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Thulasinathan B, Suvilesh KN, Maram S, Grossmann E, Ghouri Y, Teixeiro EP, Chan J, Kaif JT, Rachagani S. The impact of gut microbial short-chain fatty acids on colorectal cancer development and prevention. Gut Microbes 2025; 17:2483780. [PMID: 40189834 PMCID: PMC11980463 DOI: 10.1080/19490976.2025.2483780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 02/18/2025] [Accepted: 03/18/2025] [Indexed: 04/11/2025] Open
Abstract
Cancer is a long-term illness that involves an imbalance in cellular and immune functions. It can be caused by a range of factors, including exposure to environmental carcinogens, poor diet, infections, and genetic alterations. Maintaining a healthy gut microbiome is crucial for overall health, and short-chain fatty acids (SCFAs) produced by gut microbiota play a vital role in this process. Recent research has established that alterations in the gut microbiome led to decreased production of SCFA's in lumen of the colon, which associated with changes in the intestinal epithelial barrier function, and immunity, are closely linked to colorectal cancer (CRC) development and its progression. SCFAs influence cancer progression by modifying epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNA functions thereby affecting tumor initiation and metastasis. This suggests that restoring SCFA levels in colon through microbiota modulation could serve as an innovative strategy for CRC prevention and treatment. This review highlights the critical relationship between gut microbiota and CRC, emphasizing the potential of targeting SCFAs to enhance gut health and reduce CRC risk.
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Affiliation(s)
- Boobalan Thulasinathan
- Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO, USA
- Roy Blunt NextGen Precision Health Institute, University of Missouri, Columbia, MO, USA
| | - Kanve N. Suvilesh
- Roy Blunt NextGen Precision Health Institute, University of Missouri, Columbia, MO, USA
- Department of Surgery, Ellis Fischel Cancer Centre, University of Missouri, Columbia, MO, USA
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO, USA
| | - Sumanas Maram
- Roy Blunt NextGen Precision Health Institute, University of Missouri, Columbia, MO, USA
| | - Erik Grossmann
- Department of Surgery, Ellis Fischel Cancer Centre, University of Missouri, Columbia, MO, USA
- Department of Medicine, Digestive Centre, Ellis Fischel Cancer Centre, University of Missouri, Columbia, MO, USA
| | - Yezaz Ghouri
- Department of Medicine, Digestive Centre, Ellis Fischel Cancer Centre, University of Missouri, Columbia, MO, USA
| | - Emma Pernas Teixeiro
- Roy Blunt NextGen Precision Health Institute, University of Missouri, Columbia, MO, USA
- Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, USA
| | - Joshua Chan
- Chemical and Biological Engineering, Colorado State University, Fort Collins, CO, USA
| | - Jussuf T. Kaif
- Department of Surgery, Ellis Fischel Cancer Centre, University of Missouri, Columbia, MO, USA
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO, USA
- Siteman Cancer Centre, Washington University, St. Louis, MO, USA
| | - Satyanarayana Rachagani
- Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO, USA
- Roy Blunt NextGen Precision Health Institute, University of Missouri, Columbia, MO, USA
- Department of Surgery, Ellis Fischel Cancer Centre, University of Missouri, Columbia, MO, USA
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO, USA
- Siteman Cancer Centre, Washington University, St. Louis, MO, USA
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2
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Jin ZY, Ling ZQ. PAQR4: From spatial regulation of cell signaling to physiological homeostasis and diseases. Biochim Biophys Acta Rev Cancer 2025; 1880:189314. [PMID: 40194713 DOI: 10.1016/j.bbcan.2025.189314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 04/02/2025] [Accepted: 04/03/2025] [Indexed: 04/09/2025]
Abstract
Progestin and adipoQ receptor family member 4 (PAQR4) gene is a recently discovered seven-transmembrane protein-coding gene that belongs to the PAQR family. An increasing amount of evidence suggests that PAQR4 is upregulated in multiple tumors and participates in tumor progression and chemotherapy resistance via different signaling pathways; PAQR4 regulates cellular ceramide homeostasis by influencing sphingolipid metabolism and glycerol metabolism, and plays a significant role in adipose tissue remodeling. Meanwhile, it is known that the differential expression of PAQR4 is associated with the occurrence of various diseases and is a potential biomarker and therapeutic target. This article conducts a systematic review of the subcellular localization of PAQR4, its topological structure characteristics, and its functions in cancer occurrence, metabolic diseases, and fertility, and provides clues for the future research and translational application of PAQR4.
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Affiliation(s)
- Zi-Yan Jin
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; Postgraduate Training base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, China
| | - Zhi-Qiang Ling
- Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China.
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3
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Liu D, Liu L, Zhang X, Zhao X, Li X, Che X, Wu G. Decoding driver and phenotypic genes in cancer: Unveiling the essence behind the phenomenon. Mol Aspects Med 2025; 103:101358. [PMID: 40037122 DOI: 10.1016/j.mam.2025.101358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 01/25/2025] [Accepted: 02/26/2025] [Indexed: 03/06/2025]
Abstract
Gray hair, widely regarded as a hallmark of aging. While gray hair is associated with aging, reversing this trait through gene targeting does not alter the fundamental biological processes of aging. Similarly, certain oncogenes (such as CXCR4, MMP-related genes, etc.) can serve as markers of tumor behavior, such as malignancy or prognosis, but targeting these genes alone may not lead to tumor regression. We pioneered the name of this class of genes as "phenotypic genes". Historically, cancer genetics research has focused on tumor driver genes, while genes influencing cancer phenotypes have been relatively overlooked. This review explores the critical distinction between driver genes and phenotypic genes in cancer, using the MAPK and PI3K/AKT/mTOR pathways as key examples. We also discuss current research techniques for identifying driver and phenotypic genes, such as whole-genome sequencing (WGS), RNA sequencing (RNA-seq), RNA interference (RNAi), CRISPR-Cas9, and other genomic screening methods, alongside the concept of synthetic lethality in driver genes. The development of these technologies will help develop personalized treatment strategies and precision medicine based on the characteristics of relevant genes. By addressing the gap in discussions on phenotypic genes, this review significantly contributes to clarifying the roles of driver and phenotypic genes, aiming at advancing the field of targeted cancer therapy.
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Affiliation(s)
- Dequan Liu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Lei Liu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Xiaoman Zhang
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Xinming Zhao
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Xiaorui Li
- Department of Oncology, Cancer Hospital of Dalian University of Technology, Shenyang, 110042, China.
| | - Xiangyu Che
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
| | - Guangzhen Wu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
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4
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Sriramadasu K, Ravichandran S, Li YH, Lai MT, Chiang AJ, Li CJ, Tsui KH, Chen CM, Chuang HH, Hwang T, Ding WY, Chung C, Chang CYY, Sheu JJC. Molecular evolution of driver mutations in cancer with microsatellite instability and their impact on tumor progression: Implications for precision medicine in patients with UCEC. Comput Biol Med 2025; 192:110275. [PMID: 40311467 DOI: 10.1016/j.compbiomed.2025.110275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 04/07/2025] [Accepted: 04/24/2025] [Indexed: 05/03/2025]
Abstract
Cancer development is driven by genetic alterations, particularly cancer driver mutations (CDMs), which are associated with aggressive phenotypes and shorter survival. In contrast, higher mutation loads caused by microsatellite instability (MSI) or mismatch repair deficiency (MMRd) can induce anti-cancer immunity, leading to tumor shrinkage and improved responses to immune checkpoint inhibitor (ICI) therapies. However, understanding how CDMs and MSI/MMRd influence cancer evolution remains limited. We opted uterine corpus endometrial carcinoma (UCEC) as a model in this study due to its MSI-high/MMRd characteristics. Somatic mutation screening revealed that UCEC has a significantly higher mutation rate in cancer driver genes compared to ovarian cancer (OVCA) and cervical squamous cell carcinoma (CSCC), despite these cancers arising from histologically connected organs in the reproductive tract. Interestingly, these CDMs did not necessarily drive tumor progression. Using a cutoff of 7.0 (mutations/Mb) for tumor mutation burden (TMB), we classified UCEC patients into two groups with distinct clinical features, genetic profiles, and drug sensitivities. Among the known CDMs, TP53 mutations and their functional networks emerged as key drivers in UCEC progression, while mutations in CTNNB1, PTEN, and ARID1A may enhance anti-tumor immunity, correlating with longer overall survivals. Drug screening using GDSC and CTRPv2 databases suggested that GSK-3 inhibitor IX may be effective for treating aggressive UCEC patients with a non-MSI phenotype. Curcumin showed efficacy for UCEC patients with MSI, especially with ICI therapy. Our study highlights the importance of immune regulation and tolerance over CDMs in cancer development, particularly in those with an MSI-high/MMRd phenotype. We propose that TMB could serve as a valuable screening method alongside molecular and histopathological classifications to guide treatment strategies for UCEC patients.
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Affiliation(s)
- Kalpana Sriramadasu
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804201, Taiwan
| | - Senthilkumar Ravichandran
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804201, Taiwan; Department of Dermatology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - Yau-Hong Li
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804201, Taiwan; Department of Obstetrics and Gynecology, Pingtung Veterans General Hospital, Pingtung, 900053, Taiwan
| | - Ming-Tsung Lai
- Department of Pathology, Taichung Hospital, Ministry of Health and Welfare, Taichung, 403301, Taiwan
| | - An-Jen Chiang
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804201, Taiwan; Department of Obstetrics and Gynecology, Kaohsiung Veterans General Hospital, Kaohsiung, 813414, Taiwan
| | - Chia-Jung Li
- Department of Obstetrics and Gynecology, Kaohsiung Veterans General Hospital, Kaohsiung, 813414, Taiwan; Institute of Biopharmaceutical Sciences, National Sun Yat-Sen University, Kaohsiung, 804201, Taiwan
| | - Kuan-Hao Tsui
- Department of Obstetrics and Gynecology, Kaohsiung Veterans General Hospital, Kaohsiung, 813414, Taiwan; Institute of Biopharmaceutical Sciences, National Sun Yat-Sen University, Kaohsiung, 804201, Taiwan
| | - Chih-Mei Chen
- Genetics Center, China Medical University Hospital, Taichung, 404332, Taiwan
| | - Hsiang-Hao Chuang
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804201, Taiwan
| | - Tritium Hwang
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804201, Taiwan
| | - Wendy Yarou Ding
- Genetics Center, China Medical University Hospital, Taichung, 404332, Taiwan
| | - Ching Chung
- Genetics Center, China Medical University Hospital, Taichung, 404332, Taiwan
| | - Cherry Yin-Yi Chang
- Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, 404332, Taiwan; Department of Medicine, School of Medicine, China Medical University Hospital, Taichung, 404333, Taiwan.
| | - Jim Jinn-Chyuan Sheu
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804201, Taiwan; Institute of Biopharmaceutical Sciences, National Sun Yat-Sen University, Kaohsiung, 804201, Taiwan; School of Chinese Medicine, China Medical University, Taichung, 404333, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 807378, Taiwan.
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5
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Gupta T, Murtaza M. Advancing targeted therapies in pancreatic cancer: Leveraging molecular abberrations for therapeutic success. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2025; 196:19-32. [PMID: 39988056 DOI: 10.1016/j.pbiomolbio.2025.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 02/03/2025] [Accepted: 02/20/2025] [Indexed: 02/25/2025]
Abstract
Pancreatic cancer is one of the most deadly with poor prognosis and overall survival rate due to the dense stroma in the tumors which often is challenging for the delivery of drug to penetrate deep inside the tumor bed and usually results in the progression of cancer. The conventional treatment such as chemotherapy, radiotherapy or surgery shows a minimal benefit in the survival due to the drug resistance, poor penetration, less radiosensitivity or recurrence of tumor. There is an urgent demand to develop molecular-level targeted therapies to achieve therapeutic efficacy in the pancreatic ductal adenocarcinoma (PDAC) patients. The precision oncology focuses on the unique attributes of the patient such as epigenome, proteome, genome, microbiome, lifestyle and diet habits which contributes to promote oncogenesis. The targeted therapy helps to target the mutated proteins responsible for controlling growth, division and metastasis of tumor in the cancer cells. It is very important to consider all the attributes of the patient to provide the suitable personalized treatment to avoid any severe side effects. In this review, we have laid emphasis on the precision medicine; the utmost priority is to improve the survival of cancer patients by targeting molecular mutations through transmembrane proteins, inhibitors, signaling pathways, immunotherapy, gene therapy or the use of nanocarriers for the delivery at the tumor site. It will become beneficial therapeutic window to be considered for the advanced stage pancreatic cancer patients to prolong their survival rate.
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Affiliation(s)
- Tanvi Gupta
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan.
| | - Mohd Murtaza
- Fermentation & Microbial Biotechnology Division, CSIR- Indian Institute of Integrative Medicine, Jammu, 180016, India.
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6
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Yang D, Sun W, Gao L, Zhao K, Zhuang Q, Cai Y. Cell competition as an emerging mechanism and therapeutic target in cancer. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167769. [PMID: 40054587 DOI: 10.1016/j.bbadis.2025.167769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 01/18/2025] [Accepted: 02/27/2025] [Indexed: 03/17/2025]
Abstract
Cell competition, as an internal quality control mechanism that constantly monitor cell fitness and eliminate unfit cells, maintains proper embryogenesis and tissue integrity during early development and adult homeostasis. Recent studies have revealed that cell competition functions as a tumor-suppressive mechanism to defend against cancer by removing neoplastic cell, which however, is hijacked by tumor cells and drive cell competition in favor of mutant cells, thereby promoting cancer initiation and progression. In this review, with a special focus on mammalian systems, we discuss the latest insights into the mechanisms regulating cell competition and its dual role in tumor development. We also provide current strategies to modulate the direction of cell competition for the prevention and treatment of cancers.
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Affiliation(s)
- Dakai Yang
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jintan, People's Republic of China; Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, People's Republic of China.
| | - Wenyue Sun
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, People's Republic of China
| | - Lu Gao
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, People's Republic of China
| | - Kai Zhao
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jintan, People's Republic of China
| | - Qin Zhuang
- Department of General Practice, Affiliated Hospital of Jiangsu University, Zhenjiang, People's Republic of China.
| | - Yun Cai
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jintan, People's Republic of China.
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7
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Jeon Y, Bae H, Woo SW, Kim J, Yu D. Identifying functional roles and pathways of shared mutations in canine solid tumors by whole-genome sequencing. PLoS One 2025; 20:e0307792. [PMID: 40446009 PMCID: PMC12124556 DOI: 10.1371/journal.pone.0307792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 02/04/2025] [Indexed: 06/02/2025] Open
Abstract
Identifying genetic mutations contributing to solid tumors by altering the biological pathways related to tumor formation and development is essential for the development of targeted therapies. This study aimed to identify commonly mutated genes and altered pathways in canine solid tumors. Four dogs with different types of naturally occurring neoplasias (urothelial carcinoma, adenocarcinoma, rhabdomyosarcoma, and chondrosarcoma) were randomly selected and classified into carcinoma and sarcoma groups based on histopathological findings. Tumor tissues were analyzed using whole-genome sequencing, and significant variants shared within each tumor group were identified. Gene set enrichment analyses were conducted to compare the biological and functional pathways altered by the mutations in each carcinoma and sarcoma group. Forty-three and fifty-eight genes were identified in the carcinoma and sarcoma groups, respectively. Distinctions between the two tumor groups were noted for mutations related to tumor metastatic function. Mutations were identified in genes encoding cell adhesion molecules in the carcinoma group, whereas significant variations in extracellular matrix-related molecules were evident in the sarcoma group. This study revealed mutations and modified pathways associated with immune and tumor metastatic functions in canine carcinoma and sarcoma, indicating their significant relevance to the development and progression of each tumor group. Additionally, the distinctions indicated that different therapeutic approaches were required for each tumor group.
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Affiliation(s)
- YeSeul Jeon
- College of Veterinary Medicine, Gyeongsang National University, Jinju, Republic of Korea
| | - Hyeona Bae
- College of Veterinary Medicine, Gyeongsang National University, Jinju, Republic of Korea
| | - Seung-Wan Woo
- Division of Applied Life Science, Gyeongsang National University, Jinju, Republic of Korea
| | - Jaemin Kim
- Division of Applied Life Science, Gyeongsang National University, Jinju, Republic of Korea
- Institute of Agriculture and Life Sciences, Gyeongsang National University, Jinju, Republic of Korea
| | - DoHyeon Yu
- College of Veterinary Medicine, Gyeongsang National University, Jinju, Republic of Korea
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Mao L, Lu J, Wen X, Song Z, Sun C, Zhao Y, Huang F, Chen S, Jiang D, Che W, Zhong C, Yu C, Li K, Lu X, Shi J. Cuproptosis: mechanisms and nanotherapeutic strategies in cancer and beyond. Chem Soc Rev 2025. [PMID: 40433941 DOI: 10.1039/d5cs00083a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/29/2025]
Abstract
Cuproptosis, a novel form of copper (Cu)-dependent programmed cell death, is induced by directly binding Cu species to lipoylated components of the tricarboxylic acid (TCA) cycle. Since its discovery in 2022, cuproptosis has been closely linked to the field of materials science, offering a biological basis and bright prospects for the use of Cu-based nanomaterials in various disease treatments. Owing to the unique physicochemical properties of nanomaterials, Cu delivery nanosystems can specifically increase Cu levels at disease sites, inducing cuproptosis to achieve disease treatment while minimizing the undesirable release of Cu in normal tissues. This innovative nanomaterial-mediated cuproptosis, termed as "nanocuproptosis", positions at the intersection of chemistry, materials science, pharmaceutical science, and clinical medicine. This review aims to comprehensively summarize and discuss recent advancements in cuproptosis across various diseases, with a particular focus on cancer. It delves into the biochemical basis of nanomaterial-mediated cuproptosis, the rational design for cuproptosis inducers, strategies for enhancing therapeutic specificity, and cuproptosis-centric synergistic cancer therapeutics. Beyond oncology, this review also explores the expanded applications of cuproptosis, such as antibacterial, wound healing, and bone tissue engineering, highlighting its great potential to open innovative therapeutic strategies. Furthermore, the clinical potential of cuproptosis is assessed from basic, preclinical to clinical research. Finally, this review addresses current challenges, proposes potential solutions, and discusses the future prospects of this burgeoning field, highlighting cuproptosis nanomedicine as a highly promising alternative to current clinical therapeutics.
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Affiliation(s)
- Lijie Mao
- Department of Cardiology, Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai 200092, China
- Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China.
| | - Ji Lu
- Department of Cardiology, Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai 200092, China
| | - Xinyu Wen
- Shanghai Skin Disease Hospital, Institute of Dermatology, School of Medicine, Tongji University, Shanghai 200443, China
| | - Zhiyi Song
- Department of Cardiology, Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai 200092, China
| | - Cai Sun
- Department of Cardiology, Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai 200092, China
| | - Yuanru Zhao
- Department of Cardiology, Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai 200092, China
| | - Fang Huang
- Department of Cardiology, Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai 200092, China
| | - Si Chen
- Department of Cardiology, Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai 200092, China
- Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China.
| | - Dongyang Jiang
- Department of Cardiology, Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai 200092, China
| | - Wenliang Che
- Department of Cardiology, Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai 200092, China
| | - Cheng Zhong
- Department of Nephrology, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China.
| | - Chen Yu
- Department of Nephrology, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China.
| | - Ke Li
- School of Materials Science and Engineering, Hainan University, Haikou 570228, China.
| | - Xiangyu Lu
- Department of Nephrology, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China.
- Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China.
| | - Jianlin Shi
- Department of Cardiology, Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai 200092, China
- Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, China.
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Xu Y, Zhang H, Jiao X, Zhang Y, Yin G, Wang C, Du Z, Liang M, Gao X, Gu Z, Jiang Y, Du B, Bi X. Dysregulations of C1QA, C1QB, C1QC and C5AR1 as candidate biomarkers of vascular dementia. NPJ AGING 2025; 11:42. [PMID: 40414977 DOI: 10.1038/s41514-025-00228-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 04/22/2025] [Indexed: 05/27/2025]
Abstract
Vascular dementia (VaD) is the second most common cause of dementia. Few bioinformatic analysis has been done to explore its biomarkers. This study aimed to excavate potential biomarkers for VaD using bioinformatic analysis and validate them at both animal and patient levels. Based on microarray data of GSE122063, bioinformatic analysis revealed 502 DEGs in the frontal and 674 DEGs in the temporal cortex of VaD patients. Afterward, the hub genes between two regions, including C1QA, C1QB, C1QC, and C5AR1, were dugout. Interestingly, compared with sham mice or controls, the above four complements were highly expressed in the cortices of VaD animals and in the peripheral serum of VaD patients. Moreover, receiver operating characteristic curve analysis conformed to good diagnostic powers of these complements, with C1QB having the most prominent capacity (AUC = 0.799, 95%CI 0.722-0.875). That means the complements, especially subunits of C1Q, might be used as specific early VaD diagnostic biomarkers.
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Affiliation(s)
- Yawen Xu
- Department of Neurology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, PR China
- Department of Neurology, Dalian Municipal Central Hospital Affiliated to Dalian University of Technology, Dalian, PR China
| | - Hailing Zhang
- Department of Neurology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, PR China
| | - Xuehao Jiao
- Department of Neurology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, PR China
| | - Yanbo Zhang
- Department of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Ge Yin
- Department of Neurology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, PR China
| | - Cui Wang
- Department of Neurology, Dalian Municipal Central Hospital Affiliated to Dalian University of Technology, Dalian, PR China
| | - Zengkan Du
- Faculty of Basic Medical Sciences, Second Military Medical University, Shanghai, PR China
| | - Meng Liang
- Department of Neurology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, PR China
| | - Xin Gao
- Department of Neurology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, PR China
| | - Zhengsheng Gu
- Department of Neurology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, PR China
| | - Yan Jiang
- School of Pharmacy, Second Military Medical University, Shanghai, PR China
- Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Bingying Du
- Department of Neurology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, PR China.
- State Key Laboratory of Medical Neurobiology, Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, MOE Innovative Center for New Drug Development of Immune Inflammatory Disease, Fudan University, Shanghai, PR China.
| | - Xiaoying Bi
- Department of Neurology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, PR China.
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10
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Kiś J, Sikora D, Jarosz MJ, Polz-Dacewicz M. JC Polyomavirus in Prostate Cancer-Friend or Foe? Cancers (Basel) 2025; 17:1725. [PMID: 40427223 PMCID: PMC12109926 DOI: 10.3390/cancers17101725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2025] [Accepted: 05/19/2025] [Indexed: 05/29/2025] Open
Abstract
Background/Objectives: Recently, many researchers have evaluated various viruses, including polyomaviruses (JCV, BKV) and EBV, as potential factors playing a role in the development and/or progression of prostate cancer (PCa), one of the most common cancers in men. Therefore, we aimed to assess the frequency of the JCPyV DNA in tissue collected from PCa patients. Methods: We detected the presence of viral DNA (PCR) in 49.6% of clinical samples, including 71.9% with single EBV infection and 28.1% with EBV/JCV co-infection. We did not detect BKV or a single JCV infection. Therefore, we compared patients with EBV mono-infection with EBV/JCV co-infected patients in the context of risk group, Gleason score, and TNM classification. Results: Our results showed differences in clinicopathological features between single EBV infection and EBV/JCV co-infection. In the group of patients with single EBV infection, most patients were classified as medium/high risk, while in the group with EBV/JCV co-infection, most patients were classified as low risk. Conclusions: Among patients with single EBV infection, a more advanced stage of cancer was observed than in EBV/JCV co-infection. Moreover, the level of anti-EBVCA and anti-EBNA antibodies as well as EBV load was higher in the case of single infection compared to EBV/JCV co-infection. Higher antibody levels were detected in more advanced tumor stages in single EBV infection. Does JCV only "reside" in prostate cells or is it a co-factor in EBV infection? In light of these studies, there is a need to clarify the role of JCV virus in the development and/or progression of prostate cancer.
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Affiliation(s)
- Jacek Kiś
- Department of General and Oncological Urology, 1st Clinical Military Hospital with Outpatient Clinic in Lublin, 20-049 Lublin, Poland;
| | - Dominika Sikora
- Department of Virology with Viral Diagnostics Laboratory, Medical University of Lublin, 20-093 Lublin, Poland;
| | - Mirosław J. Jarosz
- Faculty of Human Sciences, University of Economics and Innovation, 20-209 Lublin, Poland;
| | - Małgorzata Polz-Dacewicz
- Department of Virology with Viral Diagnostics Laboratory, Medical University of Lublin, 20-093 Lublin, Poland;
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11
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Grassi E, Vurchio V, Cresswell GD, Catalano I, Lupo B, Sassi F, Galimi F, Borgato S, Ferri M, Viviani M, Pompei S, Urgese G, Chen B, Zanella ER, Cottino F, Russo M, Mauri G, Pietrantonio F, Zampino MG, Lazzari L, Marsoni S, Bardelli A, Lagomarsino MC, Sottoriva A, Trusolino L, Bertotti A. Heterogeneity and evolution of DNA mutation rates in microsatellite stable colorectal cancer. Sci Transl Med 2025; 17:eado1641. [PMID: 40397712 DOI: 10.1126/scitranslmed.ado1641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 12/05/2024] [Accepted: 04/23/2025] [Indexed: 05/23/2025]
Abstract
Historically, DNA sequence mutability has been considered relatively uniform and low in tumors with chromosomal instability (CIN), based on the assumption that high mutability would be detrimental in karyotypically aberrant contexts. Recent in silico analyses have challenged this view, suggesting some heterogeneity in mutation rates across CIN tumors; however, these predictions lack experimental validation. It also remains unclear how the intertumor variability of mutation rates compares to intratumor diversification and evolves along disease progression, whether mutation rates are functionally relevant in CIN cancers, and which mutational processes shape mutational accrual during CIN tumor onset and evolution. To address these gaps, we performed mutation accumulation experiments using clonal populations of patient-derived tumoroids from seven CIN, microsatellite-stable colorectal cancers (CRCs), and one microsatellite-unstable CRC. Each tumor exhibited a distinctive mutation rate footprint that was conserved among different clones from the same ancestor. In contrast, mutation rates diverged markedly across different tumors, with variations in magnitude within microsatellite-stable tumors as prominent as those distinguishing them from microsatellite-unstable tumors. New mutations reflected mutational processes associated with defective DNA replication and repair, which were not detected in normal tissues. Last, both mutation accumulation assays and high-depth whole-exome sequencing of subclonal variants showed higher mutation rates in metastatic lesions compared with matched primary tumors, suggesting positive selection for cells with increasing mutability during cancer dissemination. By providing an empirical assessment of mutation rates in human cancer, our data delineate heterogeneity, heritability, and progression-associated evolvability of DNA mutational instability as hallmarks of microsatellite-stable CRC.
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Affiliation(s)
- Elena Grassi
- Department of Oncology, University of Torino, 10060 Candiolo, Torino, Italy
- Candiolo Cancer Institute-FPO IRCCS, 10060 Candiolo, Torino, Italy
| | - Valentina Vurchio
- Department of Oncology, University of Torino, 10060 Candiolo, Torino, Italy
- Candiolo Cancer Institute-FPO IRCCS, 10060 Candiolo, Torino, Italy
| | - George D Cresswell
- Centre for Evolution and Cancer, Institute of Cancer Research, London SW7 3RP, UK
- St. Anna Children's Cancer Research Institute, 1090 Vienna, Austria
| | - Irene Catalano
- Candiolo Cancer Institute-FPO IRCCS, 10060 Candiolo, Torino, Italy
| | - Barbara Lupo
- Department of Oncology, University of Torino, 10060 Candiolo, Torino, Italy
- Candiolo Cancer Institute-FPO IRCCS, 10060 Candiolo, Torino, Italy
| | - Francesco Sassi
- Candiolo Cancer Institute-FPO IRCCS, 10060 Candiolo, Torino, Italy
| | - Francesco Galimi
- Department of Oncology, University of Torino, 10060 Candiolo, Torino, Italy
- Candiolo Cancer Institute-FPO IRCCS, 10060 Candiolo, Torino, Italy
| | - Sofia Borgato
- Department of Oncology, University of Torino, 10060 Candiolo, Torino, Italy
- Candiolo Cancer Institute-FPO IRCCS, 10060 Candiolo, Torino, Italy
| | - Martina Ferri
- Department of Oncology, University of Torino, 10060 Candiolo, Torino, Italy
- Candiolo Cancer Institute-FPO IRCCS, 10060 Candiolo, Torino, Italy
| | - Marco Viviani
- Department of Oncology, University of Torino, 10060 Candiolo, Torino, Italy
- Candiolo Cancer Institute-FPO IRCCS, 10060 Candiolo, Torino, Italy
| | - Simone Pompei
- IFOM ETS-AIRC Institute of Molecular Oncology, 20139 Milano, Italy
| | - Gianvito Urgese
- Interuniversity Department of Regional and Urban Studies and Planning, Polytechnic University of Torino, 10129 Torino, Italy
| | - Bingjie Chen
- Centre for Evolution and Cancer, Institute of Cancer Research, London SW7 3RP, UK
- GMU-GIBH Joint School of Life Sciences, Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, 510580 Guangzhou, China
| | | | | | - Mariangela Russo
- IFOM ETS-AIRC Institute of Molecular Oncology, 20139 Milano, Italy
- Department of Oncology, Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy
| | - Gianluca Mauri
- IFOM ETS-AIRC Institute of Molecular Oncology, 20139 Milano, Italy
- Department of Hematology, Oncology and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy
| | - Filippo Pietrantonio
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milano, Italy
| | - Maria Giulia Zampino
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology IRCCS, 20141 Milano, Italy
| | - Luca Lazzari
- IFOM ETS-AIRC Institute of Molecular Oncology, 20139 Milano, Italy
| | - Silvia Marsoni
- IFOM ETS-AIRC Institute of Molecular Oncology, 20139 Milano, Italy
| | - Alberto Bardelli
- IFOM ETS-AIRC Institute of Molecular Oncology, 20139 Milano, Italy
- Department of Oncology, Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy
| | | | - Andrea Sottoriva
- Centre for Evolution and Cancer, Institute of Cancer Research, London SW7 3RP, UK
- Computational Biology Research Centre, Human Technopole, 20157 Milano, Italy
| | - Livio Trusolino
- Department of Oncology, University of Torino, 10060 Candiolo, Torino, Italy
- Candiolo Cancer Institute-FPO IRCCS, 10060 Candiolo, Torino, Italy
| | - Andrea Bertotti
- Department of Oncology, University of Torino, 10060 Candiolo, Torino, Italy
- Candiolo Cancer Institute-FPO IRCCS, 10060 Candiolo, Torino, Italy
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12
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Niknejad A, Esmaealzadeh N, Peyrovinasab A, Sirouskabiri S, Gholami M, Pasha AVK, Shahri S, Büsselberg D, Abdolghaffari AH. Phytochemicals Alleviate Tumorigenesis by Regulation of M1/M2 Polarization: A Systematic Review of the Current Evidence. Phytother Res 2025. [PMID: 40393795 DOI: 10.1002/ptr.8522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Revised: 01/25/2025] [Accepted: 04/27/2025] [Indexed: 05/22/2025]
Abstract
Cancers are increasingly common and significantly impact patients' quality of life and longevity. The role of macrophages in tumorigenesis is critical, and natural compounds have long been recognized as valuable sources of bioactive agents for treating this condition. However, no systematic review has been performed on the role of phytochemicals impacting tumorigenesis by M1/M2 macrophage polarization. The aim of this study is to systematically review phytochemicals that relieve tumorigenesis by impacting M1/M2 macrophage polarization and investigate related signaling pathways. This systematic review adheres to PRISMA 2020 guidelines and statements. Scientific databases, MEDLINE, Scopus, and Web of Science, have been searched from inception to October 2023. This review includes English original articles on the role of phytochemicals, whole plant extracts, and polyherbal formulas in ameliorating tumorigenesis through M1/M2 polarization while excluding non-English articles, non-original research, and unrelated studies according to title, abstract, and full-text screening. Shreds of evidence were gathered from cellular and animal studies about the beneficial impacts of phytochemicals against tumorigenesis by impacting M1/M2 macrophage polarization. Critical assessment of in vitro and in vivo studies was performed by the CRIS and ARRIVE guidelines. Due to the high level of heterogeneity of the collected data, only a narrative synthesis was performed. Of 741 collected articles, only 35 remained. Polyphenols are the most highlighted group. Phytochemicals affect cytokines related to M1, such as CD80, CD86, CD64, and iNOS, and M2, like CXCR-1, CXCR-2, and TGF-β, in various cancer models. Together, these compounds exerted protective effects against tumorigenesis in preclinical cancer models. Furthermore, high-quality clinical experiments are recommended to cover the limitations of the current study, which are reliance on preclinical evidence, lack of clinical trials, and exclusion of non-English and grey literature.
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Affiliation(s)
- Amirhossein Niknejad
- Department of Toxicology & Pharmacology, TeMS.C., Islamic Azad University, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Niusha Esmaealzadeh
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Department of Traditional Pharmacy, School of Persian Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Traditional Persian Medicine and Complementary Medicine (PerCoMed) Student Association, Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Amirreza Peyrovinasab
- Department of Toxicology & Pharmacology, TeMS.C., Islamic Azad University, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Shirin Sirouskabiri
- Department of Toxicology & Pharmacology, TeMS.C., Islamic Azad University, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Mahsa Gholami
- Department of Toxicology & Pharmacology, TeMS.C., Islamic Azad University, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Aytak Vahdat Khajeh Pasha
- Department of Toxicology & Pharmacology, TeMS.C., Islamic Azad University, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Saleh Shahri
- Department of Toxicology & Pharmacology, TeMS.C., Islamic Azad University, Tehran, Iran
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha, Qatar
| | - Amir Hossein Abdolghaffari
- Department of Toxicology & Pharmacology, TeMS.C., Islamic Azad University, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
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13
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Deng Q, Yang K, Liao Q, Tang X, Quan H, Yuan G, Hu X, Jiang Z, Wu L. Comprehensive analysis and experiment validation of five cuproptosis-related genes in prognosis, immune infiltration and metabolic characterization of pancreatic cancer. PLoS One 2025; 20:e0323458. [PMID: 40367233 PMCID: PMC12077771 DOI: 10.1371/journal.pone.0323458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Accepted: 04/07/2025] [Indexed: 05/16/2025] Open
Abstract
BACKGROUND Cuproposis is a new-found mechanism of cell death, and the role of cuproposis-related genes (CRGs) in pancreatic cancer prognosis remains uncertain. METHODS DECRGs were identified from TCGA and GTEx databases. Five OS-associated hub genes were screened using Cox regression and LASSO analyses. A prognostic model was constructed and validated by survival analysis. GSEA, gene mutation, small-molecule drugs, immune-infiltrating and TF/miRNA/mRNA network were investigated to determine the underlying mechanism of 5-CRGs. In addition, RT-qPCR, and WB were applied to validate the expression of 5-CRGs. CCK8, colony formation and transwell assays were used to prove the function of LIPT1 in PC. RESULTS PDP1, DLAT, DBT, LIAS, and LIPT1 were screened as hub genes. 5-CRGs prognostic model established the low-risk population has a longer OS. There was a high the risk score value for the prediction in clinicopathological features. The forest plots showed that age, N stage and the RiskScore were the significant independent risk indicators. T cells CD4 memory resting and Mast cells are the amplest immune cell subpopulations in the high-score individuals. The expression of 5 CRGs exhibited significant differences in PC cell lines and tissues, LIPT1-knockdowning inhibited proliferation and invasion of pancreatic cancer cell lines. CONCLUSION Five CRGs relevant to pancreatic cancer prognosis were identified. Meanwhile, a new and accurate five CRGs prognostic model of pancreatic cancer was constructed. In addition, LIPT1 may promote proliferation, invasion and migration of pancreatic cancer cell lines. This may have a specific guiding value for future development of precise anti-cancer treatment strategies.
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Affiliation(s)
- Qianxi Deng
- Department of Gastroenterology, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, Sichuan, China
| | - Kun Yang
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qiaoling Liao
- The Second Department of Severe Psychiatry, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, Sichuan, China
| | - Xueli Tang
- Department of Science and Technology, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, Sichuan, China
| | - Honglin Quan
- Department of Gastroenterology, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, Sichuan, China
| | - Guojun Yuan
- Department of Gastroenterology, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, Sichuan, China
| | - Xia Hu
- Department of Gastroenterology, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, Sichuan, China
| | - Zheng Jiang
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Linju Wu
- Department of Anesthesiology, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, Sichuan, China
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14
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Yi Y, Song P, Li Z, Ju J, Sun G, Ren Q, Zhou K, Liu L, Wu HC. Nanopore-based enzyme-linked immunosorbent assay for cancer biomarker detection. NATURE NANOTECHNOLOGY 2025:10.1038/s41565-025-01918-z. [PMID: 40369343 DOI: 10.1038/s41565-025-01918-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Accepted: 03/25/2025] [Indexed: 05/16/2025]
Abstract
Enzyme-linked immunosorbent assay (ELISA) has been widely used in cancer diagnostics due to its specificity, sensitivity and high throughput. However, conventional ELISA is semiquantitative and has an insufficiently low detection limit for applications requiring ultrahigh sensitivity. In this study, we developed an α-hemolysin-nanopore-based ELISA for detecting cancer biomarkers. After forming the immuno-sandwich complex, peptide probes carrying enzymatic cleavage sites are introduced, where they interact with enzymes conjugated to the detection antibodies within the complex. These probes generate distinct current signatures when translocated through the nanopore after enzymatic cleavage, enabling precise biomarker quantification. This approach offers a low detection limit of up to 0.03 fg ml-1 and the simultaneous detection of six biomarkers, including antigen and antibody biomarkers in blood samples. Overall, the nanopore-based ELISA demonstrates high sensitivity and multiplexing capability, making it suitable for next-generation diagnostic and point-of-care testing applications.
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Affiliation(s)
- Yakun Yi
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Peng Song
- Department of Medical Oncology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Ziyi Li
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jinzhou Ju
- University of Chinese Academy of Sciences, Beijing, China
- Beijing National Laboratory for Molecular Sciences, Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China
| | - Guixiang Sun
- Department of Laboratory Medicine, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Qianyuan Ren
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China
| | - Ke Zhou
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China
| | - Lei Liu
- College of Food and Bioengineering, Xihua University, Chengdu, China.
| | - Hai-Chen Wu
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China.
- University of Chinese Academy of Sciences, Beijing, China.
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Liou K, Wang JP. Integrating genetic and gene expression data in network-based stratification analysis of cancers. BMC Bioinformatics 2025; 26:126. [PMID: 40360993 PMCID: PMC12070578 DOI: 10.1186/s12859-025-06143-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 04/15/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Cancers are complex diseases that have heterogeneous genetic drivers and varying clinical outcomes. A critical area of cancer research is organizing patient cohorts into subtypes and associating subtypes with clinical and biological outcomes for more effective prognosis and treatment. Large-scale studies have collected a plethora of omics data across multiple tumor types, providing an extensive dataset for stratifying patient cohorts. Network-based stratification (NBS) approaches have been presented to classify cancer tumors using somatic mutation data. A challenge in cancer stratification is integrating omics data to yield clinically meaningful subtypes. In this study, we investigate a novel approach to the NBS framework by integrating somatic mutation data with RNA sequencing data and investigating the effectiveness of integrated NBS on three cancers: ovarian, bladder, and uterine cancer. RESULTS We show that integrated NBS subtypes are more significantly associated with overall survival or histology. Specifically, we observe that integrated NBS subtypes for ovarian and bladder cancer were more significantly associated with patient survival than single-data type NBS subtypes, even when accounting for covariates. In addition, we show that integrated NBS subtypes for bladder and uterine are more significantly associated with tumor histology than single-data type NBS subtypes. Integrated NBS networks also reveal highly influential genes that span across multiple integrated NBS subtypes and subtype-specific genes. Pathway enrichment analysis of integrated NBS subtypes reveal overarching biological differences between subtypes. These genes and pathways are involved in a heterogeneous set of cell functions, including ubiquitin homeostasis, p53 regulation, cytokine and chemokine signaling, and cell proliferation, emphasizing the importance of identifying not only cancer-specific gene drivers but also subtype-specific tumor drivers. CONCLUSIONS Our study highlights the significance of integrating multi-omics data within the NBS framework to enhance cancer subtyping, specifically its utility in offering profound implications for personalized prognosis and treatment strategies. These insights contribute to the ongoing advancement of computational subtyping methods to uncover more targeted and effective therapeutic treatments while facilitating the discovery of cancer driver genes.
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Affiliation(s)
- Kenny Liou
- Stevens Neuroimaging and Informatics Institute, University of Southern California, 2025 Zonal Ave, Los Angeles, CA, 90033, USA
| | - Ji-Ping Wang
- Department of Statistics and Data Science, Northwestern University, 2006 Sheridan Road, Evanston, IL, 60208, USA.
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Zhang L, Gao H, Ma S, Fan X, Guo H, Sun M, Wen S, Liu T, Yu G, Yuan X, Sun X, Fan B. Functional screening of somatic mutant events in extranodal natural killer/T-cell lymphoma with adrenal involvement. Front Immunol 2025; 16:1566794. [PMID: 40433378 PMCID: PMC12106576 DOI: 10.3389/fimmu.2025.1566794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2025] [Accepted: 04/22/2025] [Indexed: 05/29/2025] Open
Abstract
Background Extranodal natural killer/T-cell lymphoma (ENKTL) involving the adrenal glands is extremely rare, and only a few cases have been reported. However, the genetic alterations, clinicopathological features and prognosis of these patients have not yet been fully elucidated. Methods Profiling of tumor mutations in ENKTL patients with adrenal involvement was conducted by whole-genome sequencing, and the predisposing genes and driver mutation gene variants were verified through Sanger sequencing. Immunohistochemical analysis of markers for the diagnosis and tumor microenvironment competent were performed to identify histopathological features. In addition, we searched the Surveillance, Epidemiology, and End Results (SEER), PubMed, Embase, and Scopus databases to perform a population-based study to compare the prognosis between adrenocortical carcinoma (ACC) patients and adrenal ENKTL patients using Kaplan-Meier survival curves and log-rank tests and analyzed the prognostic factors affecting the overall survival (OS) of adrenal ENKTL patients via univariate and multivariate Cox regression analyses. Results We screened 15892 somatic single-nucleotide variants (SNVs), 364 somatic insertions and deletions (INDELs), and four driver mutation genes, namely, TET2, STAT3, FAS, and TP53. In addition, immunohistochemical analysis revealed that tumor cells were positive for CD3, CD43, CD56, TIA1, granzyme B, CD2, CD4, and CD7. The immunohistochemistry for detecting components of the tumor microenvironment reveled the infiltration of tumor-associated macrophages (CD68, CD163) and tumor-associated fibroblasts (vimentin, SMA) in the tumor sample. According to our population-based analysis, Kaplan-Meier survival curves revealed that ENKTL patients with adrenal involvement had a significantly poorer prognosis than did patients with ACC (p<0.001), and chemotherapy was a significant prognostic factor for OS in ENKTL patients with adrenal involvement according to Cox multivariate analysis (hazard ratio = 0.318; p=0.027). Conclusions The metastasis of ENKTL to the adrenal gland may be due to gene mutations caused by genetic variations, which may provide new therapeutic targets for this disease. The prognosis of adrenal ENKTL patients is markedly worse than that of ACC patients, and chemotherapy may serve as an independent factor of OS in adrenal ENKTL patients. However, our findings still need to be validated in additional studies.
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Affiliation(s)
- Luxin Zhang
- Department of Urology, Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Haifeng Gao
- Department of Urology, Central Hospital of Dalian, Dalian, Liaoning, China
| | - Shuang Ma
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning, China
| | - Xiaoming Fan
- Department of Pathology, Central Hospital of Dalian, Dalian, Liaoning, China
| | - Huahang Guo
- Department of Pathology, Dalian Friendship Hospital, Dalian, Liaoning, China
| | - Man Sun
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Shuang Wen
- Department of Pathology, Dalian Friendship Hospital, Dalian, Liaoning, China
| | - Tianqing Liu
- Department of Pathology, Dalian Friendship Hospital, Dalian, Liaoning, China
| | - Guanghai Yu
- Department of Urology, Central Hospital of Dalian, Dalian, Liaoning, China
| | - Xiaoying Yuan
- College of Humanities and Social Sciences, Dalian Medical University, Dalian, Liaoning, China
| | - Xiuhua Sun
- Department of Oncology, Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Bo Fan
- Department of Urology, Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
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Romani A, Melloni E, Lodi G, Bompan F, Foschi R, Zauli E, Pozza E, Secchiero P, Zauli G, Previati M, Voltan R. Role of miRNA in adult ocular tumorigenesis. Front Mol Biosci 2025; 12:1459761. [PMID: 40406621 PMCID: PMC12095013 DOI: 10.3389/fmolb.2025.1459761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 04/24/2025] [Indexed: 05/26/2025] Open
Abstract
In recent years, cancer research has made huge advances also thanks to the discovery of the role of non-coding RNAs in the control of tumorigenesis, tumor proliferation, migration and metastasis and therefore also in the diagnosis and therapy of tumors. This work aims to review the most recent literature involving the study of miRNAs in ocular tumors affecting adult patients. We will introduce the role of miRNAs in tumorigenesis, and we will focus on summarizing the studies on uveal intraocular melanomas in which a role of microRNAs has been demonstrated. Similarly, we will also cover observations on miRNAs and eyelid cancers, especially sebaceous gland carcinoma, and cancers of the conjunctiva and the retina, excluding retinoblastoma which is typically a pediatric-onset tumor. We will summarize specific miRNAs that could be considered as diagnostic molecules or as therapeutic targets against some ocular cancer diseases, indicating their potentialities and limitations, considering also their administration as nanomedicine for the eye.
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Affiliation(s)
- Arianna Romani
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- LTTA Centre, University of Ferrara, Ferrara, Italy
| | - Elisabetta Melloni
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- LTTA Centre, University of Ferrara, Ferrara, Italy
| | - Giada Lodi
- LTTA Centre, University of Ferrara, Ferrara, Italy
- Department of Environmental and Prevention Sciences, University of Ferrara, Ferrara, Italy
| | - Francesca Bompan
- Department of Environmental and Prevention Sciences, University of Ferrara, Ferrara, Italy
| | - Rebecca Foschi
- LTTA Centre, University of Ferrara, Ferrara, Italy
- Department of Environmental and Prevention Sciences, University of Ferrara, Ferrara, Italy
| | - Enrico Zauli
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Elena Pozza
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Paola Secchiero
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- LTTA Centre, University of Ferrara, Ferrara, Italy
| | - Giorgio Zauli
- Research Department, King Khaled Eye Specialistic Hospital, Riyadh, Saudi Arabia
| | - Maurizio Previati
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Rebecca Voltan
- LTTA Centre, University of Ferrara, Ferrara, Italy
- Department of Environmental and Prevention Sciences, University of Ferrara, Ferrara, Italy
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Xu Y, Luo H, Wang J, Liu H, Chen L, Ji H, Deng Z, Liu X. CD103 + T Cells Eliminate Damaged Alveolar Epithelial Type II Cells Under Oxidative Stress to Prevent Lung Tumorigenesis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2503557. [PMID: 40344646 DOI: 10.1002/advs.202503557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 04/20/2025] [Indexed: 05/11/2025]
Abstract
The nexus between aging-associated immune deteriorations and tumorigenesis of lung cancers remains elusive. In a mouse model with Med23 depletion in T cells (Med23 -/-), it is found a strong association between the decline of CD103+ T cells and spontaneous alveolar epithelial type II cell (AT2 cell)-originated lung adenocarcinomas. The reduction of CD103+ T cells in the lung results in an accumulation of AT2 cells bearing oxidative damages, which appears to be the major origin of the lung adenocarcinoma. Functional experiments reveal CD103+ T cells can eradicate oxidative-damage-bearing AT2 cells as well as ROS-dependent, KRAS (G12D)-driven tumorigenesis. In vitro co-cultures prove CD103+ T cells, especially CD103+ CD8+ T cells, exhibit a killing capacity that matches the oxidative stress level in the target cells. In aged animals, it is found the abundance of CD103+ CD8+ T cells in the lung declines with age, accompanied by an accumulation of oxidative-damage-bearing AT2 cells. Collectively, the study establishes the vital function of CD103+ T cells in surveilling epithelial cells under oxidative stress to prevent malignancies, and unravels a potential immuno-dysregulation in the aged lung which contributes to tumorigenesis.
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Affiliation(s)
- Yu Xu
- Key Laboratory of Multicellular Systems, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
| | - Haorui Luo
- Key Laboratory of Multicellular Systems, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
| | - Jiahao Wang
- Key Laboratory of Multicellular Systems, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
| | - Haifeng Liu
- Key Laboratory of Multicellular Systems, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
| | - Luonan Chen
- Key Laboratory of Multicellular Systems, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
| | - Hongbin Ji
- Key Laboratory of Multicellular Systems, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
| | - Zimu Deng
- Key Laboratory of Multicellular Systems, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
- Zhongshan Institute for Drug discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China
| | - Xiaolong Liu
- Key Laboratory of Multicellular Systems, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou, 310024, China
- School of Life Science and Technology, ShanghaiTech University, 319 Yueyang Road, Shanghai, 200031, China
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19
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Li X, Pan B, Zhao X, Su Y, Lai J, Li S, He Y, Wu J, Han J. ProgModule: A novel computational framework to identify mutation driver modules for predicting cancer prognosis and immunotherapy response. J Transl Med 2025; 23:518. [PMID: 40340863 PMCID: PMC12063272 DOI: 10.1186/s12967-025-06497-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 04/13/2025] [Indexed: 05/10/2025] Open
Abstract
BACKGROUND Cancer originates from dysregulated cell proliferation driven by driver gene mutations. Despite numerous algorithms developed to identify genomic mutational signatures, they often suffer from high computational complexity and limited clinical applicability. METHODS Here, we presented ProgModule, an advanced computational framework designed to identify mutation driver modules for cancer prognosis and immunotherapy response prediction. In ProgModule, we introduced the Prognosis-Related Mutually Exclusive Mutation (PRMEM) score, which optimizes the balance between exclusive mutation coverage and the incorporation of mutation combination mechanisms critical for cancer prognosis. RESULTS Applying to BLCA and HNSC cohorts, ProgModule successfully identified driver modules that stratify patients into distinct prognostic subgroups, and the combination of these modules could serve as an effective prognostic biomarker. Extending our method to diverse cancers, ProgModule presented robust prognostic performance and stability across model parameters, including stopping criteria and network topology. Moreover, our analysis suggested that driver modules can predict immunotherapeutic benefit more effectively than existing signatures. Further analyses based on published CRISPR data indicated that genes within these modules may serve as potential therapeutic targets. CONCLUSIONS Altogether, ProgModule emerges as a powerful tool for identifying mutation driver modules as prognostic and immunotherapy response biomarkers, and genes within these modules may be used as potential therapeutic targets for cancer, offering new insights into precision oncology.
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Affiliation(s)
- Xiangmei Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Bingyue Pan
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Xilong Zhao
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Yinchun Su
- Department of Neurobiology, Harbin Medical University, Harbin, 150081, China
| | - Jiyin Lai
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Siyuan Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Yalan He
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Jiashuo Wu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China
| | - Junwei Han
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
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20
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Krauß D, Moreno-Viedma V, Adachi-Fernandez E, de Sá Fernandes C, Genger JW, Fari O, Blauensteiner B, Kirchhofer D, Bradaric N, Gushchina V, Fotakis G, Mohr T, Abramovich I, Mor I, Holcmann M, Bergthaler A, Haschemi A, Trajanoski Z, Winkler J, Gottlieb E, Sibilia M. EGFR controls transcriptional and metabolic rewiring in KRAS G12D colorectal cancer. EMBO Mol Med 2025:10.1038/s44321-025-00240-4. [PMID: 40329096 DOI: 10.1038/s44321-025-00240-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 03/26/2025] [Accepted: 04/02/2025] [Indexed: 05/08/2025] Open
Abstract
Inhibition of the epidermal growth factor receptor (EGFR) shows clinical benefit in metastatic colorectal cancer (CRC) patients, but KRAS-mutations are known to confer resistance. However, recent reports highlight EGFR as a crucial target to be co-inhibited with RAS inhibitors for effective treatment of KRAS mutant CRC. Here, we investigated the tumor cell-intrinsic contribution of EGFR in KRASG12D tumors by establishing murine CRC organoids with key CRC mutations (KRAS, APC, TP53) and inducible EGFR deletion. Metabolomic, transcriptomic, and scRNA-analyses revealed that EGFR deletion in KRAS-mutant organoids reduced their phenotypic heterogeneity and activated a distinct cancer-stem-cell/WNT signature associated with reduced cell size and downregulation of major signaling cascades like MAPK, PI3K, and ErbB. This was accompanied by metabolic rewiring with a decrease in glycolytic routing and increased anaplerotic glutaminolysis. Mechanistically, following EGFR loss, Smoc2 was identified as a key upregulated target mediating these phenotypes that could be rescued upon additional Smoc2 deletion. Validation in patient-datasets revealed that the identified signature is associated with better overall survival of RAS mutant CRC patients possibly allowing to predict therapy responses in patients.
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Affiliation(s)
- Dana Krauß
- Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria
| | - Veronica Moreno-Viedma
- Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria
| | - Emi Adachi-Fernandez
- Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria
| | - Cristiano de Sá Fernandes
- Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, 1090, Austria
| | - Jakob-Wendelin Genger
- Institute of Hygiene and Applied Immunology, Department of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, 1090, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, 1090, Austria
| | - Ourania Fari
- Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria
| | - Bernadette Blauensteiner
- Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria
| | - Dominik Kirchhofer
- Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria
| | - Nikolina Bradaric
- Department of Laboratory Medicine, Medical University of Vienna, 1090, Vienna, Austria
| | - Valeriya Gushchina
- Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria
| | - Georgios Fotakis
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Thomas Mohr
- Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria
| | - Ifat Abramovich
- Department of Cell Biology and Cancer Science, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Inbal Mor
- Department of Cell Biology and Cancer Science, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Department of Molecular Biology, Ariel University, Ariel, 4070000, Israel
| | - Martin Holcmann
- Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria
| | - Andreas Bergthaler
- Institute of Hygiene and Applied Immunology, Department of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, 1090, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, 1090, Austria
| | - Arvand Haschemi
- Department of Laboratory Medicine, Medical University of Vienna, 1090, Vienna, Austria
| | - Zlatko Trajanoski
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Juliane Winkler
- Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria
| | - Eyal Gottlieb
- Department of Cell Biology and Cancer Science, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Maria Sibilia
- Center for Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, Vienna, Austria.
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21
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Harary PM, Hori YS, Kassu R, Persad ARL, Tayag A, Ustrzynski L, Emrich SC, Gibbs IC, Park DJ, Chang SD, Fernandez-Miranda JC. Paired molecular profiling of malignant transformation of an epidermoid cyst for potential genetic drivers: illustrative case. JOURNAL OF NEUROSURGERY. CASE LESSONS 2025; 9:CASE24849. [PMID: 40324326 PMCID: PMC12051990 DOI: 10.3171/case24849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Accepted: 01/28/2025] [Indexed: 05/07/2025]
Abstract
BACKGROUND Malignant transformation of an intracranial epidermoid cyst (EC) into squamous cell carcinoma (SCC) is an exceedingly rare occurrence that is typically diagnosed on postoperative histology. The mechanisms underlying transformation remain poorly understood, with limited characterization of genetic changes associated with progression. OBSERVATIONS A 55-year-old female presented with a large cerebellopontine angle EC with an enhancing nodule in the left tectum, for which she underwent resection. Three months following surgery, rapid enlargement of the residual tectal component required reoperation, with pathology showing SCC. Paired next-generation sequencing of the EC and SCC revealed multiple shared variants, including a pathogenic TP53 mutation. Additionally, the SCC contained a pathogenic PTEN variant absent in the EC, suggesting a second driver mutation contributing to malignant transformation of an EC (MTEC). Her SCC was resistant to volumetric modulated arc therapy, requiring subsequent chemotherapy and pembrolizumab combined with stereotactic radiosurgery. Despite a favorable initial response, she died 26 months following MTEC diagnosis. LESSONS To the authors' knowledge, this represents the first use of paired molecular profiling to link intracranial SCC to an EC precursor, enhancing precision of this rare diagnosis. Additionally, this case identifies specific genetic alterations associated with transformation, providing insight into the largely unknown mechanisms underlying MTEC. https://thejns.org/doi/10.3171/CASE24849.
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Affiliation(s)
- Paul M. Harary
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, California
| | - Yusuke S. Hori
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, California
| | - Rodas Kassu
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, California
| | - Amit R. L. Persad
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, California
| | - Armine Tayag
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, California
| | - Louisa Ustrzynski
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, California
| | - Sara C. Emrich
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, California
| | - Iris C. Gibbs
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California
| | - David J. Park
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, California
| | - Steven D. Chang
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, California
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22
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Tang L, Hill MC, He M, Chen J, Wang Z, Ellinor PT, Li M. A 3D Genome Atlas of Genetic Variants and Their Pathological Effects in Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2408420. [PMID: 40134047 PMCID: PMC12097094 DOI: 10.1002/advs.202408420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 03/03/2025] [Indexed: 03/27/2025]
Abstract
The hierarchical organization of the eukaryotic genome is crucial for nuclear activities and cellular development. Genetic aberrations can disrupt this 3D genomic architecture, potentially driving oncogenesis. However, current research often lacks a comprehensive perspective, focusing on specific mutation types and singular 3D structural levels. Here, pathological changes from chromosomes to nucleotides are systematically cataloged, including 10 789 interchromosomal translocations (ICTs), 18 863 structural variants (SVs), and 162 769 single nucleotide polymorphisms (SNPs). The multilayered analysis reveals that fewer than 10% of ICTs disrupt territories via potent 3D interactions, and only a minimal fraction of SVs disrupt compartments or intersect topologically associated domain structures, yet these events significantly influence gene expression. Pathogenic SNPs typically show reduced interactions within the 3D genomic space. To investigate the effects of variants in the context of 3D organization, a two-phase scoring algorithm, 3DFunc, is developed to evaluate the pathogenicity of variant-gene pairs in cancer. Using 3DFunc, IGHV3-23's critical role in chronic lymphocytic leukemia is identified and it is found that three pathological SNPs (rs6605578, rs7814783, rs2738144) interact with DEFA3. Additionally, 3DGAtlas is introduced, which provides a highly accessible 3D genome atlas and a valuable resource for exploring the pathological effects of genetic mutations in cancer.
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Affiliation(s)
- Li Tang
- School of Computer Science and EngineeringCentral South UniversityChangsha410083China
| | - Matthew C. Hill
- Cardiovascular Research CenterMassachusetts General HospitalBostonMA02129USA
- Cardiovascular Disease InitiativeThe Broad Institute of MIT and HarvardCambridgeMA02142USA
| | - Mingxing He
- School of Computer Science and EngineeringCentral South UniversityChangsha410083China
| | - Junhao Chen
- School of Computer Science and EngineeringCentral South UniversityChangsha410083China
| | - Zirui Wang
- School of Computer Science and EngineeringCentral South UniversityChangsha410083China
| | - Patrick T. Ellinor
- Cardiovascular Research CenterMassachusetts General HospitalBostonMA02129USA
- Cardiovascular Disease InitiativeThe Broad Institute of MIT and HarvardCambridgeMA02142USA
| | - Min Li
- School of Computer Science and EngineeringCentral South UniversityChangsha410083China
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23
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Hao S, Liu Z, Lenz HJ, Yu J, Zhang L. Werner helicase as a therapeutic target in mismatch repair deficient colorectal cancer. DNA Repair (Amst) 2025; 149:103831. [PMID: 40203476 DOI: 10.1016/j.dnarep.2025.103831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 02/16/2025] [Accepted: 03/20/2025] [Indexed: 04/11/2025]
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths in the United States. A key driver of CRC development is microsatellite instability (MSI), which is caused by DNA mismatch repair deficiency and characterized by hypermutability of short-tandem repeat sequences. A significant portion of MSI CRCs do not respond to checkpoint immunotherapy treatments, highlighting an unmet need for improved therapies. Recent studies have revealed that MSI cancer cells require Werner (WRN), a RecQ family DNA helicase, for survival. Inhibiting WRN has emerged as a promising approach for targeting MSI CRCs that are insensitive to standard therapies. Several highly potent small-molecule WRN inhibitors have been developed and exhibited striking in vitro and in vivo activities against MSI cancers. Two of these WRN inhibitors, HRO761 and VVD-133214, have recently entered clinical trials. In this review, we summarize recent studies on WRN as a synthetic lethal target in MSI CRC and the development of WRN inhibitors as a new class of anticancer agents.
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Affiliation(s)
- Suisui Hao
- Department of Medicine, Keck School of Medicine of University of Southern California (USC), Los Angeles, CA 90033, USA; Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, CA 90033, USA
| | - Zhaojin Liu
- Department of Medicine, Keck School of Medicine of University of Southern California (USC), Los Angeles, CA 90033, USA; Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, CA 90033, USA
| | - Heinz-Josef Lenz
- Department of Medicine, Keck School of Medicine of University of Southern California (USC), Los Angeles, CA 90033, USA; Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, CA 90033, USA
| | - Jian Yu
- Department of Medicine, Keck School of Medicine of University of Southern California (USC), Los Angeles, CA 90033, USA; Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, CA 90033, USA
| | - Lin Zhang
- Department of Medicine, Keck School of Medicine of University of Southern California (USC), Los Angeles, CA 90033, USA; Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, CA 90033, USA.
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24
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Lima I, Borges F, Pombinho A, Chavarria D. The spindle assembly checkpoint: Molecular mechanisms and kinase-targeted drug discovery. Drug Discov Today 2025; 30:104355. [PMID: 40216293 DOI: 10.1016/j.drudis.2025.104355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 03/27/2025] [Accepted: 04/04/2025] [Indexed: 04/20/2025]
Abstract
The spindle assembly checkpoint (SAC) is a surveillance mechanism required for the fidelity of chromosome segregation, ensuring that anaphase is not initiated until all chromosomes are properly attached to the mitotic spindle. In cancer cells, SAC inactivation leads to aneuploidy beyond the cell's adaptation, culminating in cell death. This review provides a concise overview of the SAC signaling process and properties. Recent drug discovery strategies to selectively target kinases, particularly Aurora B and monopolar spindle kinase (MPS1), aimed at developing innovative anticancer agents able to override SAC are also presented.
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Affiliation(s)
- Inês Lima
- CIQUP-IMS - Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, R. Campo Alegre s/n, 4169-007 Porto, Portugal
| | - Fernanda Borges
- CIQUP-IMS - Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, R. Campo Alegre s/n, 4169-007 Porto, Portugal
| | - António Pombinho
- i3S, Institute for Research and Innovation in Health, University of Porto 4200-135 Porto, Portugal; IBMC, Institute for Molecular and Cell Biology, University of Porto 4200-135 Porto, Portugal
| | - Daniel Chavarria
- CIQUP-IMS - Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, R. Campo Alegre s/n, 4169-007 Porto, Portugal.
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25
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Mitelman F, Mandahl N. Distinct Signatures of Chromosomal Involvement in 59 251 Translocations Across 58 Tumor Types. A Novel Perspective. Genes Chromosomes Cancer 2025; 64:e70053. [PMID: 40346909 PMCID: PMC12065015 DOI: 10.1002/gcc.70053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Revised: 04/10/2025] [Accepted: 04/17/2025] [Indexed: 05/12/2025] Open
Abstract
Chromosomal translocations are key events in cancer, driving oncogenesis by disrupting and deregulating critical genes. While specific tumor-associated translocations are well studied, the frequencies and distributions of most remain unknown. Additionally, the role of chromosomal reshuffling in translocations has received little attention. This study presents data on the chromosomal involvement in 59 251 translocations reported in 58 tumor entities, including both benign and malignant tumors. Unlike studies focusing on tumor-specific abnormalities identified at the chromosome band level, this study examines translocations at the chromosomal level, offering a novel perspective on their distribution. This broader approach aims to uncover patterns that do not emerge or are disregarded in studies limited to tumor-specific aberrations. The resulting dataset provides a novel resource for deepening our understanding of the chromosomal origins of translocations in neoplasia. Comparisons of translocation frequency distributions among tumor types, when excluding the characteristic tumor-associated translocations, revealed that the patterns of chromosomal involvement in translocations are largely unique to each tumor entity. Statistical analyses of 241 pairwise comparisons of translocation spectra within hematologic disorders, solid tumors, and between groups of hematologic malignancies and both benign and malignant solid tumors showed insignificant/very weak associations (R2 ≤ 0.3) in 98% of the comparisons. The findings hence demonstrate that different tumor types are characterized by distinct chromosomal translocation signatures, strongly suggesting that most translocations encountered in tumor cells are not merely random events. Consequently, our study highlights the potential of rare translocations to serve as indicators of disease-specific processes.
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Affiliation(s)
- Felix Mitelman
- Division of Clinical Genetics, Department of Laboratory MedicineLund UniversityLundSweden
| | - Nils Mandahl
- Division of Clinical Genetics, Department of Laboratory MedicineLund UniversityLundSweden
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26
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Qiu SQ, He XF, Liang XL, Shi GY, Zhao ML, Li F, Wu ZY, Tian J, Zhai TT, Du Y. GLUT1 as a generic biomarker enables near-infrared fluorescence molecular imaging guided precise intraoperative tumor detection in breast cancer. Eur J Nucl Med Mol Imaging 2025; 52:2171-2186. [PMID: 39833507 DOI: 10.1007/s00259-025-07095-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 01/14/2025] [Indexed: 01/22/2025]
Abstract
PURPOSE Precise tumor excision is important but challenging in breast-conserving surgery (BCS). Tumor-specific fluorescence imaging may be used for intraoperative tumor detection and, therefore, to guide precise tumor excision. The aims of this study are to develop a glucose transporter 1 (GLUT1)-targeted near-infrared fluorescence tracer and evaluate its accuracy for breast cancer detection using fresh surgical breast specimens. METHODS Bioinformatic analysis was performed to compare GLUT1 expression between breast cancer and normal breast tissues. A GLUT1-targeted fluorescence imaging tracer WZB117-CY7.5 was developed. In combination with fluorescence imaging (FMI), its binding specificity to GLUT1 was examined in in vitro breast cancer cell experiments, in vivo 4T1 breast tumor-bearing mouse models, and 60 freshly resected human breast tumor tissues. The diagnostic accuracy of WZB117-CY7.5, was evaluated in fresh specimens derived from 60 patients diagnosed with breast cancer. RESULTS GLUT1 expression is higher in breast cancer tissues compared with normal tissues. WZB117-CY7.5 specifically bound to breast cancer cells in in vitro cell experiments and accumulated in tumor areas in a 4T1 tumor-bearing mice after intravenous injection by FMI. Moreover, WZB117-CY7.5 specifically bound to freshly resected human breast cancer and demonstrated excellent diagnostic performance in discriminating breast cancer, irrespective of cancer subtype, from normal breast tissue on fresh surgically resected breast tissues. CONCLUSIONS WZB117-CY7.5 showed high accuracy in intraoperative breast cancer detection, irrespective of the cancer subtype. This highlights its potential for clinical applications as a generic tracer for fluorescence image-guided surgery (FIGS) in BCS and fluorescence image-guided pathology for tissue sampling.
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Affiliation(s)
- Si-Qi Qiu
- Diagnosis and Treatment Center of Breast Diseases, Shantou Central Hospital, No.114 Waima Road, Shantou, 515041, Shantou, China
- Clinical Research Center, Shantou Central Hospital, Shantou, 515041, China
| | - Xiao-Feng He
- Shantou University Medical College, Shantou, 515041, China
| | - Xiao-Long Liang
- Department of Ultrasound, Peking University Third Hospital, Beijing, 100191, China
| | - Guang-Yuan Shi
- CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, No.95 Zhongguancun East Road, Hai Dian District, Beijing, 100190, China
| | - Meng-Long Zhao
- Clinical Research Center, Shantou Central Hospital, Shantou, 515041, China
| | - Fan Li
- Biobank, Shantou Central Hospital, Shantou, 515041, China
| | - Zhi-Yong Wu
- Diagnosis and Treatment Center of Breast Diseases, Shantou Central Hospital, No.114 Waima Road, Shantou, 515041, Shantou, China.
| | - Jie Tian
- CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, No.95 Zhongguancun East Road, Hai Dian District, Beijing, 100190, China.
- Beijing Advanced Innovation Centre for Big Data-Based Precision Medicine, School of Medicine, Beihang University, Beijing, 100191, China.
| | - Tian-Tian Zhai
- Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, No.7 Raoping Road, Jinping District, Shantou, 515041, China.
| | - Yang Du
- CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, No.95 Zhongguancun East Road, Hai Dian District, Beijing, 100190, China.
- The University of Chinese Academy of Sciences, Beijing, 100080, China.
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27
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Yin D, Wang P, Hao Y, Yue W, Jiang X, Yao K, Wang Y, Hang X, Xiao A, Zhou J, Lin L, Rao Z, Wu H, Liu F, Dong Z, Wu M, Xu C, Huang J, Chang H, Fan Y, Yu X, Yu C, Chang L, Li M. A battery-free nanofluidic intracellular delivery patch for internal organs. Nature 2025:10.1038/s41586-025-08943-x. [PMID: 40307560 DOI: 10.1038/s41586-025-08943-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 03/26/2025] [Indexed: 05/02/2025]
Abstract
The targeted delivery of therapeutics to internal organs to, for example, promote healing or apoptosis holds promise in the treatment of numerous diseases1-4. Currently, the prevailing delivery modality relies on the circulation; however, this modality has substantial efficiency, safety and/or controllability limitations5-9. Here we report a battery-free, chipless, soft nanofluidic intracellular delivery (NanoFLUID) patch that provides enhanced and customized delivery of payloads in targeted internal organs. The chipless architecture and the flexible nature of thin functional layers facilitate integration with internal organs. The nanopore-microchannel-microelectrode structure enables safe, efficient and precise electroperforation of the cell membrane, which in turn accelerates intracellular payload transport by approximately 105 times compared with conventional diffusion methods while operating under relatively low-amplitude pulses (20 V). Through evaluations of the NanoFLUID patch in multiple in vivo scenarios, including treatment of breast tumours and acute injury in the liver and modelling tumour development, we validated its efficiency, safety and controllability for organ-targeted delivery. NanoFLUID-mediated in vivo transfection of a gene library also enabled efficient screening of essential drivers of breast cancer metastasis in the lung and liver. Through this approach, DUS2 was identified as a lung-specific metastasis driver. Thus, NanoFLUID represents an innovative bioelectronic platform for the targeted delivery of payloads to internal organs to treat various diseases and to uncover new insights in biology.
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Affiliation(s)
- Dedong Yin
- Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Institute of Science and Technology of National Health Commission, Beijing, China
| | - Pan Wang
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
| | - Yongcun Hao
- MOE Key Laboratory of Micro and Nano Systems for Aerospace, School of Mechanical Engineering, Northwestern Polytechnical University, Xi'an, China
- Ningbo Institute of Northwestern Polytechnical University, Ningbo, China
| | - Wei Yue
- Interdisciplinary Eye Research Institute (EYE-X Institute), Bengbu Medical University, Bengbu, China
| | - Xinran Jiang
- Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Kuanming Yao
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, China
| | - Yuqiong Wang
- Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Xinxin Hang
- Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Ao Xiao
- Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Jingkun Zhou
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, China
| | - Long Lin
- Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Zhoulyu Rao
- Materials Research Laboratory, University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - Han Wu
- Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Feng Liu
- Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Zaizai Dong
- Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Meng Wu
- Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Joint Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, China
| | - Chenjie Xu
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, China
| | - Jiandong Huang
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Materials Innovation Institute for Life Sciences and Energy (MILES), HKU-SIRI, Shenzhen, China
| | - Honglong Chang
- MOE Key Laboratory of Micro and Nano Systems for Aerospace, School of Mechanical Engineering, Northwestern Polytechnical University, Xi'an, China
| | - Yubo Fan
- Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Xinge Yu
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, China.
- Institute of Digital Medicine, City University of Hong Kong, Hong Kong, China.
- Hong Kong Institute for Clean Energy, City University of Hong Kong, Hong Kong, China.
| | - Cunjiang Yu
- Materials Research Laboratory, University of Illinois Urbana-Champaign, Urbana, IL, USA.
- Department of Electrical and Computer Engineering, Department of Materials Science and Engineering, Department of Bioengineering, Department of Mechanical Science and Engineering, Nick Holonyak Micro and Nanotechnology Laboratory, Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, IL, USA.
| | - Lingqian Chang
- Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China.
| | - Mo Li
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
- National Clinical Research Center for Obstetrics and Gynecology, Third Hospital, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China.
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Li Z, Ren H, Zhang S, Sun C, Li Z, Niu P, Fei H, Xing C, Shi S, Zhao D. PD-L1 levels, TP53 mutation profiles, and survival outcomes in pancreatic cancer differ by immune-nutritional status. World J Surg Oncol 2025; 23:174. [PMID: 40301983 PMCID: PMC12042528 DOI: 10.1186/s12957-025-03818-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 04/15/2025] [Indexed: 05/01/2025] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) frequently exhibits an immunosuppressive microenvironment coupled with malnutrition status. These features are instrumental in clinical management strategies for PDAC. METHODS Immune-nutrition status of patients was evaluated by integrating systemic immune-inflammatory index (SII) and prognostic nutritional index (PNI). Individuals were divided into SII-PNI Status positive (SPS+) group and SPS negative (SPS-) group. Morphology of tissues was evaluated by hematoxylin-eosin (H&E) staining. Expression of PD-L1 and p53 was detected using immunohistochemistry (IHC). RESULTS In this study, 530 eligible patients (mean ± SD age, 60.5 ± 9.17 years, 296 males [55.8%], 74 SPS+ [14.0%]) were included. These patients exhibited a median survival of 24 months (1-, 3- and 5-year survival rate; 72.9%, 34.7% and 25.1%, respectively). In the multivariate analysis, independent indicators for outcomes were identified as tumor size, lymph node metastasis and SPS (all p <.01). After matching and adjusting, patients with SPS+ exhibited a notably reduced overall survival compared to those with SPS- (14 vs. 25 months, p <.001), with hazard ratio (95% CI) of 1.79 (1.25-2.56). IHC revealed markedly elevated positive cell proportion of PD-L1 in SPS+ group (p <.01) and distinct p53 mutation patterns between SPS+ and SPS- groups (p =.03). Morphology demonstrated a dissimilar trend of differentiation levels between the two groups (p =.08). CONCLUSION The findings suggest poorer outcome, higher PD-L1 expression and distinct p53 mutation status of patients with SPS+. These patterns may contribute to PDAC management and strategic deployment of immunotherapy and targeted therapy.
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Affiliation(s)
- Zheng Li
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/ National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100021, China
| | - Hu Ren
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/ National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100021, China
| | - Shihui Zhang
- Department of Pathology, National Cancer Center, National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Chongyuan Sun
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/ National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100021, China
| | - Zefeng Li
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/ National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100021, China
| | - Penghui Niu
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/ National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100021, China
| | - He Fei
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/ National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100021, China
| | - Cheng Xing
- Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, P.R. China.
| | - Susheng Shi
- Department of Pathology, National Cancer Center, National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Dongbing Zhao
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/ National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100021, China.
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Liu J, Wu Z, Zhou S, Lv W, Wang Y, Xia P, Zhu L, Hu J. Neoadjuvant immunochemotherapy for locally advanced esophageal squamous cell carcinoma in real-world practice: an analysis of the clinical outcomes and long-term survival, and the feasibility of using major pathological response as a surrogate endpoint. Eur J Med Res 2025; 30:342. [PMID: 40301916 PMCID: PMC12038973 DOI: 10.1186/s40001-025-02599-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 04/15/2025] [Indexed: 05/01/2025] Open
Abstract
BACKGROUND Neoadjuvant immunochemotherapy is expected to become the standard treatment mode for locally advanced esophageal squamous cell carcinoma (ESCC). This study aims to analyze the clinical outcomes and long-term survival of neoadjuvant immunochemotherapy for locally advanced ESCC, and explore the feasibility of using major pathological response (MPR) as a surrogate endpoint. METHODS This real-world retrospective study consecutively included eligible patients with stage II-IVA locally advanced ESCC who received neoadjuvant immunochemotherapy and surgery between 2019 and 2022 at the Department of Thoracic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine. RESULTS This study collected a total of 166 patients, and ultimately included 126 patients after screening. The objective response rate (ORR) was 69.8% (88/126). The incidence of grade 3-4 adverse events (AEs) was 13.5% (17/126). MPR was observed in 49 (38.9%) patients, and 24 (19.0%) patients achieved a complete pathological response (pCR). The median progression-free survival (PFS) was 31.7 months and the 3-year PFS rate was 56.3%. The median overall survival (OS) was not reached and the 3-year OS rate was 70.6%. The median PFS of the non-MPR group was 25.0 months, with the MPR group not achieved (hazard ratio [HR], 2.503; 95% CI 1.359-4.610; P = 0.0022). The median OS in the non-MPR group was 31.7 months and not reached in the MPR group (HR, 3.607; 95% CI 1.576-8.254; P = 0.0012). MPR is an independent prognostic factor affecting OS (HR, 2.522; 95% CI 1.018-6.401; P = 0.046). CONCLUSIONS Neoadjuvant immunochemotherapy is safe and effective for locally advanced ESCC, and can result in certain survival benefits. MPR can serve as a surrogate endpoint for predicting long-term OS.
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Affiliation(s)
- Jiacong Liu
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, China
| | - Ziheng Wu
- Department of Thoracic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Shihong Zhou
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, China
| | - Wang Lv
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, China
| | - Yiqing Wang
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, China
| | - Pinghui Xia
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, China
| | - Linhai Zhu
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, China.
| | - Jian Hu
- Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, China.
- Key Laboratory of Clinical Evaluation Technology for Medical Device of Zhejiang Province, Hangzhou, 310003, China.
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Mahjabeen I, Hussain MZ, Haq MFU, Mehmood A, Haris MS, Khan SA, Chaudhry A, Hakim F, Abbasi AZ, Kayani MA. Exploring the Role of Mitochondrial Sirtuin 3 Gene in Gastric Cancer Risk Based on SNP Analysis and LORD-Q Assay. Biochem Genet 2025:10.1007/s10528-025-11119-x. [PMID: 40293630 DOI: 10.1007/s10528-025-11119-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Accepted: 04/22/2025] [Indexed: 04/30/2025]
Abstract
Mitochondrial sirtuin 3 (SIRT3) is a gene involved in key functions like acetylation, DNA repair, stress response, and tumorigenesis. Several studies have been published that showed the role of SIRT3 in various cancers. Still, few studies have been reported on the genetic and expression variation of the SIRT3 gene in gastric carcinogenesis. This study was designed to explore the involvement of the SIRT3 gene in gastric cancer. In this study, we used two study cohorts, cohort 1 contained 510 gastric cancer (GC) patients and an equal number of age and gender-matched controls. Cohort 2 included 220 GC tissue samples along with adjacent control tissues. Tetra Arms PCR was used to measure the frequency of three selected SNPs of the SIRT3 gene (rs28365927, rs11246029, and rs3817629) in cohort 1. Quantitative PCR and immunohistochemistry were performed to analyze the SIRT3 expression variation in cohort 2 GC patients. The superoxide dismutase (SOD), and 8-hydroxydeoxyguanosine (8-OHdG) levels were measured using ELISA, and DNA damage was measured using the LORD-Q assay. Statistical analysis showed the significant increased frequency of mutant allele of selected SNPs (rs28365927 (p < 0.0001); rs11246029 (p < 0.0001); and rs3817629 (p < 0.0001) in GC patients compared to controls. Expression analysis results showed significant downregulation of the SIRT3 gene at mRNA level (P < 0.001) and protein level (P < 0.001) in gastric tumor section vs control tissues. Multivariant Cox regression analysis showed that downregulated SIRT3 expression (p < 0.000001), H. pylori status (p < 0.0001), T-stage (p < 0.008), and N-stage (p < 0.001) act as prognostic markers in GC patients. ROC curve analysis showed the 90% and 100% specificity of the SIRT3 gene as a diagnostic marker in GC at the mRNA level and protein level, respectively. Significant increased oxidative stress (antioxidant enzyme level p < 0.0001; 8-OHdG level p < 0.0001) and lesion frequency/10 kb (p < 0.03) were indicated in the gastric tumor tissue sections vs controls. The result showed the tumor suppressor role of the SIRT3 gene in GC and was found linked with the surge in oxidative stress and damage in GC patients.
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Affiliation(s)
- Ishrat Mahjabeen
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan.
| | | | - Maria Fazal-Ul Haq
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Azhar Mehmood
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Muhammad Shahbaz Haris
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Shereen Ali Khan
- Department of Rheumatology, CMH Multan Institute of Medical Sciences, Multan, Pakistan
| | - Anum Chaudhry
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Farzana Hakim
- Department of Biochemistry, Foundation University Medical College, Islamabad, Pakistan
| | - Ayesha Zulfiqar Abbasi
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Mahmood Akhtar Kayani
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
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Ren H, Zou Q, Song K, Yu Y, Zhou J, Mo W, Lu H. Enhancing recombinant protein production through Cre-loxP mediated chromosomal rearrangement evolution in Kluyveromyces marxianus. Commun Biol 2025; 8:672. [PMID: 40295765 PMCID: PMC12038034 DOI: 10.1038/s42003-025-08110-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 04/22/2025] [Indexed: 04/30/2025] Open
Abstract
Chromosomal rearrangements can drive adaptive evolution; however, whether the rearrangements in non-coding and non-promoter regions can lead to new phenotypes under selective pressures remains unclear. Additionally, highly producing recombinant proteins is a key industrial task but poses stress on host cells. Therefore, it is desirable to investigate the role of chromosomal rearrangement in non-coding and non-promoter regions during high-yield recombinant protein phenotype formation. In this study, we utilize the Kluyveromyces marxianus strain as the host for recombinant protein production, with the recombinant fusion protein comprising leghemoglobin (LBA) and enhanced green fluorescent protein serving as a reporter. Iterative evolution is conducted to select high-yield strains using Cre-loxP mediated chromosomal rearrangement technology and high-throughput fluorescence intensity screening. The evolved strains exhibit ~seven-fold increase in fluorescence intensity and a 1.7-fold improvement in LBA yield, identified with chromosome VIII inversion and chromosomes III and V translocation. Introducing these rearrangements into wild-type strains significantly increase recombinant protein yield to about 1.5-fold. Cascade networks are reconstructed based on RNA-seq analysis to elucidate rearrangements' impact on global metabolic processes. Our study confirms that chromosomal rearrangements in non-coding regions can establish adaptive phenotypes and provides new ways of engineering host cells to improve recombinant protein productivity.
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Affiliation(s)
- Haiyan Ren
- State Key Laboratory of Genetic and Development of Complex Phenotypes, School of Life Sciences, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan University, Shanghai, China
| | - Qiyuan Zou
- State Key Laboratory of Genetic and Development of Complex Phenotypes, School of Life Sciences, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan University, Shanghai, China
| | - Kunfeng Song
- State Key Laboratory of Genetic and Development of Complex Phenotypes, School of Life Sciences, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan University, Shanghai, China
| | - Yao Yu
- State Key Laboratory of Genetic and Development of Complex Phenotypes, School of Life Sciences, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan University, Shanghai, China
| | - Jungang Zhou
- State Key Laboratory of Genetic and Development of Complex Phenotypes, School of Life Sciences, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan University, Shanghai, China
| | - Wenjuan Mo
- State Key Laboratory of Genetic and Development of Complex Phenotypes, School of Life Sciences, Fudan University, Shanghai, China.
- Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan University, Shanghai, China.
| | - Hong Lu
- State Key Laboratory of Genetic and Development of Complex Phenotypes, School of Life Sciences, Fudan University, Shanghai, China.
- Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan University, Shanghai, China.
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32
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Zheng Y, Zhang Y, Wang Z, Guo X, Zhang L, Zhang Y. Multiple data sets to explore the key molecules and mechanism of lymph node metastasis in gastric cancer. Discov Oncol 2025; 16:606. [PMID: 40272615 PMCID: PMC12021760 DOI: 10.1007/s12672-025-02360-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Accepted: 04/10/2025] [Indexed: 04/27/2025] Open
Abstract
OBJECTIVE To explore the key molecules and regulatory mechanisms of lymph node metastasis in gastric cancer. METHODS The differential genes and key genes of lymph node metastasis in gastric cancer were analyzed by utilizing multiple data sets. The key genes were analyzed by GSEA analysis, transcription factor analysis, nomogram prediction model construction, immune infiltration analysis, GSVA analysis, drug sensitive analysis and single cell data analysis. RESULTS Abnormal expression of key genes including CDRT15P1, DENND3, F2R, FNDC3B, IRAK3, MS4A2, PDK4, PKIA and activation of related signaling pathways might be the result of ultraviolet radiation-induced DNA damage, which was closely related to lymph node metastasis in gastric cancer. The key genes were regulated by a variety of transcription factors, which were strongly connected with the invasion of immune cells and the sensitivity of a variety of drugs. The nomogram prediction model, which is based on the key genes associated with lymph node metastasis and the TNM of gastric cancer, demonstrated a high level of predictive efficiency. CONCLUSION CDRT15P1, DENND3, F2R, FNDC3B, IRAK3, MS4A2, PDK4 and PKIA may be the key genes affecting lymph node metastasis in gastric cancer, and F2R has higher biological importance.
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Affiliation(s)
- Yijun Zheng
- Lanzhou University Second Clinical Medical School, Lanzhou, 730030, China
- Lanzhou University Second Hospital Department of General Surgery, Lanzhou, 730030, China
| | - Yawu Zhang
- Lanzhou University Second Clinical Medical School, Lanzhou, 730030, China
- Lanzhou University Second Hospital Department of General Surgery, Lanzhou, 730030, China
| | - Zheyuan Wang
- Lanzhou University Second Clinical Medical School, Lanzhou, 730030, China
- Lanzhou University Second Hospital Department of General Surgery, Lanzhou, 730030, China
| | - Xiaohu Guo
- Lanzhou University Second Clinical Medical School, Lanzhou, 730030, China
- Lanzhou University Second Hospital Department of General Surgery, Lanzhou, 730030, China
| | - Lingyi Zhang
- Lanzhou University Second Clinical Medical School, Lanzhou, 730030, China
- Lanzhou University Second Hospital Department of General Surgery, Lanzhou, 730030, China
| | - Youcheng Zhang
- Lanzhou University Second Clinical Medical School, Lanzhou, 730030, China.
- Lanzhou University Second Hospital Department of General Surgery, Lanzhou, 730030, China.
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Fukuda A, Mizuno T, Yoshida T, Sunami K, Kubo T, Koyama T, Yonemori K, Okusaka T, Kato K, Ohe Y, Yatabe Y, Yamamoto N. Upfront liquid biopsy in patients with advanced solid tumors who were not feasible for tissue-based next-generation sequencing. Jpn J Clin Oncol 2025:hyaf065. [PMID: 40251768 DOI: 10.1093/jjco/hyaf065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 02/03/2025] [Accepted: 04/09/2025] [Indexed: 04/21/2025] Open
Abstract
BACKGROUND Liquid biopsy has been developed as an alternative to tissue-based sequencing for detecting genomic alterations in solid tumors. However, the clinical utility of liquid biopsy in patients with solid tumors for whom tissue-based next-generation sequencing (NGS) is infeasible has not been well-characterized, particularly in previously untreated individuals. METHODS This prospective study evaluated the clinical impact of liquid biopsy, focusing on six solid tumor types. Overall, 109 patients were enrolled and underwent liquid biopsy using Guardant360 (Guardant Health, Redwood City, CA, USA). Among these, 94 (86.3%) patients were previously untreated. RESULTS The most common cancer type was non-small cell lung cancer (n = 57, 52.3%), followed by pancreatic (n = 35, 32.1%), biliary tract (n = 8, 7.3%), gastric (n = 5, 4.6%), colorectal (n = 3, 2.8%), and triple-negative breast (n = 1, 0.9%) cancers. The success rate of liquid biopsy was 99.1%, and the median turnaround time from blood collection to results was 7 days (range: 5-22 days). Actionable alterations were detected in 31 (28.4%) patients, and 8.3% of them received matched therapy based on alterations identified by liquid biopsy. Among previously untreated patients, actionable mutations were identified in 29.8%, and 8.5% received matched therapy. CONCLUSIONS In patients with advanced solid tumors for which tissue-based NGS is not feasible, performing upfront liquid biopsy could lead to the detection of actionable alterations and help guide targeted therapies. CLINICAL TRIAL REGISTRY UMIN Clinical Trials Registry (UMIN000041722).
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Affiliation(s)
- Akito Fukuda
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Takaaki Mizuno
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
- Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan
| | - Tatsuya Yoshida
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
- Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan
| | - Kuniko Sunami
- Department of Laboratory Medicine, National Cancer Center Hospital, Tokyo, Japan
| | - Takashi Kubo
- Department of Laboratory Medicine, National Cancer Center Hospital, Tokyo, Japan
| | - Takafumi Koyama
- Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan
| | - Kan Yonemori
- Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan
- Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Ken Kato
- Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Yuichiro Ohe
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Yasushi Yatabe
- Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan
| | - Noboru Yamamoto
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
- Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan
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Ren J, Yan G, Yang L, Kong L, Guan Y, Sun H, Liu C, Liu L, Han Y, Wang X. Cancer chemoprevention: signaling pathways and strategic approaches. Signal Transduct Target Ther 2025; 10:113. [PMID: 40246868 PMCID: PMC12006474 DOI: 10.1038/s41392-025-02167-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 12/01/2024] [Accepted: 02/04/2025] [Indexed: 04/19/2025] Open
Abstract
Although cancer chemopreventive agents have been confirmed to effectively protect high-risk populations from cancer invasion or recurrence, only over ten drugs have been approved by the U.S. Food and Drug Administration. Therefore, screening potent cancer chemopreventive agents is crucial to reduce the constantly increasing incidence and mortality rate of cancer. Considering the lengthy prevention process, an ideal chemopreventive agent should be nontoxic, inexpensive, and oral. Natural compounds have become a natural treasure reservoir for cancer chemoprevention because of their superior ease of availability, cost-effectiveness, and safety. The benefits of natural compounds as chemopreventive agents in cancer prevention have been confirmed in various studies. In light of this, the present review is intended to fully delineate the entire scope of cancer chemoprevention, and primarily focuses on various aspects of cancer chemoprevention based on natural compounds, specifically focusing on the mechanism of action of natural compounds in cancer prevention, and discussing in detail how they exert cancer prevention effects by affecting classical signaling pathways, immune checkpoints, and gut microbiome. We also introduce novel cancer chemoprevention strategies and summarize the role of natural compounds in improving chemotherapy regimens. Furthermore, we describe strategies for discovering anticancer compounds with low abundance and high activity, revealing the broad prospects of natural compounds in drug discovery for cancer chemoprevention. Moreover, we associate cancer chemoprevention with precision medicine, and discuss the challenges encountered in cancer chemoprevention. Finally, we emphasize the transformative potential of natural compounds in advancing the field of cancer chemoprevention and their ability to introduce more effective and less toxic preventive options for oncology.
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Affiliation(s)
- Junling Ren
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Guangli Yan
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Le Yang
- State Key Laboratory of Dampness Syndrome, The Second Affiliated Hospital Guangzhou University of Chinese Medicine, Dade Road 111, Guangzhou, China
| | - Ling Kong
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Yu Guan
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Hui Sun
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China.
| | - Chang Liu
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Lei Liu
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Ying Han
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China
| | - Xijun Wang
- State key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin, 150040, China.
- State Key Laboratory of Dampness Syndrome, The Second Affiliated Hospital Guangzhou University of Chinese Medicine, Dade Road 111, Guangzhou, China.
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Pathak GP, Shah R, Reiman T, Wallace A, Carter MD, Snow S, Fris J, Xu Z. Identification of Driver Mutations and Risk Stratification in Lung Adenocarcinoma via Liquid Biopsy. Cancers (Basel) 2025; 17:1340. [PMID: 40282516 PMCID: PMC12025768 DOI: 10.3390/cancers17081340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 04/10/2025] [Accepted: 04/11/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND Liquid biopsy using plasma cfDNA has been established as a tool for informing the management of advanced-stage NSCLC. However, its effectiveness in early lung cancer detection, including the identification of high-risk cases, remains to be determined. METHODS We analyzed plasma cfDNA and matched tumors from 117 stage I-IV lung adenocarcinoma cases and compared the variants identified across all stages using the Oncomine Precision Assay on the GenexusTM next-generation sequencing platform. RESULTS Cancer-specific mutations were detected in plasma from approximately 72% (84/117) of cases (all stages), with detection rates increasing by stage. Concordance between cfDNA and tumor tissue also increased with stage 0% (stage I), 19% (stage II), 45% (stage III), and 75% (stage IV). KRAS mutations were concordant in approximately 22% (6/27) of stage II and 46% (11/24) of stage III cases. Clinically important EGFR variants showed concordance in 11% (1/9) of stage II and 80% (8/10) in stage III/IV cases. Actionable mutations, targetable with FDA-approved drugs, were detected in 11% (4/37) of stage II, 27% (12/45) of stage III, and 55% (4/9) of stage IV cases, underscoring the potential of liquid biopsy for early detection of therapeutic targets. Moreover, co-occurring mutations with varying actionability were identified more frequently in plasma than in tumor tissues. Plasma detection of clinically important KRAS and EGFR variants was mostly associated with advanced-stage disease, suggesting the presence of these variants in plasma as a potential indication of disease progression. CONCLUSIONS Liquid biopsy holds promise for identifying high-risk lung adenocarcinoma cases and serves as a complementary diagnostic tool in advanced stages, enhancing disease management strategies.
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Affiliation(s)
- Gopal P. Pathak
- Department of Pathology, QEII Health Sciences Centre, Dalhousie University, Halifax, NS B3H 1V8, Canada; (G.P.P.); (R.S.); (M.D.C.); (J.F.)
| | - Rashmi Shah
- Department of Pathology, QEII Health Sciences Centre, Dalhousie University, Halifax, NS B3H 1V8, Canada; (G.P.P.); (R.S.); (M.D.C.); (J.F.)
| | - Tony Reiman
- Department of Oncology, Saint John Regional Hospital, Saint John, NB E2L 4L2, Canada;
- Department of Biological Sciences, University of New Brunswick, Saint John, NB E2L 4L2, Canada
- Department of Medicine, Dalhousie University, Saint John, NB E2L 4L2, Canada
| | - Alison Wallace
- Division of Thoracic Surgery, QEII Health Sciences Centre, Dalhousie University, Halifax, NS B3H 2Y9, Canada;
| | - Michael D. Carter
- Department of Pathology, QEII Health Sciences Centre, Dalhousie University, Halifax, NS B3H 1V8, Canada; (G.P.P.); (R.S.); (M.D.C.); (J.F.)
| | - Stephanie Snow
- Division of Medical Oncology, QEII Health Sciences Centre, Dalhousie University, Halifax, NS B3H 2Y9, Canada;
| | - John Fris
- Department of Pathology, QEII Health Sciences Centre, Dalhousie University, Halifax, NS B3H 1V8, Canada; (G.P.P.); (R.S.); (M.D.C.); (J.F.)
| | - Zhaolin Xu
- Department of Pathology, QEII Health Sciences Centre, Dalhousie University, Halifax, NS B3H 1V8, Canada; (G.P.P.); (R.S.); (M.D.C.); (J.F.)
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Peng S, Long M, Chen Q, Yin Z, Zeng C, Zhang W, Wen Q, Zhang X, Ke W, Wu Y. Perspectives on cancer therapy-synthetic lethal precision medicine strategies, molecular mechanisms, therapeutic targets and current technical challenges. Cell Death Discov 2025; 11:179. [PMID: 40240755 PMCID: PMC12003663 DOI: 10.1038/s41420-025-02418-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 02/27/2025] [Accepted: 03/19/2025] [Indexed: 04/18/2025] Open
Abstract
In recent years, synthetic lethality has become an important theme in the field of targeted cancer therapy. Synthetic lethality refers to simultaneous defects in two or more genes leading to cell death, whereas defects in any single gene do not lead to cell death. Taking advantage of the genetic vulnerability that exists within cancer cells, it theoretically has no negative impact on healthy cells and has fewer side effects than non-specific chemotherapy. Currently, targeted cancer therapies focus on inhibiting key pathways in cancer. However, it has been found that over-activation of oncogenic-related signaling pathways can also induce cancer cell death, which is a major breakthrough in the new field of targeted therapies. In this review, we summarize the conventional gene targets in synthetic lethality (PARP, ATR, ATM, WEE1, PRMT) and provide an in-depth analysis of their latest potential mechanisms. We explore the impact of over-activation of pathways such as PI3K/AKT, MAPK, and WNT on cancer cell survival, and present the technical challenges of current research. Important theoretical foundations and insights are provided for the application of synthetic lethal strategies in cancer therapy, as well as future research directions.
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Affiliation(s)
- Shixuan Peng
- Department of Oncology, Graduate Collaborative Training Base of The First People's Hospital of Xiangtan City, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- Department of Oncology, The First People's Hospital of Xiangtan City, Xiangtan, Hunan, 411101, China
| | - Mengle Long
- Department of Oncology, Graduate Collaborative Training Base of The First People's Hospital of Xiangtan City, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- Department of Oncology, The First People's Hospital of Xiangtan City, Xiangtan, Hunan, 411101, China
| | - Qisheng Chen
- Department of Anesthesiology, The First People's Hospital of Chenzhou, The Chenzhou Affiliated Hospital, Hengyang Medical School, University of South China, Chenzhou, Hunan, 423000, China
| | - Zhijian Yin
- Department of Oncology, Graduate Collaborative Training Base of The First People's Hospital of Xiangtan City, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- Department of Oncology, The First People's Hospital of Xiangtan City, Xiangtan, Hunan, 411101, China
| | - Chang Zeng
- Department of Pathology, Yueyang Central Hospital, Yueyang, China
| | - Wanyong Zhang
- Department of Pathology, Xianning Central Hospital, The First Affiliated Hospital of Hubei University of Science and Technology, Xianning, 437100, Hubei, China
| | - Qingyang Wen
- Department of Oncology, Graduate Collaborative Training Base of The First People's Hospital of Xiangtan City, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- Department of Oncology, The First People's Hospital of Xiangtan City, Xiangtan, Hunan, 411101, China
| | - Xinwen Zhang
- Department of Oncology, Graduate Collaborative Training Base of The First People's Hospital of Xiangtan City, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- Department of Oncology, The First People's Hospital of Xiangtan City, Xiangtan, Hunan, 411101, China
| | - Weiqi Ke
- Department of Anesthesiology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong Province, China.
| | - Yongjun Wu
- Department of Pathology, Xiangtan Center Hospital, Xiangtan City, Hunan province, 411100, China.
- Department of Pathology, The Affiliated Hospital of Hunan University, Xiangtan City, Hunan Province, China.
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Lu D, Zheng Y, Yi X, Hao J, Zeng X, Han L, Li Z, Jiao S, Jiang B, Ai J, Peng J. Identifying potential risk genes for clear cell renal cell carcinoma with deep reinforcement learning. Nat Commun 2025; 16:3591. [PMID: 40234405 PMCID: PMC12000451 DOI: 10.1038/s41467-025-58439-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 03/18/2025] [Indexed: 04/17/2025] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is the most prevalent type of renal cell carcinoma. However, our understanding of ccRCC risk genes remains limited. This gap in knowledge poses challenges to the effective diagnosis and treatment of ccRCC. To address this problem, we propose a deep reinforcement learning-based computational approach named RL-GenRisk to identify ccRCC risk genes. Distinct from traditional supervised models, RL-GenRisk frames the identification of ccRCC risk genes as a Markov Decision Process, combining the graph convolutional network and Deep Q-Network for risk gene identification. Moreover, a well-designed data-driven reward is proposed for mitigating the limitation of scant known risk genes. The evaluation demonstrates that RL-GenRisk outperforms existing methods in ccRCC risk gene identification. Additionally, RL-GenRisk identifies eight potential ccRCC risk genes. We successfully validated epidermal growth factor receptor (EGFR) and piccolo presynaptic cytomatrix protein (PCLO), corroborated through independent datasets and biological experimentation. This approach may also be used for other diseases in the future.
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Affiliation(s)
- Dazhi Lu
- AI for Science Interdisciplinary Research Center, School of Computer Science, Northwestern Polytechnical University, Xi'an, China
| | - Yan Zheng
- College of Intelligence and Computing, Tianjin University, Tianjin, China
| | - Xianyanling Yi
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Jianye Hao
- College of Intelligence and Computing, Tianjin University, Tianjin, China.
| | - Xi Zeng
- AI for Science Interdisciplinary Research Center, School of Computer Science, Northwestern Polytechnical University, Xi'an, China
| | - Lu Han
- AI for Science Interdisciplinary Research Center, School of Computer Science, Northwestern Polytechnical University, Xi'an, China
| | - Zhigang Li
- College of Intelligence and Computing, Tianjin University, Tianjin, China
| | - Shaoqing Jiao
- School of Software, Northwestern Polytechnical University, Xi'an, China
| | - Bei Jiang
- Tianjin Second People's Hospital, Tianjin, China
| | - Jianzhong Ai
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.
| | - Jiajie Peng
- AI for Science Interdisciplinary Research Center, School of Computer Science, Northwestern Polytechnical University, Xi'an, China.
- Key Laboratory of Big Data Storage and Management, Northwestern Polytechnical University, Ministry of Industry and Information Technology, Xi'an, China.
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38
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Seyfried TN, Lee DC, Duraj T, Ta NL, Mukherjee P, Kiebish M, Arismendi-Morillo G, Chinopoulos C. The Warburg hypothesis and the emergence of the mitochondrial metabolic theory of cancer. J Bioenerg Biomembr 2025:10.1007/s10863-025-10059-w. [PMID: 40199815 DOI: 10.1007/s10863-025-10059-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 03/20/2025] [Indexed: 04/10/2025]
Abstract
Otto Warburg originally proposed that cancer arose from a two-step process. The first step involved a chronic insufficiency of mitochondrial oxidative phosphorylation (OxPhos), while the second step involved a protracted compensatory energy synthesis through lactic acid fermentation. His extensive findings showed that oxygen consumption was lower while lactate production was higher in cancerous tissues than in non-cancerous tissues. Warburg considered both oxygen consumption and extracellular lactate as accurate markers for ATP production through OxPhos and glycolysis, respectively. Warburg's hypothesis was challenged from findings showing that oxygen consumption remained high in some cancer cells despite the elevated production of lactate suggesting that OxPhos was largely unimpaired. New information indicates that neither oxygen consumption nor lactate production are accurate surrogates for quantification of ATP production in cancer cells. Warburg also did not know that a significant amount of ATP could come from glutamine-driven mitochondrial substrate level phosphorylation in the glutaminolysis pathway with succinate produced as end product, thus confounding the linkage of oxygen consumption to the origin of ATP production within mitochondria. Moreover, new information shows that cytoplasmic lipid droplets and elevated aerobic lactic acid fermentation are both biomarkers for OxPhos insufficiency. Warburg's original hypothesis can now be linked to a more complete understanding of how OxPhos insufficiency underlies dysregulated cancer cell growth. These findings can also address several questionable assumptions regarding the origin of cancer thus allowing the field to advance with more effective therapeutic strategies for a less toxic metabolic management and prevention of cancer.
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Affiliation(s)
- Thomas N Seyfried
- Biology Department, Boston College, 140 Commonwealth Ave, Chestnut Hill, Boston, MA, 02467, USA.
| | - Derek C Lee
- Biology Department, Boston College, 140 Commonwealth Ave, Chestnut Hill, Boston, MA, 02467, USA
| | - Tomas Duraj
- Biology Department, Boston College, 140 Commonwealth Ave, Chestnut Hill, Boston, MA, 02467, USA
| | - Nathan L Ta
- Biology Department, Boston College, 140 Commonwealth Ave, Chestnut Hill, Boston, MA, 02467, USA
| | - Purna Mukherjee
- Biology Department, Boston College, 140 Commonwealth Ave, Chestnut Hill, Boston, MA, 02467, USA
| | | | - Gabriel Arismendi-Morillo
- Facultad de Medicina, Instituto de Investigaciones Biológicas, Universidad del Zulia, Maracaibo, Venezuela
- Department of Medicine, Faculty of Health Sciences, University of Deusto, Bilbao (Bizkaia), Spain
| | - Christos Chinopoulos
- Department of Medical Biochemistry, Semmelweis University, Budapest, 1094, Hungary
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Keskus AG, Bryant A, Ahmad T, Yoo B, Aganezov S, Goretsky A, Donmez A, Lansdon LA, Rodriguez I, Park J, Liu Y, Cui X, Gardner J, McNulty B, Sacco S, Shetty J, Zhao Y, Tran B, Narzisi G, Helland A, Cook DE, Chang PC, Kolesnikov A, Carroll A, Molloy EK, Bi C, Walter A, Gibson M, Pushel I, Guest E, Pastinen T, Shafin K, Miga KH, Malikic S, Day CP, Robine N, Sahinalp C, Dean M, Farooqi MS, Paten B, Kolmogorov M. Severus detects somatic structural variation and complex rearrangements in cancer genomes using long-read sequencing. Nat Biotechnol 2025:10.1038/s41587-025-02618-8. [PMID: 40185952 DOI: 10.1038/s41587-025-02618-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 02/26/2025] [Indexed: 04/07/2025]
Abstract
For the detection of somatic structural variation (SV) in cancer genomes, long-read sequencing is advantageous over short-read sequencing with respect to mappability and variant phasing. However, most current long-read SV detection methods are not developed for the analysis of tumor genomes characterized by complex rearrangements and heterogeneity. Here, we present Severus, a breakpoint graph-based algorithm for somatic SV calling from long-read cancer sequencing. Severus works with matching normal samples, supports unbalanced cancer karyotypes, can characterize complex multibreak SV patterns and produces haplotype-specific calls. On a comprehensive multitechnology cell line panel, Severus consistently outperforms other long-read and short-read methods in terms of SV detection F1 score (harmonic mean of the precision and recall). We also illustrate that compared to long-read methods, short-read sequencing systematically misses certain classes of somatic SVs, such as insertions or clustered rearrangements. We apply Severus to several clinical cases of pediatric leukemia/lymphoma, revealing clinically relevant cryptic rearrangements missed by standard genomic panels.
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Affiliation(s)
- Ayse G Keskus
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Asher Bryant
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Tanveer Ahmad
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Byunggil Yoo
- Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
| | | | - Anton Goretsky
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
- Department of Computer Science, University of Maryland, College Park, MD, USA
| | - Ataberk Donmez
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
- Department of Computer Science, University of Maryland, College Park, MD, USA
| | - Lisa A Lansdon
- Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
| | - Isabel Rodriguez
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA
| | - Jimin Park
- University of California, Santa Cruz, Genomics Institute, Santa Cruz, CA, USA
| | - Yuelin Liu
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
- Department of Computer Science, University of Maryland, College Park, MD, USA
| | - Xiwen Cui
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Joshua Gardner
- University of California, Santa Cruz, Genomics Institute, Santa Cruz, CA, USA
| | - Brandy McNulty
- University of California, Santa Cruz, Genomics Institute, Santa Cruz, CA, USA
| | - Samuel Sacco
- University of California, Santa Cruz, Genomics Institute, Santa Cruz, CA, USA
| | - Jyoti Shetty
- Sequencing Facility, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Yongmei Zhao
- Sequencing Facility Bioinformatics Group, Biomedical Informatics and Data Science Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Bao Tran
- Sequencing Facility, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | | | | | | | | | | | | | - Erin K Molloy
- Department of Computer Science, University of Maryland, College Park, MD, USA
| | - Chengpeng Bi
- Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
| | - Adam Walter
- Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
| | - Margaret Gibson
- Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
| | - Irina Pushel
- Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
| | - Erin Guest
- Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
| | - Tomi Pastinen
- Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
| | - Kishwar Shafin
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA
| | - Karen H Miga
- University of California, Santa Cruz, Genomics Institute, Santa Cruz, CA, USA
| | - Salem Malikic
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Chi-Ping Day
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
| | | | - Cenk Sahinalp
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Michael Dean
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA
| | - Midhat S Farooqi
- Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
| | - Benedict Paten
- University of California, Santa Cruz, Genomics Institute, Santa Cruz, CA, USA
| | - Mikhail Kolmogorov
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
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40
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Yi H, Zhang S, Swinderman J, Wang Y, Kanakaveti V, Hung KL, Wong ITL, Srinivasan S, Curtis EJ, Bhargava-Shah A, Li R, Jones MG, Luebeck J, Zhao Y, Belk JA, Kraft K, Shi Q, Yan X, Pritchard SK, Liang FM, Felsher DW, Gilbert LA, Bafna V, Mischel PS, Chang HY. EcDNA-borne PVT1 fusion stabilizes oncogenic mRNAs. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.04.01.646515. [PMID: 40236070 PMCID: PMC11996508 DOI: 10.1101/2025.04.01.646515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
Extrachromosomal DNA (ecDNA) amplifications are prevalent drivers of human cancers. We show that ecDNAs exhibit elevated structural variants leading to gene fusions that produce oncogene fusion transcripts. The long noncoding RNA (lncRNA) gene PVT1 is the most recurrent structural variant across cancer genomes, with PVT1-MYC fusions arising most frequently on ecDNA. PVT1 exon 1 is the predominant 5' partner fused to MYC or other oncogenes on the 3' end. Mechanistic studies demonstrate that PVT1 exon 1 confers enhanced RNA stability for fusion transcripts, which requires PVT1 exon 1 interaction with SRSF1 protein. Genetic rescue of MYC-addicted cancer models and isoform-specific single-cell RNA sequencing of tumors reveal that PVT1-MYC better supports MYC dependency and better activates MYC target genes in vivo . Thus, the mutagenic landscape of ecDNA contributes to genome instability and generates chimeric fusions of lncRNA and mRNA genes, selecting PVT1 5' region as a stabilizer of oncogene mRNAs.
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41
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Lan Y, Xia Z, Shao Q, Lin P, Lu J, Xiao X, Zheng M, Chen D, Dou Y, Xie Q. Synonymous mutations promote tumorigenesis by disrupting m 6A-dependent mRNA metabolism. Cell 2025; 188:1828-1841.e15. [PMID: 39952247 DOI: 10.1016/j.cell.2025.01.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 11/04/2024] [Accepted: 01/17/2025] [Indexed: 02/17/2025]
Abstract
Cancer cells acquire numerous mutations during tumorigenesis, including synonymous mutations that do not change the amino acid sequence of a protein. RNA N6-methyladenosine (m6A) is a post-transcriptional modification that plays critical roles in oncogenesis. Herein, we identified 12,849 mutations in the cancer genome with the potential to perturb m6A modification patterns, which we refer to as "m6A disruption mutations (m6A-DMs)." These are either synonymous m6A-DMs (sm6A-DMs) or missense m6A-DMs (mm6A-DMs) mutations, and the former is enriched within tumor suppressor genes, such as CDKN2A and BRCA2. Using epitranscriptomic editing, we demonstrate that manipulating m6A levels at specific sm6A-DM sites influences mRNA stability. Furthermore, introducing CDKN2A sm6A-DMs into cancer cells promotes tumor growth while BRCA2 sm6A-DMs sensitize tumors to the poly (ADP-ribose) polymerase inhibitor (PARPi) treatment. Our findings demonstrate sm6A-DMs as potential oncogenic drivers, unveiling implications for synonymous mutations in tumorigenesis and beyond.
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Affiliation(s)
- Yiheng Lan
- Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China; School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China
| | - Zhen Xia
- School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China
| | - Qizhe Shao
- Center for Regeneration and Cell Therapy of Zhejiang University, University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Peng Lin
- School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China
| | - Jinhong Lu
- School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China; Fudan University, Shanghai 200433, China
| | - Xiaoying Xiao
- Center for Regeneration and Cell Therapy of Zhejiang University, University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Mengyue Zheng
- School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China
| | - Di Chen
- Center for Regeneration and Cell Therapy of Zhejiang University, University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China.
| | - Yanmei Dou
- School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China.
| | - Qi Xie
- Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China; School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China.
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Bhattacharya R, Avdieiev SS, Bukkuri A, Whelan CJ, Gatenby RA, Tsai KY, Brown JS. The Hallmarks of Cancer as Eco-Evolutionary Processes. Cancer Discov 2025; 15:685-701. [PMID: 40170539 DOI: 10.1158/2159-8290.cd-24-0861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 11/19/2024] [Accepted: 01/28/2025] [Indexed: 04/03/2025]
Abstract
SIGNIFICANCE Viewing the hallmarks as a sequence of adaptations captures the "why" behind the "how" of the molecular changes driving cancer. This eco-evolutionary view distils the complexity of cancer progression into logical steps, providing a framework for understanding all existing and emerging hallmarks of cancer and developing therapeutic interventions.
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Affiliation(s)
- Ranjini Bhattacharya
- Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Cancer Biology, University of South Florida, Tampa, Florida
| | - Stanislav S Avdieiev
- Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Anuraag Bukkuri
- Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania
- Center for Evolutionary Biology and Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Christopher J Whelan
- Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, Illinois
| | - Robert A Gatenby
- Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Radiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Kenneth Y Tsai
- Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Tumor Microenvironment & Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Joel S Brown
- Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, Illinois
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Hoang TT, Herceg Z, Coulter DW, de Smith A, Arora M, Funk WE, Haynes D, Linder SH, Nogueira LM, Hughes AE, Williams LA, Schraw JM, Scheurer ME, Lupo PJ. Environmental health disparities in pediatric cancer: a report from the Fourth Symposium on Childhood Cancer Health Disparities. Pediatr Hematol Oncol 2025; 42:186-203. [PMID: 40110606 DOI: 10.1080/08880018.2025.2479479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 02/19/2025] [Accepted: 03/09/2025] [Indexed: 03/22/2025]
Abstract
The 4th Symposium on Childhood Cancer Health Disparities was held at Texas Children's Hospital in Houston, Texas, on September 26, 2023. The symposium registered 94 attendees from different backgrounds (e.g. clinicians, epidemiologists, exposure assessment scientists, geospatial experts) with an interest in environmental health disparities of pediatric cancer susceptibility and treatment outcomes. The focus of the symposium was to provide an overview of the role of environmental risk factors in studies of pediatric cancer, introduce novel exposure assessment tools that can be applied to the field, and highlight opportunities to study the impact of environmental health disparities in pediatric cancer susceptibility and outcomes. This report summarizes the scientific content of the symposium and highlights priorities to advance the field.
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Affiliation(s)
- Thanh T Hoang
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
- Texas Children's Cancer and Hematology Center, Texas Children's Hospital, Houston, Texas, USA
| | - Zdenko Herceg
- Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, World Health Organization, Lyon Cedex 07, France
| | - Don W Coulter
- Division of Hematology/Oncology, Department of Pediatrics, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Adam de Smith
- Department of Population and Public Health Sciences, Center for Genetic Epidemiology, University of Southern California Keck School of Medicine, Los Angeles, California, USA
- USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Manish Arora
- The Senator Frank R. Lautenberg Environmental Health Science Laboratory, Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - William E Funk
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - David Haynes
- Institute for Health Informatics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Stephen H Linder
- Department of Management, Policy and Community Health, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Leticia M Nogueira
- Surveillance & Health Equity Science, American Cancer Society, Kennesaw, Georgia, USA
| | - Amy E Hughes
- Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Lindsay A Williams
- Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
- Brain Tumor Program, University of Minnesota, Minneapolis, MN, USA
| | - Jeremy M Schraw
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
- Texas Children's Cancer and Hematology Center, Texas Children's Hospital, Houston, Texas, USA
| | - Michael E Scheurer
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
- Texas Children's Cancer and Hematology Center, Texas Children's Hospital, Houston, Texas, USA
| | - Philip J Lupo
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
- Texas Children's Cancer and Hematology Center, Texas Children's Hospital, Houston, Texas, USA
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Kashif M. Gene expression profiling to uncover prognostic and therapeutic targets in colon cancer, combined with docking and dynamics studies to discover potent anticancer inhibitor. Comput Biol Chem 2025; 115:108349. [PMID: 39813876 DOI: 10.1016/j.compbiolchem.2025.108349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 12/05/2024] [Accepted: 01/06/2025] [Indexed: 01/18/2025]
Abstract
Drug resistance poses a major obstacle to the efficient treatment of colorectal cancer (CRC), which is one of the cancers that kill people most often in the United States. Advanced colorectal cancer patients frequently pass away from the illness, even with advancements in chemotherapy and targeted therapies. Developing new biomarkers and therapeutic targets is essential to enhancing prognosis and therapy effectiveness. My goal in this study was to use bioinformatics analysis of microarray data to find possible biomarkers and treatment targets for colorectal cancer. Using an ArrayExpress database, I examined a dataset on colon cancer to find genes that were differentially expressed (DEGs) in tumor versus healthy tissues. Integration of advanced bioinformatics tools provided robust insights into the identification and analysis of EGFR as a key player. STRING and Cytoscape enabled the construction and visualization of protein-protein interaction networks, highlighting EGFR as a hub gene due to its centrality and interaction profile. Functional enrichment analysis through DAVID revealed EGFR's involvement in critical biological pathways, as identified in GO and KEGG analyses. This underscores the power of combining computational tools to uncover significant biomarkers like EGFR. Autodock Vina screening of the NCI diversity dataset identified two potential EGFR inhibitors, ZINC13597410 and ZINC04896472. MD simulation data revealed that ZINC04896472 could be potential anticancer inhibitor. These findings serve as a basis for the creation of novel therapeutic approaches that target EGFR and other discovered pathways in CRC. The suggested strategy may improve the efficacy of CRC therapy and advance personalized medicine.
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Affiliation(s)
- Mohammad Kashif
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
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Pavinato L, Baggiolini A. Oncogenic competence: balancing mutations, cellular state, and microenvironment. Trends Cancer 2025; 11:276-285. [PMID: 39875306 DOI: 10.1016/j.trecan.2025.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 12/18/2024] [Accepted: 01/06/2025] [Indexed: 01/30/2025]
Abstract
Cancer development is driven by mutations, yet tumor-causing mutations only lead to tumor formation within specific cellular contexts. The reasons why certain mutations trigger malignant transformation in some contexts but not others remain often unclear. Both intrinsic and extrinsic factors play a key role in driving carcinogenesis by leading the cells toward a state of 'oncogenic competence'. This state is shaped by the transcriptional and epigenetic programs that define a specific cell in time and space. These programs arise from the interplay between genetic mutations, cellular lineage, differentiation state, and microenvironment. A deeper understanding of oncogenic competence is essential to uncover the mechanisms behind tumor initiation and, ultimately, advance the development of novel targeted therapies for cancer treatment and prevention.
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Affiliation(s)
- Lisa Pavinato
- Institute of Oncology Research (IOR), Bellinzona Institutes of Science (BIOS+), Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland
| | - Arianna Baggiolini
- Institute of Oncology Research (IOR), Bellinzona Institutes of Science (BIOS+), Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland.
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Nourbakhsh M, Zheng Y, Noor H, Chen H, Akhuli S, Tiberti M, Gevaert O, Papaleo E. Revealing cancer driver genes through integrative transcriptomic and epigenomic analyses with Moonlight. PLoS Comput Biol 2025; 21:e1012999. [PMID: 40258059 PMCID: PMC12058160 DOI: 10.1371/journal.pcbi.1012999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 05/07/2025] [Accepted: 03/26/2025] [Indexed: 04/23/2025] Open
Abstract
Cancer involves dynamic changes caused by (epi)genetic alterations such as mutations or abnormal DNA methylation patterns which occur in cancer driver genes. These driver genes are divided into oncogenes and tumor suppressors depending on their function and mechanism of action. Discovering driver genes in different cancer (sub)types is important not only for increasing current understanding of carcinogenesis but also from prognostic and therapeutic perspectives. We have previously developed a framework called Moonlight which uses a systems biology multi-omics approach for prediction of driver genes. Here, we present an important development in Moonlight2 by incorporating a DNA methylation layer which provides epigenetic evidence for deregulated expression profiles of driver genes. To this end, we present a novel functionality called Gene Methylation Analysis (GMA) which investigates abnormal DNA methylation patterns to predict driver genes. This is achieved by integrating the tool EpiMix which is designed to detect such aberrant DNA methylation patterns in a cohort of patients and further couples these patterns with gene expression changes. To showcase GMA, we applied it to three cancer (sub)types (basal-like breast cancer, lung adenocarcinoma, and thyroid carcinoma) where we discovered 33, 190, and 263 epigenetically driven genes, respectively. A subset of these driver genes had prognostic effects with expression levels significantly affecting survival of the patients. Moreover, a subset of the driver genes demonstrated therapeutic potential as drug targets. This study provides a framework for exploring the driving forces behind cancer and provides novel insights into the landscape of three cancer sub(types) by integrating gene expression and methylation data.
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Affiliation(s)
- Mona Nourbakhsh
- Cancer Systems Biology, Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Lyngby, Denmark
- Cancer Structural Biology, Danish Cancer Institute, Copenhagen, Denmark
| | - Yuanning Zheng
- Department of Biomedical Data Science, Stanford Center for Biomedical Informatics Research, Palo Alto, California, United States of America
| | - Humaira Noor
- Department of Biomedical Data Science, Stanford Center for Biomedical Informatics Research, Palo Alto, California, United States of America
| | - Hongjin Chen
- Cancer Systems Biology, Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Lyngby, Denmark
| | - Subhayan Akhuli
- Cancer Systems Biology, Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Lyngby, Denmark
| | - Matteo Tiberti
- Cancer Structural Biology, Danish Cancer Institute, Copenhagen, Denmark
| | - Olivier Gevaert
- Department of Biomedical Data Science, Stanford Center for Biomedical Informatics Research, Palo Alto, California, United States of America
| | - Elena Papaleo
- Cancer Systems Biology, Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Lyngby, Denmark
- Cancer Structural Biology, Danish Cancer Institute, Copenhagen, Denmark
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Zhou DDX, Dalrymple J, Klingberg D, Lin FPY, Lord SJ, Cooper WA, Zaheed M, Simes RJ, John T, Lee CK. Clinical Impact of Somatic Genomic Variants of Oncogenes and Tumor Suppressor Genes in Previously Treated Advanced Non-Small Cell Lung Cancer. JCO Precis Oncol 2025; 9:e2400673. [PMID: 40239138 DOI: 10.1200/po-24-00673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 12/18/2024] [Accepted: 03/12/2025] [Indexed: 04/18/2025] Open
Abstract
PURPOSE Next-generation sequencing in non-small cell lung cancer (NSCLC) identifies somatic genomic variants (SGVs) in cancer susceptibility genes (CSGs). We hypothesized that SGVs would be associated with poorer overall survival (OS) but greater benefit with immune checkpoint inhibitors over chemotherapy. We investigated the prevalence and predictive value of SGVs, using data from OAK and POPLAR trials comparing atezolizumab with docetaxel. METHODS We curated a list of SGVs (excluding TP53, EGFR, ALK, and ROS1) on the basis of CSGs associated with tumorigenesis. We classified participants as SGV mutant or wild-type using baseline plasma analyzed by the FoundationOne Liquid CDx assay. Cox regression analyses and interaction tests between SGV status and treatment were performed. RESULTS Of 762 participants, 29% harbored an SGV. The SGV mutant group had worse OS (hazard ratio [HR], 1.28, 95% CI, 1.06 to 1.54), and within each treatment arm (docetaxel: HR, 1.31; atezolizumab: HR, 1.27). In the atezolizumab arm, the SGV mutant group compared with wild-type had worse OS in the PD-L1 high (HR, 1.31 [95% CI, 0.59 to 2.91]) and low (HR, 1.38 [95% CI, 0.98 to 1.93]) subgroups. SGV with missense, splice, and nonsense mutations had significantly worse OS than wild-type in the docetaxel arm (log-rank P = .01) but not in the atezolizumab arm (log-rank P = .33). SGV status did not predict greater OS benefit with atezolizumab over docetaxel (interaction P = .67). CONCLUSION In advanced NSCLC after chemotherapy progression, plasma-detected SGVs are common, and associated with inferior OS. Plasma SGV status should be considered as a stratification factor in future trials.
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Affiliation(s)
- Deborah Di-Xin Zhou
- NHMRC Clinical Trials Centre, University of Sydney, Camperdown, NSW, Australia
- St George Hospital, Kogarah, NSW, Australia
| | | | | | - Frank Po-Yen Lin
- NHMRC Clinical Trials Centre, University of Sydney, Camperdown, NSW, Australia
| | - Sarah J Lord
- NHMRC Clinical Trials Centre, University of Sydney, Camperdown, NSW, Australia
| | - Wendy A Cooper
- Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, NSW Health Pathology, Camperdown, NSW, Australia
- Faculty of Medicine and Health and Western Sydney University School of Medicine, University of Sydney, Camperdown, NSW, Australia
| | - Milita Zaheed
- Prince of Wales Hereditary Cancer Centre, Randwick, NSW, Australia
| | - Robert John Simes
- NHMRC Clinical Trials Centre, University of Sydney, Camperdown, NSW, Australia
| | - Thomas John
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Chee Khoon Lee
- NHMRC Clinical Trials Centre, University of Sydney, Camperdown, NSW, Australia
- St George Hospital, Kogarah, NSW, Australia
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48
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Yao Y, Lee VKM, Chen ES. Molecular pathological insights into tumorigenesis and progression of giant cell tumor of bone. J Bone Oncol 2025; 51:100665. [PMID: 40092569 PMCID: PMC11909452 DOI: 10.1016/j.jbo.2025.100665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 02/08/2025] [Accepted: 02/10/2025] [Indexed: 03/19/2025] Open
Abstract
Giant cell tumor of bone (GCTB) is a primary bone tumor that typically exhibits benign histological appearance and clinical behavior in most cases, with local aggressiveness and rare metastasis. It predominantly affects individuals in the young adult age group. It is characterized by the presence of multinucleated osteoclastic giant cells and a stromal population of neoplastic cells. A key hallmark for GCTB pathogenesis is the G34W genetic mutation in the histone H3.3 gene, which is restricted to the population of cancerous stromal cells and is absent in osteoclasts and their progenitor cells. This review presents a comprehensive overview of the pathology of GCTB, including its histopathological characteristics, cytological features, histopathological variants, and their clinical relevance. We also discuss recent insights into genetic alterations in relation to the molecular pathways implicated in GCTB. A summary of the current understanding of GCTB pathology will update the knowledge base to guide the diagnosis and management of this unique bone tumor.
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Affiliation(s)
- Yibing Yao
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Victor Kwan Min Lee
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- National University Health System, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- National University Cancer Institute, Singapore
| | - Ee Sin Chen
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- National University Health System, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Integrative Sciences & Engineering Programme, National University of Singapore, Singapore
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Morand S, Rager L, Craig D, Nemunaitis A, Choucair K, Rao D, Stanbery L, Phinney RC, Walter A, Ghisoli M, Nemunaitis J. Clinical characterization and therapeutic targeting of fusion genes in oncology. Future Oncol 2025; 21:1249-1260. [PMID: 40128124 PMCID: PMC11988278 DOI: 10.1080/14796694.2025.2477974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 03/07/2025] [Indexed: 03/26/2025] Open
Abstract
Gene fusions represent important oncogenic driver mutations resulting in aberrant cellular signaling. In up to 17% of all solid tumors at least one gene fusion can be identified. Precision therapy targeting fusion gene signaling has demonstrated effective clinical benefit. Advancements in clinically relevant next-generation sequencing and bioinformatic techniques have enabled expansion of therapeutic opportunity to subpopulations of patients with fusion gene expression. Clinically, tyrosine inhibitors have shown efficacy in treating fusion gene expressing cancers. Fusion genes are also clonal mutations, meaning it is a personal cancer target involving all cancer cells of that patient, not just a subpopulation of cancer cells within the cancer mass. Thus, both fusion signal disruption and immune signal targeting are effective therapeutic directions. This review discusses fusion gene targeting, therapeutic resistance, and molecular biomarkers.
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Affiliation(s)
- Susan Morand
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
| | - Lauren Rager
- Department of Medicine, University of Toledo College of Medicine, Toledo, OH, USA
| | - Daniel Craig
- Department of Medicine, University of Toledo College of Medicine, Toledo, OH, USA
| | | | - Khalil Choucair
- Department of Hematology/Oncology, Barbara Karmanos Cancer Institute,Wayne State University, Detroit, MI, USA
| | - Donald Rao
- Medical Affairs, Gradalis Inc, Dallas, TX, USA
| | - Laura Stanbery
- Taylor Cancer Research Center, Maumee, OH, USA
- Medical Affairs, Gradalis Inc, Dallas, TX, USA
| | - Richard C. Phinney
- Taylor Cancer Research Center, Maumee, OH, USA
- Department of Hematology/Oncology, Toledo Clinic Cancer Center, Maumee, OH, USA
| | - Adam Walter
- Medical Affairs, Gradalis Inc, Dallas, TX, USA
- Department of Gynecologic Oncology, Promedica Health System, Toledo, OH, USA
| | - Maurizio Ghisoli
- Department of Pediatric Hematology/Oncology, Texas Oncology, P.A, Dallas, TX, USA
| | - John Nemunaitis
- Taylor Cancer Research Center, Maumee, OH, USA
- Medical Affairs, Gradalis Inc, Dallas, TX, USA
- Department of Hematology/Oncology, Toledo Clinic Cancer Center, Maumee, OH, USA
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50
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Huang P, Fu J, Hu J, Lei Y, Wu T, Liu J. Identification of aberrantly expressed genes during aging in the mouse heart via integrated bioinformatics analysis. Medicine (Baltimore) 2025; 104:e41972. [PMID: 40153770 PMCID: PMC11957657 DOI: 10.1097/md.0000000000041972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 03/07/2025] [Indexed: 03/30/2025] Open
Abstract
Cardiovascular disease (CVD) represents a global problem and is associated with high levels of morbidity/mortality in the elderly (>65 years old). The present study aimed to identify the key candidate genes and pathways in cardiac aging via integrated bioinformatics analysis. The GSE43556 and GSE8146 gene expression datasets were obtained from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs), defined as P < .05 and |log fold-change (FC)| >0.5, were identified. Functional enrichment and protein-protein interaction network construction were subsequently performed. First, 142 DEGs shared between the two GEO datasets were identified. Second, biological functional enrichment analysis illustrated that these DEGs mainly participate in "inflammatory response" and "monocarboxylic acid metabolic process." Moreover, Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the DEGs were mainly enriched in the PI3K-Akt signaling pathway. Subsequently, the association between the expression of DEGs in the aged heart was evaluated using the Search Tool for the Retrieval of Interacting Genes database and Cytoscape software. The present study elucidated the key genes and signaling pathways associated with cardiac aging, thus improving the understanding of the molecular mechanisms underlying cardiac aging. These identified genes may be used as molecular biomarkers for the diagnosis and treatment of cardiac aging.
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Affiliation(s)
- Pianpian Huang
- Departments of Geriatrics, Wuhan No. 1 Hospital, Wuhan, China
| | - Jun Fu
- Departments of Radiology, Wuhan No. 1 Hospital, Wuhan, China
| | - Ji Hu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yinghong Lei
- Departments of Geriatrics, Wuhan No. 1 Hospital, Wuhan, China
| | - Tingyu Wu
- Departments of Geriatrics, Wuhan No. 1 Hospital, Wuhan, China
| | - Ju Liu
- Departments of Geriatrics, Wuhan No. 1 Hospital, Wuhan, China
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