Cancer research最新文献_第4页

Arginine Deprivation Induces Quiescence and Confers Vulnerability to Ferroptosis in Colorectal Cancer. 精氨酸剥夺诱导结直肠癌的静止和易致铁下垂。

IF 12.5 1区医学

Cancer research Pub Date : 2025-05-02 DOI: 10.1158/0008-5472.CAN-24-1940

Yanyun Lin, Yanhong Zhang, Tianze Huang, Junguo Chen, Guanman Li, Bin Zhang, Liang Xu, Kai Wang, Hui He, Hao Chen, Danling Liu, Shuang Guo, Xiaosheng He, Ping Lan

{"title":"Arginine Deprivation Induces Quiescence and Confers Vulnerability to Ferroptosis in Colorectal Cancer.","authors":"Yanyun Lin, Yanhong Zhang, Tianze Huang, Junguo Chen, Guanman Li, Bin Zhang, Liang Xu, Kai Wang, Hui He, Hao Chen, Danling Liu, Shuang Guo, Xiaosheng He, Ping Lan","doi":"10.1158/0008-5472.CAN-24-1940","DOIUrl":"10.1158/0008-5472.CAN-24-1940","url":null,"abstract":"Metabolic reprogramming is a hallmark of cancer. Rewiring of amino acid metabolic processes provides the basis for amino acid deprivation therapies. In this study, we found that arginine biosynthesis is limited in colorectal cancer because of the deficiency of ornithine transcarbamylase. Accordingly, colorectal cancer cells met the demand for arginine by increasing external uptake. The addiction to environmental arginine resulted in the susceptibility of colorectal cancer to arginine deprivation, which dramatically decreased proliferation in colorectal cancer cells and promoted these cells to enter a reversible quiescence state. Arginine deprivation induced quiescence by activating the AMPK-p53-p21 pathway. RNA sequencing data indicated that colorectal cancer cells may be vulnerable to ferroptosis during arginine deprivation and the combination of ferroptosis inducers and arginine deprivation strongly impeded tumor growth in vivo. These findings suggest that dietary modification combined with ferroptosis induction could be a potential therapeutic strategy for colorectal cancer. Significance: Colorectal cancer dependency on arginine uptake creates a metabolic vulnerability to arginine deficiency that causes cell cycle arrest and ferroptosis sensitivity, highlighting arginine deprivation plus ferroptosis induction as a promising treatment.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"1663-1679"},"PeriodicalIF":12.5,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12046318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482283","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}

引用次数: 0

A 3D Self-Assembly Platform Integrating Decellularized Matrix Recapitulates In Vivo Tumor Phenotypes and Heterogeneity. 整合去细胞化基质的三维自组装平台概括了体内肿瘤表型和异质性。

IF 12.5 1区医学

Cancer research Pub Date : 2025-05-02 DOI: 10.1158/0008-5472.CAN-24-1954

Michael J Buckenmeyer, Elizabeth A Brooks, Madison S Taylor, Ireolu K Orenuga, Liping Yang, Ronald J Holewinski, Thomas J Meyer, Melissa Galloux, Marcial Garmendia-Cedillos, Thomas J Pohida, Thorkell Andresson, Brad St Croix, Matthew T Wolf

{"title":"A 3D Self-Assembly Platform Integrating Decellularized Matrix Recapitulates In Vivo Tumor Phenotypes and Heterogeneity.","authors":"Michael J Buckenmeyer, Elizabeth A Brooks, Madison S Taylor, Ireolu K Orenuga, Liping Yang, Ronald J Holewinski, Thomas J Meyer, Melissa Galloux, Marcial Garmendia-Cedillos, Thomas J Pohida, Thorkell Andresson, Brad St Croix, Matthew T Wolf","doi":"10.1158/0008-5472.CAN-24-1954","DOIUrl":"10.1158/0008-5472.CAN-24-1954","url":null,"abstract":"Three-dimensional (3D) in vitro cell culture models are invaluable tools for investigating the tumor microenvironment. However, analyzing the impact of critical stromal elements, such as extracellular matrix (ECM), remains a challenge. In this study, we developed a hydrogel-free self-assembly platform to establish ECM-rich 3D \"MatriSpheres\" to deconvolute cancer cell-ECM interactions. Mouse and human colorectal cancer MatriSpheres actively incorporated microgram quantities of decellularized small intestine submucosa ECM, which proteomically mimicked colorectal cancer tumor ECM compared with traditional formulations like Matrigel. Solubilized ECM, at subgelation concentrations, was organized by colorectal cancer cells into intercellular stroma-like regions within 5 days, displaying morphologic similarity to colorectal cancer clinical pathology. MatriSpheres featured ECM-dependent transcriptional and cytokine profiles associated with malignancy, lipid metabolism, and immunoregulation. Model benchmarking with single-cell RNA sequencing demonstrated that MatriSpheres enhanced correlation with in vivo tumor cells over traditional ECM-poor spheroids. This facile approach enables tumor-specific tissue morphogenesis, promoting cell-ECM communication to improve fidelity for disease modeling applications. Significance: MatriSpheres provide a hydrogel-free 3D platform for decoupling the influence of heterogeneous extracellular matrix components on tumor biology and can broadly facilitate high-throughput drug discovery and screening applications. See related commentary by Ernst and De Wever, p. 1568.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"1577-1595"},"PeriodicalIF":12.5,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063836","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}

引用次数: 0

The Glycosyltransferase XYLT1 Activates NF-κB Signaling to Promote Metastasis of Early-Stage Lung Adenocarcinoma. 糖基转移酶XYLT1激活NF-κB信号通路促进早期肺腺癌转移。

IF 12.5 1区医学

Cancer research Pub Date : 2025-05-02 DOI: 10.1158/0008-5472.CAN-24-1893

Jian Han, Jianan Du, Xiangmeng Li, Qingbo Zhou, Jiayu Zeng, Jun-Tao Lin, Wenle Zhou, Jiayi Cai, Yaokai Ye, Bosui Yang, Junsheng Wang, Xiang Zhou, Rong Lian, Yi Yang, Xun Zhu, Hongyu Guan, Liping Liu, Junchao Cai, Jueheng Wu, Yun Li, Mengfeng Li, Han Tian

{"title":"The Glycosyltransferase XYLT1 Activates NF-κB Signaling to Promote Metastasis of Early-Stage Lung Adenocarcinoma.","authors":"Jian Han, Jianan Du, Xiangmeng Li, Qingbo Zhou, Jiayu Zeng, Jun-Tao Lin, Wenle Zhou, Jiayi Cai, Yaokai Ye, Bosui Yang, Junsheng Wang, Xiang Zhou, Rong Lian, Yi Yang, Xun Zhu, Hongyu Guan, Liping Liu, Junchao Cai, Jueheng Wu, Yun Li, Mengfeng Li, Han Tian","doi":"10.1158/0008-5472.CAN-24-1893","DOIUrl":"10.1158/0008-5472.CAN-24-1893","url":null,"abstract":"Early-stage lung adenocarcinoma generally has a favorable prognosis. However, more than 30% of early-stage lung adenocarcinoma cases relapse within 5 years of initial treatment, even after complete removal of the primary tumor. Identification of the factors contributing to early-stage lung adenocarcinoma metastasis is needed to develop effective prevention and treatment strategies. In this study, we found upregulation of xylosyltransferase 1 (XYLT1), a glycosyltransferase that initiates the biosynthesis of sulfated glycosaminoglycan (sGAG) chains, in metastatic recurrent lesions of early-stage lung adenocarcinoma, which correlated with poor prognosis. In vitro and in vivo experiments showed that XYLT1 promoted lung adenocarcinoma cell survival and metastasis by activating the NF-κB pathway. Mechanistically, XYLT1 interacted with IκBα and facilitated the biosynthesis of sGAG-conjugated IκBα, which enhanced the interaction between IκBα and IKKs to promote the proteasomal degradation of IκBα. These results illustrate that proteoglycan modification-mediated activation of NF-κB signaling is a driver of early-stage lung adenocarcinoma metastasis, providing a possibility for the detection and intervention of early lung adenocarcinoma metastasis. Significance: XYLT1 promotes metastatic recurrence of early-stage lung adenocarcinoma by facilitating sulfated glycosaminoglycan conjugation and proteasomal degradation of IκBα to activate NF-κB, providing potential biomarker and treatment strategies for lung cancer metastasis.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"1628-1643"},"PeriodicalIF":12.5,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482353","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

Longitudinal Profiling of Circulating Tumor DNA Reveals the Evolutionary Dynamics of Metastatic Prostate Cancer during Serial Therapy. 循环肿瘤DNA的纵向分析揭示了转移性前列腺癌在连续治疗期间的进化动力学。

IF 12.5 1区医学

Cancer research Pub Date : 2025-05-02 DOI: 10.1158/0008-5472.CAN-24-1943

Yuehui Zhao, Naveen Ramesh, Ping Xu, Emi Sei, Min Hu, Shanshan Bai, Patricia Troncoso, Ana M Aparicio, Christopher J Logothetis, Paul G Corn, Nicholas E Navin, Amado J Zurita

{"title":"Longitudinal Profiling of Circulating Tumor DNA Reveals the Evolutionary Dynamics of Metastatic Prostate Cancer during Serial Therapy.","authors":"Yuehui Zhao, Naveen Ramesh, Ping Xu, Emi Sei, Min Hu, Shanshan Bai, Patricia Troncoso, Ana M Aparicio, Christopher J Logothetis, Paul G Corn, Nicholas E Navin, Amado J Zurita","doi":"10.1158/0008-5472.CAN-24-1943","DOIUrl":"10.1158/0008-5472.CAN-24-1943","url":null,"abstract":"Treatment decisions in metastatic castration-resistant prostate cancer are mostly guided by clinical variables, but efforts to molecularly monitor the disease remain hampered by challenges in acquiring tumor tissue repeatedly. In this study, we simultaneously profiled the genome copy number and exome in longitudinal plasma circulating tumor DNA (ctDNA) acquired before, during, and upon progression to serial treatments with androgen signaling inhibitors and taxane chemotherapy from 60 patients with metastatic castration-resistant prostate cancer (2-10 samples per patient). The genomic data were used to delineate the clonal substructure and evolutionary dynamics of each patient, and an evolutionary dynamic index was developed to measure the longitudinal changes of the tumor subclones. Treatment with androgen signaling inhibitors resulted in greater subclonal selection and population structure changes than taxane treatment. The subclones that emerged in association with serial therapy resistance harbored recurrent aberrations in previously identified and new candidate genes, with particular enrichment in genes related to PI3K-AKT signaling. These findings indicate that the integration of detailed clinical and genomic data can provide a framework for future unbiased genomic applications for ctDNA in the clinic to enable precision medicine. Significance: Profiling of the genomic copy number changes and mutations in circulating tumor DNA collected longitudinally from prostate cancer patients receiving serial life-prolonging therapies elucidates evolutionary dynamics and identifies emerging resistant subclones.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"1680-1695"},"PeriodicalIF":12.5,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482301","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}

引用次数: 0

Correction: SCF^FBXW7/GSK3β-Mediated GFI1 Degradation Suppresses Proliferation of Gastric Cancer Cells. 更正：SCFFBXW7/ gsk3 β-介导的GFI1降解抑制胃癌细胞增殖。

IF 12.5 1区医学

Cancer research Pub Date : 2025-05-02 DOI: 10.1158/0008-5472.CAN-25-1051

Xiaoling Kuai, Long Li, Ran Chen, Kangjunjie Wang, Min Chen, Binghau Cui, Yuxue Zhang, Junqiang Li, Hongwen Zhu, Hu Zhou, Jianfei Huang, Jun Qin, Zhiwei Wang, Wenyi Wei, Daming Gao

引用次数: 0

Targeting Intracellular Innate RNA-Sensing Systems Overcomes Resistance to CAR T Cell Therapy in Solid Tumors. 靶向细胞内先天rna传感系统克服实体肿瘤对CAR - T细胞治疗的抵抗。

IF 11.2 1区医学

Cancer research Pub Date : 2025-04-30 DOI: 10.1158/0008-5472.can-24-3425

Nardine Soliman,Tatiana Nedelko,Giada Mandracci,Stefan Enssle,Vincent Grass,Julius C Fischer,Florian Bassermann,Hendrik Poeck,Sebastian Kobold,Nadia El Khawanky,Simon Heidegger

{"title":"Targeting Intracellular Innate RNA-Sensing Systems Overcomes Resistance to CAR T Cell Therapy in Solid Tumors.","authors":"Nardine Soliman,Tatiana Nedelko,Giada Mandracci,Stefan Enssle,Vincent Grass,Julius C Fischer,Florian Bassermann,Hendrik Poeck,Sebastian Kobold,Nadia El Khawanky,Simon Heidegger","doi":"10.1158/0008-5472.can-24-3425","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-3425","url":null,"abstract":"Despite the remarkable success of CAR T cells in certain hematological malignancies, only modest responses have been achieved in solid tumors. Defective cell death pathways have recently been suggested as a tumor-intrinsic form of resistance to CAR T cell treatment. Here, we showed that insufficient activity of the innate RNA-sensing receptor system, RIG I/MAVS, leads to tumor cell-inherent resistance to CAR T cell attack. Active RIG-I/MAVS signaling in tumor cells primed intrinsic mitochondrial apoptosis pathways and expression of cell death receptors, which funneled into CAR T cell-triggered cell death. CAR T cell reliance on tumor-intrinsic RIG-I signaling was observed in various murine and human cancer types, independent of the CAR construct used, and the dependence was most pronounced under conditions with low target antigen expression or low effector/target ratios. RIG-I-induced pro-apoptotic priming of CAR T cell susceptibility involved auto-/paracrine type I IFN signaling loops and could spread to bystander tumor cells. Strong tumor-intrinsic RIG I/MAVS signaling imprinted an activated cytolytic phenotype on tumor-interacting CAR T cells. Agonist-mediated targeting of the RIG-I pathway in the tumor microenvironment rendered murine melanoma susceptible to CAR T cell therapy in vivo with enhanced infiltration of active CAR T cells. Together, this data identifies insufficient RIG-I/MAVS activity and associated impaired cell death signaling in malignant cells as a resistance mechanism to CAR T cells. Targeting tumor-intrinsic RIG-I is a potential strategy to sensitize solid tumors to CAR T cell treatment.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"135 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893147","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

Large-Scale Characterization of Orthotopic Cell Line-Derived Xenografts Identifies TGF-β Signaling as a Key Regulator of Breast Cancer Morphology and Aggressiveness. 原位细胞系来源的异种移植物的大规模表征：TGF-β信号作为乳腺癌形态和侵袭性的关键调节因子

IF 11.2 1区医学

Cancer research Pub Date : 2025-04-30 DOI: 10.1158/0008-5472.can-24-2022

Catrin Lutz,Xue Chao,Bim de Klein,Jinhyuk Bhin,Madelon Badoux,Timo Eijkman,Apostolos P Nikolakopoulos,Stefan J Hutten,Natalie Proost,Bjørn Siteur,Marieke van de Ven,Ji-Ying Song,Jacco van Rheenen,Jessica Morgner,Stefan Prekovic,Jos Jonkers

{"title":"Large-Scale Characterization of Orthotopic Cell Line-Derived Xenografts Identifies TGF-β Signaling as a Key Regulator of Breast Cancer Morphology and Aggressiveness.","authors":"Catrin Lutz,Xue Chao,Bim de Klein,Jinhyuk Bhin,Madelon Badoux,Timo Eijkman,Apostolos P Nikolakopoulos,Stefan J Hutten,Natalie Proost,Bjørn Siteur,Marieke van de Ven,Ji-Ying Song,Jacco van Rheenen,Jessica Morgner,Stefan Prekovic,Jos Jonkers","doi":"10.1158/0008-5472.can-24-2022","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2022","url":null,"abstract":"Breast cancer (BC) is a heterogeneous disease with diverse morphological and molecular subtypes. Preclinical models that recapitulate the heterogeneity of human BC are needed to advance our fundamental understanding of what makes BC an aggressive disease. To study mechanisms underlying BC progression, we generated orthotopic cell line-derived xenograft (CDX) models from 20 different human BC cell lines using both mammary intraductal (MIND) injections and fat-pad transplantations (FPT). The resulting MIND-CDX and FPT-CDX models covered the full spectrum of disease progression, from in situ disease to metastatic growth. Pathological analysis revealed two distinct tumor growth morphologies, flat vs. nodular, and transcriptomics analysis identified the TGF-β pathway as a potential regulator of these two phenotypes in primary BC. Indeed, knockout of SMAD4 converted nodular-growing tumors to a more confined disease, while constitutively active TGFBR1 renders lesions more aggressive. This research not only offers insights into the factors driving BC morphology and aggressiveness but also establishes a comprehensive and valuable resource of well-characterized orthotopic CDX models for BC research.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"91 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893080","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

Multi-task Deep Learning Based on Longitudinal CT Images Facilitates Prediction of Lymph Node Metastasis and Survival in Chemotherapy-Treated Gastric Cancer. 基于纵向CT图像的多任务深度学习有助于预测化疗后胃癌的淋巴结转移和生存。

IF 11.2 1区医学

Cancer research Pub Date : 2025-04-30 DOI: 10.1158/0008-5472.can-24-4190

Bingjiang Qiu,Yunlin Zheng,Shunli Liu,Ruirui Song,Lei Wu,Cheng Lu,Xianqi Yang,Wei Wang,Zaiyi Liu,Yanfen Cui

{"title":"Multi-task Deep Learning Based on Longitudinal CT Images Facilitates Prediction of Lymph Node Metastasis and Survival in Chemotherapy-Treated Gastric Cancer.","authors":"Bingjiang Qiu,Yunlin Zheng,Shunli Liu,Ruirui Song,Lei Wu,Cheng Lu,Xianqi Yang,Wei Wang,Zaiyi Liu,Yanfen Cui","doi":"10.1158/0008-5472.can-24-4190","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-4190","url":null,"abstract":"Accurate preoperative assessment of lymph node metastasis (LNM) and overall survival (OS) status is essential for patients with locally advanced gastric cancer (LAGC) receiving neoadjuvant chemotherapy (NAC), providing timely guidance for clinical decision-making. However, current approaches to evaluate LNM and OS have limited accuracy. In this study, we used longitudinal CT images from 1,021 LAGC patients to develop and validate a multi-task deep learning model named co-attention tri-oriented spatial Mamba (CTSMamba) to simultaneously predict LNM and OS. CTSMamba was trained and validated on 398 patients, and the performance was further validated on 623 patients at two additional centers. Notably, CTSMamba exhibited significantly more robust performance than a clinical model in predicting LNM across all of the cohorts. Additionally, integrating CTSMamba survival scores with clinical predictors further improved personalized OS prediction. These results support the potential of CTSMamba to accurately predict LNM and OS from longitudinal images, potentially providing clinicians with a tool to inform individualized treatment approaches and optimized prognostic strategies.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"43 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893146","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

Integration of Germline and Somatic Variation Improves Chronic Lymphocytic Leukemia Risk Stratification. 种系和体细胞变异的整合提高了慢性淋巴细胞白血病的风险分层。

IF 11.2 1区医学

Cancer research Pub Date : 2025-04-30 DOI: 10.1158/0008-5472.can-24-4251

Aubrey K Hubbard,Derek W Brown,Jie Liu,Irenaeus C Chan,Weiyin Zhou,Giulio Genovese,Alexander DePaulis,Sruthi Srinivasan,Shu-Hong Lin,Batel Blechter,Ian D Buller,Qinglin Zeng,Yin Cao,Wen-Yi Huang,Neal D Freedman,Haoyu Zhang,Diptavo Dutta,Stephen J Chanock,Kelly L Bolton,Mitchell J Machiela

{"title":"Integration of Germline and Somatic Variation Improves Chronic Lymphocytic Leukemia Risk Stratification.","authors":"Aubrey K Hubbard,Derek W Brown,Jie Liu,Irenaeus C Chan,Weiyin Zhou,Giulio Genovese,Alexander DePaulis,Sruthi Srinivasan,Shu-Hong Lin,Batel Blechter,Ian D Buller,Qinglin Zeng,Yin Cao,Wen-Yi Huang,Neal D Freedman,Haoyu Zhang,Diptavo Dutta,Stephen J Chanock,Kelly L Bolton,Mitchell J Machiela","doi":"10.1158/0008-5472.can-24-4251","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-4251","url":null,"abstract":"Both acquired mutations and germline genetic variation are known risk factors for chronic lymphocytic leukemia (CLL). Joint characterization of germline, acquired, and clinical risk has the potential to improve CLL risk prediction. Here, we investigated whether inclusion of a CLL-associated polygenic score (PGS) and two common types of clonal hematopoiesis (CH), autosomal mosaic chromosomal alterations (mCAs) and CH of indeterminate potential (CHIP), could improve CLL risk stratification in 436,784 participants in the UK Biobank and a replication set of 35,382 participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Individual mCAs on chromosomes 11, 12, 23, 14, and 22, as well as CHIP mutations in known lymphoid driver genes, were strongly associated with CLL risk. Integrative models that included sex, age, smoking status, blood cell traits, genetic similarity, CLL PGS, autosomal mCAs, and CHIP had the greatest discriminative ability with predictive utility waning five years after measurement of CH. Sensitivity analyses removing individuals with abnormal blood cell counts and CH commonly observed in CLL showed persistent increased discriminative ability. Evaluating cumulative absolute risk, the CLL PGS and CH had improved ability to stratify CLL cases into higher risk categories and controls into lower risk categories. Overall, this analysis details the enhanced ability to identify individuals at high risk of CLL when integrating germline and somatic data derived from peripheral blood.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"18 5 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893144","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

Eco-evolutionary Guided Pathomic Analysis Detects Biomarkers to Predict Ductal Carcinoma In Situ Upstaging 生态进化引导病理分析检测生物标志物预测导管原位癌

IF 11.2 1区医学

Cancer research Pub Date : 2025-04-29 DOI: 10.1158/0008-5472.can-24-2070

Yujie Xiao, Manal Elmasry, Ji Dong K. Bai, Andrew Chen, Yuzhu Chen, Brooke Jackson, Joseph O. Johnson, Prateek Prasanna, Chao Chen, Mehdi Damaghi

{"title":"Eco-evolutionary Guided Pathomic Analysis Detects Biomarkers to Predict Ductal Carcinoma In Situ Upstaging","authors":"Yujie Xiao, Manal Elmasry, Ji Dong K. Bai, Andrew Chen, Yuzhu Chen, Brooke Jackson, Joseph O. Johnson, Prateek Prasanna, Chao Chen, Mehdi Damaghi","doi":"10.1158/0008-5472.can-24-2070","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2070","url":null,"abstract":"Cancers evolve in a dynamic ecosystem. Thus, characterizing the ecological dynamics of cancer is crucial to understanding cancer evolution, which can lead to the discovery of biomarkers to predict disease progression. Ductal carcinoma in situ (DCIS) is an early-stage breast cancer characterized by abnormal epithelial cell growth confined within the milk ducts, and biomarkers are needed to predict which cases will progress to aggressive disease. In this study, we showed that ecological analysis of hypoxia and acidosis biomarkers can significantly improve prediction of DCIS upstaging. Quantitative analyses were performed on immuno-histological images from a retrospective cohort of DCIS specimens collected from biopsy samples. First, an eco-evolutionary designed approach was developed to define habitats in the tumor intra-ductal microenvironment based on oxygen diffusion distance. Then, cancer cells with metabolic phenotypes attributed to their habitats were identified, including a hypoxia-responding CA9+ phenotype and an acid-adapted LAMP2b+ phenotype. While these markers have traditionally shown limited, if any, predictive capabilities for DCIS progression, when analyzed from an ecological perspective, their power to differentiate between non-upstaged and upstaged DCIS increased significantly. Additionally, the distribution of distinct niches with specific spatial patterns of these biomarkers predicted patient upstaging. The niches were characterized by pattern analysis of both cellular and spatial features. A random forest classifier that was trained and underwent a 5-fold validation on the biopsy cohort achieved an area under curve (AUC) of 0.74 for predicting clinical outcome. These results affirm the importance of tumor ecological features in eco-evolutionary-designed approaches for biomarker discovery.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"9 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889589","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