveals the distinct mutational landscape of PTEN hamartoma tumor syndrome–associated thyroid cancers from sporadic counterparts, providing insights into tumor progression and behavior that could help improve diagnosis, surveillance, and treatment.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"6 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317591","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":"Selective Enhancer Gain of Function Deregulates MYC Expression in Multiple Myeloma.","authors":"Mahshid Rahmat, Kendell Clement, Jean-Baptiste Alberge, Romanos Sklavenitis-Pistofidis, Rohan Kodgule, Charles P Fulco, Daniel Heilpern-Mallory, Katarina Nilsson, David Dorfman, Jesse M Engreitz, Gad Getz, Luca Pinello, Russell Ryan, Irene M Ghobrial","doi":"10.1158/0008-5472.CAN-24-1440","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-1440","url":null,"abstract":"<p><p>MYC deregulation occurs in the majority of multiple myeloma (MM) cases and is associated with progression and worse prognosis. Enhanced MYC expression occurs in about 70% of MM patients, but it is known to be driven by translocation or amplification events in only ~40% of myelomas. Here, we used CRISPR interference (CRISPRi) to uncover an epigenetic mechanism of MYC regulation whereby increased accessibility of a plasma cell-type specific enhancer leads to increased MYC expression. This native enhancer activity was not associated with enhancer hijacking events but led to specific binding of c-MAF, IRF4, and SPIB transcription factors that activated MYC expression in the absence of known genetic aberrations. In addition, focal amplification was another mechanism of activation of this enhancer in approximately 3.4% of MM patients. Together, these findings define an epigenetic mechanism of MYC deregulation in MM beyond known translocations or amplifications and point to the importance of non-coding regulatory elements and their associated transcription factor networks as drivers of MM progression.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280502","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}