1
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Xiong L, Chen S, Li S, He D, Wang Y, Zhang Q, He Z, Li M, He Q. ATP-responsive tumor targeted lipid nanoparticle for enhanced siRNA delivery and improved treatment efficacy in melanoma. J Control Release 2025; 382:113622. [PMID: 40120691 DOI: 10.1016/j.jconrel.2025.113622] [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: 12/02/2024] [Revised: 03/06/2025] [Accepted: 03/08/2025] [Indexed: 03/25/2025]
Abstract
Small interfering RNA (siRNA) plays a crucial role in tumor therapy, especially for non-druggable targets with obvious advantages. Nevertheless, its molecular weight, negative charge, and susceptibility to degradation hinder effective delivery to tumor cells for therapeutic action. Lipid nanoparticles (LNPs) serve as an excellent delivery mechanism for siRNA but still face problems such as suboptimal tumor targeting and inefficient intracellular release. To enhance melanoma treatment, we designed lipid nanoparticles modified with phenylboronic acid (PBA) for efficient delivery of siRNA targeting "undruggable" microphthalmia-associated transcription factor (MITF). This nanocarrier successfully encapsulated siRNA and improved tumor targeting by allowing phenylboronic acid to interact with sialic acid residues overexpressed in tumor cells. Furthermore, PBA-modified lipid nanoparticles facilitated the ATP-responsive release of siRNA intracellular. These two aspects enhance gene silencing efficiency. The in vivo targeting and gene silencing capabilities of PBA-modified lipid nanoparticles significantly surpassed those of unmodified LNP. Additionally, PBA-modified nanoparticles exhibited considerable anti-tumor and anti-metastatic effects in animal models, offering an alternative approach for siRNA therapy.
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Affiliation(s)
- Lin Xiong
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China
| | - Shuang Chen
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China
| | - Sihui Li
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China
| | - Dan He
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China
| | - Yashi Wang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China
| | - Qiang Zhang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China
| | - Zhidi He
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China
| | - Man Li
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
| | - Qin He
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
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2
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McGrail K, Granado-Martínez P, Orsenigo R, Caratù G, Nieto P, Heyn H, Ferrer B, Hernández-Losa J, Muñoz-Couselo E, García-Patos V, Recio JA. Transcriptional reprogramming triggered by neonatal UV radiation or Lkb1 loss prevents BRAF V600E-induced growth arrest in melanocytes. Oncogene 2025; 44:1592-1608. [PMID: 40057604 PMCID: PMC12095085 DOI: 10.1038/s41388-025-03339-7] [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: 09/30/2024] [Revised: 02/12/2025] [Accepted: 02/28/2025] [Indexed: 05/23/2025]
Abstract
The mechanisms behind UVB-initiated, neonatal-specific melanoma linked to BRAFV600E are not well understood, particularly regarding its role in growth arrest. We found that, beyond mutations, neonatal UV irradiation or Lkb1 loss promotes a cell-autonomous transcriptional reprogramming that prevents BRAFV600E-induced growth arrest, leading to melanoma development. Using UVB-dependent and independent mouse models, genomic analyses, clinical data, and single-cell transcriptomics, we identified a transcriptional program that bypasses growth arrest, promoting melanoma. In humans, many of these genes are linked to poor survival and are upregulated in melanoma progression and other RAS pathway-driven tumors. Reconstitution experiments showed these genes cooperate with BRAFV600E in melanocyte transformation, dedifferentiation, and drug resistance. Depleting gene products like UPP1 highlights their potential as therapeutic targets. Our findings reveal that BRAFV600E-mutated melanomas can develop independently of nevus progression and identify novel targets for treatment.
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Affiliation(s)
- Kimberley McGrail
- Biomedical Research in Melanoma-Animal Models and Cancer Laboratory-Vall d´Hebron Research Institute VHIR-Vall d'Hebron Hospital-UAB, Barcelona, Spain
| | - Paula Granado-Martínez
- Biomedical Research in Melanoma-Animal Models and Cancer Laboratory-Vall d´Hebron Research Institute VHIR-Vall d'Hebron Hospital-UAB, Barcelona, Spain
| | - Roberto Orsenigo
- Biomedical Research in Melanoma-Animal Models and Cancer Laboratory-Vall d´Hebron Research Institute VHIR-Vall d'Hebron Hospital-UAB, Barcelona, Spain
| | - Ginevra Caratù
- Single Cell Genomics Group at the Spanish National Centre for Genomic Analysis (CNAG), Barcelona, Spain
| | - Paula Nieto
- Single Cell Genomics Group at the Spanish National Centre for Genomic Analysis (CNAG), Barcelona, Spain
| | - Holger Heyn
- Single Cell Genomics Group at the Spanish National Centre for Genomic Analysis (CNAG), Barcelona, Spain
| | - Berta Ferrer
- Anatomy Pathology Department, Vall d'Hebron Hospital-UAB, Barcelona, Spain
| | | | - Eva Muñoz-Couselo
- Clinical Oncology Program, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Hospital-UAB, Barcelona, Spain
| | | | - Juan A Recio
- Biomedical Research in Melanoma-Animal Models and Cancer Laboratory-Vall d´Hebron Research Institute VHIR-Vall d'Hebron Hospital-UAB, Barcelona, Spain.
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3
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Meng Y, Zhou Q, Dian Y, Zeng F, Deng G, Chen X. Ferroptosis: A Targetable Vulnerability for Melanoma Treatment. J Invest Dermatol 2025; 145:1323-1344. [PMID: 39797894 DOI: 10.1016/j.jid.2024.11.007] [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: 08/08/2024] [Revised: 11/10/2024] [Accepted: 11/11/2024] [Indexed: 01/13/2025]
Abstract
Melanoma is a devastating form of skin cancer characterized by a high mutational burden, limited treatment success, and dismal prognosis. Although immunotherapy and targeted therapies have significantly revolutionized melanoma treatment, the majority of patients fail to achieve durable responses, highlighting the urgent need for novel therapeutic strategies. Ferroptosis, an iron-dependent form of regulated cell death driven by the overwhelming accumulation of lipid peroxides, has emerged as a promising therapeutic approach in preclinical melanoma models. A deeper understanding of the ferroptosis landscape in melanoma based on its biology characteristics, including phenotypic plasticity, metabolic state, genomic alterations, and epigenetic changes, as well as the complex role and mechanisms of ferroptosis in immune cells could provide a foundation for developing effective treatments. In this review, we outline the molecular mechanisms of ferroptosis, decipher the role of melanoma biology in ferroptosis regulation, reveal the therapeutic potential of ferroptosis in melanoma, and discuss the pressing questions that should guide future investigations into ferroptosis in melanoma.
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Affiliation(s)
- Yu Meng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China; Furong Laboratory, Changsha, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Qian Zhou
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China; Furong Laboratory, Changsha, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Yating Dian
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China; Furong Laboratory, Changsha, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Furong Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Guangtong Deng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China; Furong Laboratory, Changsha, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China.
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China; Furong Laboratory, Changsha, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China.
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4
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Qian C, Wang H, Bi J, Zheng X, Li R, Luo H, Qi X, Shen S, Cao J. A biomimetic manganese-phycocyanin nanodrug-carrying system and its sonodynamic-immunological anti-tumor therapy. Int J Pharm 2025; 677:125626. [PMID: 40300722 DOI: 10.1016/j.ijpharm.2025.125626] [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: 01/13/2025] [Revised: 04/04/2025] [Accepted: 04/18/2025] [Indexed: 05/01/2025]
Abstract
Cutaneous melanoma is characterized by malignant proliferation, high aggressiveness, high metastasis, rapid recurrence, and low survival rate; therefore, research on its treatment is vital. In this study, a novel nano system combining sonodynamics and immunotherapy for cutaneous melanoma treatment was designed and developed. Based on the use of phycocyanin for the biomineralization of manganese ions, smart and multifunctional manganese phycocyanin nanoparticles encapsulating the immune adjuvant levamisole (LMS) with melanoma B16-OVA cell membranes wrapped around its outer layer (Mn-PCNP-LMS@CM) were designed and prepared. The experimental results showed that Mn-PCNP-LMS@CM efficiently targeted cutaneous melanomas. Under ultrasonic excitation, it catalyzed oxygen production from hydrogen peroxide in the tumor environment, reduced high glutathione levels in tumor tissues, and significantly enhanced (reactive oxygen species) ROS generation, thus improving the outcome of sonodynamic therapy. In contrast, sonodynamic therapy induced immunogenic death of tumor cells, together with the loaded immune adjuvant levamisole, which promoted the maturation of dendritic cells (DCs), modulated the immunosuppressive microenvironment, enhanced the immunotherapeutic effect, and stimulated the function of long-term immune memory to prevent tumor growth and recurrence. This study is expected to provide new ideas for developing novel anti-tumor nano systems and achieving anti-tumor synergistic therapy.
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Affiliation(s)
- Chenyao Qian
- School of Pharmacy, Jiangsu University, Zhenjiang 212000, China
| | - Huan Wang
- School of Pharmacy, Jiangsu University, Zhenjiang 212000, China
| | - Jinyue Bi
- School of Pharmacy, Jiangsu University, Zhenjiang 212000, China
| | - Xiaodan Zheng
- School of Pharmacy, Jiangsu University, Zhenjiang 212000, China
| | - Rujia Li
- School of Pharmacy, Jiangsu University, Zhenjiang 212000, China
| | - Huan Luo
- School of Pharmacy, Jiangsu University, Zhenjiang 212000, China
| | - Xueyong Qi
- School of Pharmacy, Jiangsu University, Zhenjiang 212000, China
| | - Song Shen
- School of Pharmacy, Jiangsu University, Zhenjiang 212000, China
| | - Jin Cao
- School of Pharmacy, Jiangsu University, Zhenjiang 212000, China.
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5
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Wu F, Zhan Y, Wang S, Wang X, Hui M, Zhang J, Zhang J, Yang H, Lei Y, Yu S. VSV-CHIKV activates antitumor immunity by inducing pyroptosis in a melanoma model. Discov Oncol 2025; 16:943. [PMID: 40439822 PMCID: PMC12122967 DOI: 10.1007/s12672-025-02788-6] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Accepted: 05/22/2025] [Indexed: 06/02/2025] Open
Abstract
Melanoma is the most dangerous skin cancer due to its difficulty in treatment, high recurrence rate and metastatic ability. As a vector for oncolytic viruses (OVs), vesicular stomatitis virus (VSV) has been shown to be effective against malignant melanoma. However, the glycoprotein G protein of VSV has potential neurotoxicity. It has been shown that replacing glycoprotein G with E3-E2-6K-E1 of chikungunya virus (CHIKV) reduces its neurotoxicity and targets gliomas. Therefore, the aim of this study was to investigate the oncolytic effect of recombinant VSV-CHIKV on melanoma and the underlying mechanism. In this study, we found that recombinant VSV-CHIKV triggered GSDMD-mediated melanoma cell pyroptosis. Importantly, the NLRP3/Caspase-1/GSDMD axis was activated after VSV-CHIKV infection in melanoma cell lines and in a xenograft mouse model. Inhibition of GSDMD blocked cell pyroptosis, antitumor immunity and the tumor response in response to VSV-CHIKV treatment, suggesting that VSV-CHIKV act through the GSDMD pathway. VSV-CHIKV-triggered GSDMD-mediated tumor pyroptosis recruited cytotoxic T lymphocytes (CTLs) into the tumor microenvironment, which was accompanied by the release of inflammatory mediators. This remodeled the tumor microenvironment and turned immunologically "cold" tumors into "hot" tumors, thereby sensitized these tumors to checkpoint blockade. Finally, the combination therapy of VSV-CHIKV and an immune checkpoint inhibitor (anti-PD-1) prolonged the survival of mice. In conclusion, the VSV-CHIKV strategy is an attractive biologic therapy against melanoma.
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Affiliation(s)
- Fan Wu
- College of Life Sciences, Northwest University, Xi'an, Shannxi, China
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Ying Zhan
- College of Life Sciences, Northwest University, Xi'an, Shannxi, China
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Siyu Wang
- School of Stomatology, Guizhou Medical University, Guiyang, 561113, Guizhou, China
| | - Xiaoke Wang
- College of Life Sciences, Northwest University, Xi'an, Shannxi, China
- Department of Microbiology, School of Preclinical Medicine, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Min Hui
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, China
- College of Medicine, Northwest University, Xi'an, Shannxi, China
| | - Jian Zhang
- Department of Microbiology, School of Preclinical Medicine, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Jing Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Hongxu Yang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yingfeng Lei
- Department of Microbiology, School of Preclinical Medicine, The Fourth Military Medical University, Xi'an, Shaanxi, China.
| | - Shibin Yu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Oral Anatomy and Physiology, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, China.
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6
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Huang W, Pan Y, Zhong T, He S, Qi Y, Huang Y. Near-infrared 10B-BODIPY for precise guidance of tracer imaging and treatment in boron neutron capture therapy. Chem Commun (Camb) 2025. [PMID: 40401390 DOI: 10.1039/d5cc01671a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2025]
Abstract
A new near-infrared fluorescence probe (PBA-BDP) was developed by coupling boron-10 (10B) to a phenylboronic acid (PBA)-functionalized BODIPY dye. This multifunctional probe not only delivers 10B for boron neutron capture therapy (BNCT) but also enhances tumor-specific targeting and provides dynamic insight into boron distribution during treatment.
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Affiliation(s)
- Wenyong Huang
- Faculty of Chemistry, Northeast Normal University, Changchun 130024, P. R. China
| | - Yong Pan
- Faculty of Chemistry, Northeast Normal University, Changchun 130024, P. R. China
| | - Tianyuan Zhong
- Faculty of Chemistry, Northeast Normal University, Changchun 130024, P. R. China
| | - Shasha He
- State Key Laboratory of Physical Chemistry of Solid Surfaces, College of Chemistry and Chemical Engineering, Innovation Laboratory for Sciences and Technologies of Energy Materials of Fujian Province (IKKEM), Xiamen University, Xiamen 361005, China
| | - Yanxin Qi
- Faculty of Chemistry, Northeast Normal University, Changchun 130024, P. R. China
| | - Yubin Huang
- Faculty of Chemistry, Northeast Normal University, Changchun 130024, P. R. China
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7
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Joo H, Olea XD, Zhuang A, Zheng B, Kim H, Ronai ZA. Epigenetic mechanisms in melanoma development and progression. Trends Cancer 2025:S2405-8033(25)00099-8. [PMID: 40328568 DOI: 10.1016/j.trecan.2025.04.007] [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: 02/24/2025] [Revised: 04/08/2025] [Accepted: 04/08/2025] [Indexed: 05/08/2025]
Abstract
Knowledge of cancer development and progression gained over the last few decades has enabled mapping of genetic and epigenetic changes unique to different phases of tumor evolution. Here we focus on epigenetic changes that drive melanoma development and progression. We highlight the importance of epigenetic mechanisms which encompass crosstalk with melanoma microenvironment that affect metastasis and therapy resistance. This review summarizes recent advances and describes potential strategies to leverage this knowledge to devise new therapies.
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Affiliation(s)
- Hyunjeong Joo
- Jim and Eleanor Randall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Ximena Diaz Olea
- Jim and Eleanor Randall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Aojia Zhuang
- Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Bin Zheng
- Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Hyungsoo Kim
- Jim and Eleanor Randall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Ze'ev A Ronai
- Jim and Eleanor Randall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Translational Research Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.
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8
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Chen J, Xu M, Wu F, Wu N, Li J, Xie Y, Wang R, Xi N, Zhu Y, Xu X, Liu Y. CRKL silencing inhibits melanoma growth and enhances its chemotherapy sensitivity through the PI3K/AKT and NLRP3/GSDMD pathways. Biochem Pharmacol 2025; 235:116840. [PMID: 40024349 DOI: 10.1016/j.bcp.2025.116840] [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: 01/27/2025] [Accepted: 02/27/2025] [Indexed: 03/04/2025]
Abstract
Great advances have been made in malignant melanoma treatments, whereas drug resistance still limits many drug applications. CRKL has been reported to be overexpressed in various tumors and showed poor prognosis. However, its specific function and mechanism in melanoma remain unclear. In the present study, we investigated the expression of CRKL and its clinical association by bioinformatics and clinical analysis, and then performed a series of in vitro and in vivo experiments to demonstrate its function and mechanism. Results showed that CRKL increased during melanoma progression and was strongly associated with poor prognosis. CRKL silencing effectively inhibited melanoma cell growth and invasion via ERK/MMP9 and PI3K/AKT signaling pathways both in vitro and in vivo. Moreover, CRKL silencing induced pyroptosis in melanoma cells by upregulating the levels of pyroptosis-associated proteins, such as NLRP3, cleaved Caspase-1, and GSDMD-N. Importantly, our study demonstrated that interfering with CRKL expression enhanced the chemotherapy sensitivity of melanoma cells to cisplatin by regulating PI3K/AKT and NLRP3/GSDMD signaling pathways. In conclusion, our study uncovers a novel molecular mechanism by which CRKL functions in melanoma and highlights potential therapeutic strategies for improving chemotherapy sensitivity in melanoma patients.
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Affiliation(s)
- Jiashe Chen
- Department of Pathology, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200443, China
| | - Mingyuan Xu
- Department of Pathology, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200443, China
| | - Fei Wu
- Department of Pathology, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200443, China
| | - Nanhui Wu
- Department of Pathology, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200443, China
| | - Jie Li
- Department of Pathology, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200443, China
| | - Yongyi Xie
- Department of Pathology, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200443, China
| | - Ruoqi Wang
- Department of Pathology, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200443, China
| | - Ningyuan Xi
- Department of Pathology, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200443, China
| | - Yueyi Zhu
- Department of Pathology, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200443, China
| | - Xiaoxiang Xu
- Department of Pathology, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200443, China.
| | - Yeqiang Liu
- Department of Pathology, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200443, China.
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9
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Zhang ZL, Xu HN, Gong CM, Li YZ, Song XM, Li YM, Zhang DD, Wang R. Microorganism-Derived Bisindole Alkaloids With Anticancer Potential and Their Mechanisms: A Comprehensive Review. Chem Biodivers 2025; 22:e202402398. [PMID: 39714457 DOI: 10.1002/cbdv.202402398] [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: 09/23/2024] [Revised: 12/12/2024] [Accepted: 12/20/2024] [Indexed: 12/24/2024]
Abstract
Bisindole alkaloids constitute a significant class of natural compounds distinguished by their characteristic bisindole structure and renowned for their anticancer properties. Over the last six decades, researchers have isolated 425 microorganism-derived bisindole alkaloids (MDBAs). Among them, 187 MDBAs have demonstrated anticancer properties against various in vitro cancer cell lines, primarily by impeding the cell cycle, restraining cell proliferation, and inducing apoptosis and autophagy. These effects are mediated by regulating key targets and signaling pathways such as hypoxia-inducible factor (HIF)-1, MAPK, and phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR. This review provides a comprehensive examination of the sources, chemical diversity, and anticancer properties of these compounds. Furthermore, it summarizes the structure-activity relationship (SAR), druggability, and the mechanisms underlying MDBAs' anticancer effects. Ultimately, this article aims to furnish a thorough overview of the advancements in the investigation of microorganism-derived bisindole alkaloids for their continued development and utilization.
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Affiliation(s)
- Zi-Long Zhang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China
- School of Pharmacy, Shaanxi Key Laboratory of Research and Application of "Taibai Qi Yao", Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, P. R. China
| | - Hao-Nan Xu
- School of Pharmacy, Shaanxi Key Laboratory of Research and Application of "Taibai Qi Yao", Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, P. R. China
| | - Chuan-Ming Gong
- School of Pharmacy, Shaanxi Key Laboratory of Research and Application of "Taibai Qi Yao", Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, P. R. China
| | - Yu-Ze Li
- School of Pharmacy, Shaanxi Key Laboratory of Research and Application of "Taibai Qi Yao", Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, P. R. China
| | - Xiao-Mei Song
- School of Pharmacy, Shaanxi Key Laboratory of Research and Application of "Taibai Qi Yao", Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, P. R. China
| | - Yi-Ming Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China
| | - Dong-Dong Zhang
- School of Pharmacy, Shaanxi Key Laboratory of Research and Application of "Taibai Qi Yao", Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, P. R. China
| | - Rui Wang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China
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10
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de Arruda JAA, Drumond VZ, Tenório JR, Abreu LG, Silva TA, Mesquita RA, de Andrade BAB. Oral Melanoma in Older Adults: Epidemiology, Molecular Landscape, and Treatment Strategies. Pigment Cell Melanoma Res 2025; 38:e70017. [PMID: 40229937 DOI: 10.1111/pcmr.70017] [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: 10/29/2024] [Revised: 02/28/2025] [Accepted: 04/02/2025] [Indexed: 04/16/2025]
Abstract
Oral melanoma is an aggressive neoplasm arising from melanocytes in the mucosal epithelium, accounting for 0.2%-0.8% of all melanomas. Unlike cutaneous melanoma, it is not associated with UV exposure, and its pathogenesis involves complex genetic and molecular alterations. This neoplasm predominantly affects older adults (≥ 60 years). Clinically, lesions often present as macular or nodular with an exophytic growth pattern, sometimes ulcerated, and exhibit varied pigmentation. Diagnosis is further complicated by non-pigmented (amelanotic) variants that can resemble other oral pigmentations. Wide surgical excision remains the mainstay treatment, often combined with chemotherapy; however, recurrence and distant metastasis remain high. While immunotherapy has shown promise in other melanoma subtypes, its efficacy in oral melanoma remains uncertain. Treatment in older adults is particularly challenging due to comorbidities and treatment-related morbidity. This review summarizes the epidemiology, clinical features, and current treatment strategies for oral melanoma in older adults. Key advances in the molecular mechanisms underlying this neoplasm are also outlined. As a strategic approach, integrating oral melanoma screening into routine geriatric dental care, supported by diagnostic algorithms, may improve early detection, prognosis, and survival outcomes in this vulnerable population.
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Affiliation(s)
- José Alcides Almeida de Arruda
- Department of Oral Diagnosis and Pathology, School of Dentistry, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Victor Zanetti Drumond
- Department of Oral Surgery, Pathology and Clinical Dentistry, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Jefferson R Tenório
- Department of Oral Diagnosis and Pathology, School of Dentistry, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Lucas Guimarães Abreu
- Department of Child and Adolescent Oral Health, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Tarcília Aparecida Silva
- Department of Oral Surgery, Pathology and Clinical Dentistry, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Ricardo Alves Mesquita
- Department of Oral Surgery, Pathology and Clinical Dentistry, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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11
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Yang J, Wang Z, Zhou H, Xiong Y, Li Y, Zheng YW, Liu L. Insights into human melanocyte development and characteristics through pluripotent stem cells combined with single-cell sequencing. iScience 2025; 28:112373. [DOI: 10.1016/j.isci.2025.112373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2025] Open
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12
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Zhou JJ, Feng YC, Zhao ML, Guo Q, Zhao XB. Nanotechnology-driven strategies in postoperative cancer treatment: innovations in drug delivery systems. Front Pharmacol 2025; 16:1586948. [PMID: 40371327 PMCID: PMC12075547 DOI: 10.3389/fphar.2025.1586948] [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: 03/03/2025] [Accepted: 04/23/2025] [Indexed: 05/16/2025] Open
Abstract
Cancer remains a global health challenge, and this challenge comes with a significant burden. Current treatment modalities, such as surgery, chemotherapy, and radiotherapy, have their limitations. The emergence of nanomedicines presents a new frontier in postoperative cancer treatment, offering potential to inhibit tumor recurrence and manage postoperative complications. This review deeply explores the application and potential of nanomedicines in the treatment of cancer after surgery. In particular, it focuses on local drug delivery systems (LDDS), which consist of in situ injection, implantation, and spraying. LDDS can provide targeted drug delivery and controlled release, which enhancing therapeutic efficacy. At the same time, it minimizes damage to healthy tissues and reduces systemic side effects. The nanostructures of these systems are unique. They facilitate the sustained release of drugs, prolong the effects of treatment, and decrease the frequency of dosing. This is especially beneficial in the postoperative period. Despite their potential, nanomedicines have limitations. These include high production costs, concerns regarding long-term toxicity, and complex regulatory approval processes. This paper aims to analyze several aspects. These include the advantages of nanomedicines, their drug delivery systems, how they combine with multiple treatment methods, and the associated challenges. Future research should focus on certain issues. These issues are stability, tumor specificity, and clinical translation. By addressing these, the delivery methods can be optimized and their therapeutic efficacy enhanced. With the advancements in materials science and biomedical engineering, the future design of LDDS is set to become more intelligent and personalized. It will cater to the diverse needs of clinical treatment and offer hope for better outcomes in cancer patients after surgery.
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Affiliation(s)
- Jun-Jie Zhou
- The Stomatological Hospital, Anyang Sixth People’s Hospital, Anyang, China
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13
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Chen Q, Feng G, Shen Y, Li X, Pei Q, Wang H, Tian L, Cao Y, Wu J, Yang H, Mu L. An Anionic Cathelicidin Exerts Antimelanoma Effects in Mice by Promoting Pyroptosis. J Med Chem 2025; 68:8618-8633. [PMID: 40207383 DOI: 10.1021/acs.jmedchem.5c00281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2025]
Abstract
While cationic antimicrobial peptides (AMPs) are extensively studied for antitumor effects, anionic AMPs remain underexplored. Notably, no amphibian-derived anionic cathelicidins with antitumor activity have been reported. This study identifies Boma-CATH, a novel anionic cathelicidin (net charge-3) from Bombina maxima skin, which suppresses melanoma growth in mice and triggers pyroptosis-like morphological changes in A375 cells via the NLRP3/Caspase-1/GSDMD pathway. Further investigation revealed that ROS played a crucial role in promoting pyroptosis, as NAC (ROS scavenger) and Ac-YVAD-cmk (Caspase-1 inhibitor) reversed cell death and reduced LDH/IL-1β release in vitro and in vivo. GSDMD knockdown further validated its role. Additionally, Boma-CATH inhibited A375 cell proliferation, migration, and invasion, demonstrating dual antitumor mechanisms: pyroptosis induction and metastasis suppression. Importantly, Boma-CATH caused no adverse effects in mice, highlighting its therapeutic safety. These findings position Boma-CATH as a promising melanoma treatment and expand the mechanistic understanding of anionic AMPs in oncology.
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Affiliation(s)
- Qian Chen
- School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Guizhu Feng
- School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Yan Shen
- School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Xiang Li
- School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Qiqi Pei
- School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Hanying Wang
- School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Li Tian
- School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Yuanyuan Cao
- School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Jing Wu
- School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Hailong Yang
- School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Lixian Mu
- School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
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14
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Zheng W, Ruan Z, Chen Y, Li X, Yao Z, Wei G. ZNF280A promotes malignant melanoma development through regulating cell proliferation, apoptosis, and cell cycle. Discov Oncol 2025; 16:563. [PMID: 40251414 PMCID: PMC12008104 DOI: 10.1007/s12672-025-02347-z] [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: 11/24/2024] [Accepted: 04/09/2025] [Indexed: 04/20/2025] Open
Abstract
Malignant melanoma (MM) is the most lethal skin cancer globally, with a high incidence of over 300,000 per year. Though constant efforts have been made to elucidate the mechanisms of MM, we are still away from a complete understanding. Recently, the essential role of zinc finger proteins in tumor development was covered, but none of these roles were explored in MM. Herein, we first identified a zinc finger protein ZNF280A that serves as the risk factor in MM prognosis and acted as a driver of MM development in vitro and in vivo. The level of ZNF280A was significantly higher in the 130 MM tissues than in 18 para-carcinoma tissues. Knockdown of ZNF280A contributed to the inhibition of cell proliferation, migration, and invasion in MM. Furthermore, the mechanism of increased apoptosis and stagnant cell cycle may be associated with p53 expression regulated by ZNF280A. In conclusion, our study first displayed that ZNF280A may promote the development of MM by regulating cell proliferation, migration, invasion, cell cycle, and apoptosis.
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Affiliation(s)
- Wenjun Zheng
- Department of Dermatology and Venerology, the First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong RD, Nanning, 530021, China
| | - Zhuren Ruan
- Department of Dermatology and Venerology, the First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong RD, Nanning, 530021, China
| | - Yuanyuan Chen
- Department of Dermatology and Venerology, the First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong RD, Nanning, 530021, China
| | - Xianghui Li
- Department of Dermatology and Venerology, the First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong RD, Nanning, 530021, China.
| | - Zhijian Yao
- Department of Dermatology and Venerology, the First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong RD, Nanning, 530021, China.
| | - Gao Wei
- Department of Dermatology and Venerology, the First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong RD, Nanning, 530021, China.
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15
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Tasdogan A, Sullivan RJ, Katalinic A, Lebbe C, Whitaker D, Puig S, van de Poll-Franse LV, Massi D, Schadendorf D. Cutaneous melanoma. Nat Rev Dis Primers 2025; 11:23. [PMID: 40180935 DOI: 10.1038/s41572-025-00603-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/25/2025] [Indexed: 04/05/2025]
Abstract
Cutaneous melanoma is a common cancer in Australia and New Zealand, Europe, and North America, and its incidence is still increasing in many regions. Ultraviolet (UV) radiation exposure (for example, through excessive sunlight exposure) remains the primary risk factor for melanoma; however, public awareness campaigns have led to a marked reduction in mortality. In addition to genetic damage from UV radiation, specific genetic alterations have been linked to melanoma. The stage of the tumour at the time of diagnosis is of greater importance for melanoma prognosis than in almost any other cancer. Context-dependent genetic mutations that attenuate tumour-suppressive mechanisms or activate growth-promoting signalling pathways are crucial factors in the development of cutaneous melanoma. In addition to external factors such as UV radiation, the tumour microenvironment can contribute to melanoma progression, invasion and metastasis. Cutaneous melanoma treatment has improved considerably over the past decade with the discovery and development of immune checkpoint inhibitors and therapy targeting BRAF and MEK. Over the next decade, several priorities are likely to influence melanoma research and management, including the continued advance of precision medicine methods to identify the most suitable patients for the most effective treatment, with the aim of improving clinical outcomes.
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Affiliation(s)
- Alpaslan Tasdogan
- Department of Dermatology, University Hospital Essen & German Cancer Consortium (DKTK), Partner Site Essen, Essen, Germany.
- National Center for Tumour diseases (NCT-West), Campus Essen & Research Alliance Ruhr, Research Center One Health, University Duisburg-Essen, Essen, Germany.
| | - Ryan J Sullivan
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Alexander Katalinic
- Institute for Social Medicine and Epidemiology, University of Lübeck, Lübeck, Germany
| | - Celeste Lebbe
- Université Paris Cite, AP-HP Dermato-oncology and CIC, Cancer institute APHP.nord Paris cité, INSERM U976, Saint Louis Hospital, Paris, France
| | - Dagmar Whitaker
- Melanoma Advisory Board South Africa, Cape Town, South Africa
| | - Susana Puig
- Dermatology Department, IDIBAPS, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain
- 8CIBERER, Instituto de Salud Carlos III, Barcelona, Spain
| | - Lonneke V van de Poll-Franse
- Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands
- Department of Medical and Clinical Psychology, CoRPS - Center of Research on Psychology in Somatic Diseases, Tilburg University, Tilburg, Netherlands
| | - Daniela Massi
- Section of Pathology, Department of Health Sciences, University of Florence, Florence, Italy
- Department of Molecular Pathobiology, New York University - College of Dentistry, New York, NY, USA
| | - Dirk Schadendorf
- Department of Dermatology, University Hospital Essen & German Cancer Consortium (DKTK), Partner Site Essen, Essen, Germany.
- National Center for Tumour diseases (NCT-West), Campus Essen & Research Alliance Ruhr, Research Center One Health, University Duisburg-Essen, Essen, Germany.
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16
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Liu Z, Tang Z, Yin Y, Wan M, Zhan J, Ren L. A Microneedle Patch Delivers Mitochondria- and Lysosomes- Dual Targeting Prodrug-Like Photosensitizers with Regulated Photoactivity for Precise Photodynamic Therapy. Adv Healthc Mater 2025; 14:e2403954. [PMID: 39967393 DOI: 10.1002/adhm.202403954] [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: 10/11/2024] [Revised: 01/09/2025] [Indexed: 02/20/2025]
Abstract
Antitumor photodynamic therapy (PDT) faces huge challenges as selectivity and phototoxic damage, requiring delivery photosensitizers (PSs) to specifically accumulate in tumors even in organelle, and avoid the phototoxic damage during delivery. Herein, a microneedle patch (AIE-mito-TPP@MN) containing mitochondria- and lysosomes- dual targeting prodrug-like PSs (AIE-mito-TPP/AlPcSNa4) that is self-assembled by mitochondria-targeted aggregation-induced-emission molecule (AIE-mito-TPP) and lysosome-targeted aluminum phthalocyanine tetrasulfonate (AlPcSNa4), is developed to achieve cancer-cell-organelle-specific targeting delivery for precise PDT with high selectivity and low phototoxic damage. AIE-mito-TPP/AlPcSNa4 displays prodrug-like activity via the regulated photoactivity to reduce the phototoxic damage caused by the "always on" PSs. Meanwhile, AIE-mito-TPP/AlPcSNa4@MN can insert into the epidermis to achieve rapid AIE-mito-TPP/AlPcSNa4 delivery in tumor lesion, and enhance selective accumulation in tumor cells. The higher lysosomal acidity in tumor cells facilitates AIE-mito-TPP/AlPcSNa4 disassembly and promotes targeting. Under light irradiation, AIE-mito-TPP/AlPcSNa4@MN impairs mitochondrial and lysosomal function to induce deeper tumor cells apoptosis at a low dose (≈6 µg), presenting greater therapeutic efficacy than AIE-mito-TPP@MN, AlPcSNa4@MN, or intravenous injection. Moreover, AIE-mito-TPP/AlPcSNa4@MN presents good biocompatibility as lower accumulation and targeting in normal cells, as well as the regulated photoactivity of prodrug-like PSs. Therefore, the dual organelle-targeting microneedle possesses great potential for precise PDT with high selectivity.
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Affiliation(s)
- Zheng Liu
- School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, Guangzhou, 510006, China
| | - Zhimin Tang
- School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, Guangzhou, 510006, China
| | - Ying Yin
- School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, Guangzhou, 510006, China
| | - Miaojian Wan
- Department of Dermatology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Jiezhao Zhan
- School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, Guangzhou, 510006, China
| | - Li Ren
- School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, Guangzhou, 510006, China
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17
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Jiang J, Hu J, Li M, Luo M, Dong B, Sitti M, Yan X. NIR-II Fluorescent Thermophoretic Nanomotors for Superficial Tumor Photothermal Therapy. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2025; 37:e2417440. [PMID: 39895191 PMCID: PMC11899490 DOI: 10.1002/adma.202417440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 12/27/2024] [Indexed: 02/04/2025]
Abstract
Peritumoral subcutaneous injection has been highly envisioned as an efficient yet low-risk administration of photothermal agents for superficial tumor photothermal therapy. However, obstructed by complex subcutaneous tissue, the delivery of injected photothermal agents to the specific tumor remains a critical issue. Herein, the study reports a polydopamine (PDA)-encapsulated spherical core/shell nanomotor with fluorescent indocyanine green (ICG) immobilized on its PDA shell. Upon the first near-infrared (NIR-I) irradiation, this motor can generate favorable photothermal heat, and meantime, emit a robust ICG fluorescence in the second near-infrared window (NIR-II). The heat turns the motor into an active photothermal agent able to perform thermophoretic propulsion along the irradiation direction in subcutaneous tissue, while the ICG fluorescence can direct the subcutaneous propulsion of motors toward specific tumor through real-time NIR-II imaging. These functions endow the motor with the ability of moving to tumor after being injected at peritumoral site, enabling an enhanced photothermal therapy (PTT). The results demonstrated herein suggest an integrated nanorobotic tool for the superficial PTT using peritumoral administration, highlighting an NIR-II imaging-directed subcutaneous propulsion.
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Affiliation(s)
- Jiwei Jiang
- Institute of Functional Nano & Soft Materials (FUNSOM)Jiangsu Key Laboratory for Carbon‐Based Functional Materials & DevicesSoochow UniversitySuzhou215123China
| | - Jing Hu
- State Key Laboratory of Vaccines for Infectious DiseasesCenter for Molecular Imaging and Translational MedicineXiang An Biomedicine LaboratorySchool of Public HealthXiamen UniversityXiamen361005China
| | - Mingtong Li
- Physical Intelligence DepartmentMax Planck Institute for Intelligent Systems70569StuttgartGermany
| | - Mingzhi Luo
- Changzhou Key Laboratory of Respiratory Medical EngineeringInstitute of Biomedical Engineering and Health SciencesSchool of Medical and Health EngineeringChangzhou UniversityChangzhouJiangsu213164China
| | - Bin Dong
- Institute of Functional Nano & Soft Materials (FUNSOM)Jiangsu Key Laboratory for Carbon‐Based Functional Materials & DevicesSoochow UniversitySuzhou215123China
| | - Metin Sitti
- Physical Intelligence DepartmentMax Planck Institute for Intelligent Systems70569StuttgartGermany
- School of Medicine and College of EngineeringKoç UniversityIstanbul34450Turkey
| | - Xiaohui Yan
- State Key Laboratory of Vaccines for Infectious DiseasesCenter for Molecular Imaging and Translational MedicineXiang An Biomedicine LaboratorySchool of Public HealthXiamen UniversityXiamen361005China
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18
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Yi H, Liang W, Yang S, Liu H, Deng J, Han S, Feng X, Cheng W, Chen Y, Hang J, Lu H, Ran R. Melanin deposition and key molecular features in Xenopus tropicalis oocytes. BMC Biol 2025; 23:62. [PMID: 40016733 PMCID: PMC11866844 DOI: 10.1186/s12915-025-02168-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 02/18/2025] [Indexed: 03/01/2025] Open
Abstract
BACKGROUND Melanin pigmentation in oocytes is a critical feature for both the esthetic and developmental aspects of oocytes, influencing their polarity and overall development. Despite substantial knowledge of melanogenesis in melanocytes and retinal pigment epithelium cells, the molecular mechanisms underlying oocyte melanogenesis remain largely unknown. RESULTS Here, we compare the oocytes of wild-type, tyr-/- and mitf-/- Xenopus tropicalis and found that mitf-/- oocytes exhibit normal melanin deposition at the animal pole, whereas tyr-/- oocytes show no melanin deposition at this site. Transmission electron microscopy confirmed that melanogenesis in mitf-/- oocytes proceeds normally, similar to wild-type oocytes. Transcriptomic analysis revealed that mitf-/- oocytes still express melanogenesis-related genes, enabling them to complete melanogenesis. Additionally, in Xenopus tropicalis oocytes, the expression of the MiT subfamily factor tfe3 is relatively high, while tfeb, mitf, and tfec levels are extremely low. The expression pattern of tfe3 is similar to that of tyr and other melanogenesis-related genes. Thus, melanogenesis in Xenopus tropicalis oocytes is independent of Mitf and may be regulated by other MiT subfamily factors such as Tfe3, which control the expression of genes like tyr, dct, and tyrp1. Furthermore, transcriptomic data revealed that changes in the expression of genes related to mitochondrial cloud formation represent the most significant molecular changes during oocyte development. CONCLUSIONS Overall, these findings suggest that further elucidation of Tyr-dependent and Mitf-independent mechanisms of melanin deposition at the animal pole will enhance our understanding of melanogenesis and Oogenesis.
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Affiliation(s)
- Hongyang Yi
- National Clinical Research Centre for Infectious Diseases, the Third People'S Hospital of Shenzhenand, the Second Affiliated Hospital of Southern University of Science and Technologyaq , Shenzhen, 518112, China
- Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Weizheng Liang
- Hebei Provincial Key Laboratory of Systems Biology and Gene Regulation, Central Laboratory, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, 075000, China
| | - Sumei Yang
- National Clinical Research Centre for Infectious Diseases, the Third People'S Hospital of Shenzhenand, the Second Affiliated Hospital of Southern University of Science and Technologyaq , Shenzhen, 518112, China
| | - Han Liu
- National Clinical Research Centre for Infectious Diseases, the Third People'S Hospital of Shenzhenand, the Second Affiliated Hospital of Southern University of Science and Technologyaq , Shenzhen, 518112, China
| | - Jiayu Deng
- National Clinical Research Centre for Infectious Diseases, the Third People'S Hospital of Shenzhenand, the Second Affiliated Hospital of Southern University of Science and Technologyaq , Shenzhen, 518112, China
| | - Shuhong Han
- National Clinical Research Centre for Infectious Diseases, the Third People'S Hospital of Shenzhenand, the Second Affiliated Hospital of Southern University of Science and Technologyaq , Shenzhen, 518112, China
| | - Xiaohui Feng
- Department of Obstetrics and Gynecology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, China
| | - Wenjie Cheng
- Department of Urology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, China
| | - Yonglong Chen
- Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China.
| | - Jing Hang
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
| | - Hongzhou Lu
- National Clinical Research Centre for Infectious Diseases, the Third People'S Hospital of Shenzhenand, the Second Affiliated Hospital of Southern University of Science and Technologyaq , Shenzhen, 518112, China.
| | - Rensen Ran
- Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China.
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
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19
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Lv R, Hang S, Zhao Y, Gao W, Zhang P, Zheng K, Zhang Q, Ding C. Reactive Oxygen Species (ROS)-Tyrosinase Cascade-Activated Near-Infrared Fluorescent Probe for the Precise Imaging of Melanoma. Anal Chem 2025; 97:4241-4250. [PMID: 39946555 DOI: 10.1021/acs.analchem.5c00018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/26/2025]
Abstract
As a highly aggressive malignancy, the issue of curing melanoma at an advanced stage could suffer from severe metastasis and a lower 5-year survival rate. Therefore, the early diagnosis of melanoma with high accuracy is vital and contributes to a significantly improved 5-year survival rate. This work reports a dual-locked receptor, m-BA-Hcy, which releases the near-infrared (NIR) fluorophore Hcy-OH upon the dual activation of reactive oxygen species (ROS) and tyrosinase (TYR). The substitution of boric acid on the phenyl ring was studied, which influences the feasibility of the performance of the envisaged cascade reaction. The sensing behavior was discussed in terms of optical spectroscopy and reaction mechanism, and imaging was fully performed at the cellular and organism levels. Receptor m-BA-Hcy was hence clarified to possess supreme sensitivity and accuracy for melanoma detection.
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Affiliation(s)
- Ruidian Lv
- Key Laboratory of Optic-electric Sensing and Analytical Chemistry for Life Science, MOE, Shandong Key Laboratory of Biochemical Analysis, Key Laboratory of Analytical Chemistry for Life Science in Universities of Shandong, College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao 266042, P. R. China
| | - Sitong Hang
- Key Laboratory of Optic-electric Sensing and Analytical Chemistry for Life Science, MOE, Shandong Key Laboratory of Biochemical Analysis, Key Laboratory of Analytical Chemistry for Life Science in Universities of Shandong, College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao 266042, P. R. China
| | - Yuran Zhao
- Key Laboratory of Optic-electric Sensing and Analytical Chemistry for Life Science, MOE, Shandong Key Laboratory of Biochemical Analysis, Key Laboratory of Analytical Chemistry for Life Science in Universities of Shandong, College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao 266042, P. R. China
| | - Weijie Gao
- Key Laboratory of Optic-electric Sensing and Analytical Chemistry for Life Science, MOE, Shandong Key Laboratory of Biochemical Analysis, Key Laboratory of Analytical Chemistry for Life Science in Universities of Shandong, College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao 266042, P. R. China
| | - Peng Zhang
- Key Laboratory of Optic-electric Sensing and Analytical Chemistry for Life Science, MOE, Shandong Key Laboratory of Biochemical Analysis, Key Laboratory of Analytical Chemistry for Life Science in Universities of Shandong, College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao 266042, P. R. China
| | - Ke Zheng
- Key Laboratory of Optic-electric Sensing and Analytical Chemistry for Life Science, MOE, Shandong Key Laboratory of Biochemical Analysis, Key Laboratory of Analytical Chemistry for Life Science in Universities of Shandong, College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao 266042, P. R. China
| | - Qian Zhang
- Key Laboratory of Optic-electric Sensing and Analytical Chemistry for Life Science, MOE, Shandong Key Laboratory of Biochemical Analysis, Key Laboratory of Analytical Chemistry for Life Science in Universities of Shandong, College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao 266042, P. R. China
| | - Caifeng Ding
- Key Laboratory of Optic-electric Sensing and Analytical Chemistry for Life Science, MOE, Shandong Key Laboratory of Biochemical Analysis, Key Laboratory of Analytical Chemistry for Life Science in Universities of Shandong, College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, Qingdao 266042, P. R. China
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Li J, Jiang L, Ma Q, Zhang Z, Zheng S, Qiu J, Pang Y, Wang J. Evodiamine inhibits programmed cell death ligand 1 expression via the PI3K/AKT signaling pathway to regulate antitumor immunity in melanoma. Sci Rep 2025; 15:6649. [PMID: 39994441 PMCID: PMC11850830 DOI: 10.1038/s41598-025-91137-2] [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: 11/01/2024] [Accepted: 02/18/2025] [Indexed: 02/26/2025] Open
Abstract
Malignant melanoma, a rare and aggressive skin cancer, arises from the transformation of cutaneous melanocytes and is associated with a poor prognosis. Evodiamine (EVO), a bioactive compound derived from traditional Chinese herbal medicine, has demonstrated significant inhibitory effects on various tumor cells. In this study, we aimed to investigate the potential of EVO in regulating melanoma immunity and elucidate its underlying mechanisms. Experimental results revealed that the IC50 value of EVO in B16-F10 cells for 24, 48, and 72 h were 11.73, 5.083, and 4.604 µM, respectively. EVO inhibited the proliferation, invasion, and metastasis of B16-F10 cells by more than 50%, while promoting apoptosis of higher concentration of EVO. EVO also significantly suppressed tumor growth by more than 80% and reduced spleen damage in tumor-bearing mice. Treatment with EVO led to a marked increase in T-cell subsets in the spleen, bone marrow, and tumors, with immunohistochemical (IHC) staining in particular showing about 50% higher. Furthermore, EVO inhibited the expression of programmed cell death ligand 1 (PD-L1) and the PI3K/AKT signaling pathway-related proteins in both B16-F10 cells and tumors. These findings suggest that EVO exerts antitumor effects by enhancing the tumor immune microenvironment and indicates its potential as a therapeutic agent for melanoma.
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Affiliation(s)
- Jiamin Li
- Department of Periodontology, School/Hospital of Stomatology, Lanzhou University, 199 Donggang Western Rd, Lanzhou, 730000, Gansu, People's Republic of China
- Clinical Research Center for Oral Diseases, Lanzhou, 730000, Gansu, People's Republic of China
| | - Li Jiang
- Department of Periodontology, School/Hospital of Stomatology, Lanzhou University, 199 Donggang Western Rd, Lanzhou, 730000, Gansu, People's Republic of China
- Clinical Research Center for Oral Diseases, Lanzhou, 730000, Gansu, People's Republic of China
| | - Qianlong Ma
- Department of Periodontology, School/Hospital of Stomatology, Lanzhou University, 199 Donggang Western Rd, Lanzhou, 730000, Gansu, People's Republic of China
- Clinical Research Center for Oral Diseases, Lanzhou, 730000, Gansu, People's Republic of China
| | - Zhenglong Zhang
- Department of Periodontology, School/Hospital of Stomatology, Lanzhou University, 199 Donggang Western Rd, Lanzhou, 730000, Gansu, People's Republic of China
- Clinical Research Center for Oral Diseases, Lanzhou, 730000, Gansu, People's Republic of China
| | - Shengping Zheng
- Department of Periodontology, School/Hospital of Stomatology, Lanzhou University, 199 Donggang Western Rd, Lanzhou, 730000, Gansu, People's Republic of China
- Clinical Research Center for Oral Diseases, Lanzhou, 730000, Gansu, People's Republic of China
| | - Jing Qiu
- Department of Periodontology, School/Hospital of Stomatology, Lanzhou University, 199 Donggang Western Rd, Lanzhou, 730000, Gansu, People's Republic of China
- Clinical Research Center for Oral Diseases, Lanzhou, 730000, Gansu, People's Republic of China
| | - Yunqing Pang
- Department of Periodontology, School/Hospital of Stomatology, Lanzhou University, 199 Donggang Western Rd, Lanzhou, 730000, Gansu, People's Republic of China.
- Clinical Research Center for Oral Diseases, Lanzhou, 730000, Gansu, People's Republic of China.
| | - Jing Wang
- Department of Periodontology, School/Hospital of Stomatology, Lanzhou University, 199 Donggang Western Rd, Lanzhou, 730000, Gansu, People's Republic of China.
- Clinical Research Center for Oral Diseases, Lanzhou, 730000, Gansu, People's Republic of China.
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21
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Sánchez-Beltrán J, Soler Díaz J, Herraiz C, Olivares C, Cerdido S, Cerezuela-Fuentes P, García-Borrón JC, Jiménez-Cervantes C. An MGRN1-Based Biomarker Combination Accurately Predicts Melanoma Patient Survival. Int J Mol Sci 2025; 26:1739. [PMID: 40004203 PMCID: PMC11855888 DOI: 10.3390/ijms26041739] [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: 01/15/2025] [Revised: 02/14/2025] [Accepted: 02/16/2025] [Indexed: 02/27/2025] Open
Abstract
With ever-increasing incidence and high metastatic potential, cutaneous melanoma is the deadliest skin cancer. Risk prediction based on the Tumor-Node-Metastasis (TNM) staging system has medium accuracy with intermediate IIB-IIIB stages, as roughly 25% of patients with low-medium-grade TNM, and hence a favorable prognostic, undergo an aggressive disease with short survival and around 15% of deaths arise from metastases of thin, low-risk lesions. Therefore, reliable prognostic biomarkers are required. We used genomic and clinical information of melanoma patients from the TCGA-SKCM cohort and two GEO studies for discovery and validation of potential biomarkers, respectively. Neither mutation nor overexpression of major melanoma driver genes provided significant prognostic information. Conversely, expression of MGRN1 and the melanocyte-specific genes MLANA, PMEL, and TYRP1 provided a simple 4-gene signature identifying with high-sensitivity (>80%), low-medium TNM patients with adverse outcomes. Transcriptomic analysis of tumors with this signature, or from low-medium-grade TNM patients with poor outcomes, revealed comparable dysregulation of an inflammatory response, cell cycle progression, and DNA damage/repair programs. A functional analysis of MGRN1-knockout cells confirmed these molecular features. Therefore, the simple MGRN1-MLANA-PMEL-TYRP1 combination of biomarkers complemented TNM staging prognostic accuracy and pointed to the dysregulation of immunological responses and genomic stability as determinants of a melanoma outcome.
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Affiliation(s)
- José Sánchez-Beltrán
- Department of Biochemistry, Molecular Biology and Immunology, School of Medicine, Campus de Excelencia Internacional Regional (CEIR), Campus Mare Nostrum (CMN), University of Murcia, 30120 Murcia, Spain; (J.S.-B.); (J.S.D.); (C.H.); (C.O.); (S.C.); (J.C.G.-B.)
- Biomedical Research Institute of Murcia (Instituto Murciano de Investigación Biosanitaria, IMIB), 30120 Murcia, Spain;
| | - Javier Soler Díaz
- Department of Biochemistry, Molecular Biology and Immunology, School of Medicine, Campus de Excelencia Internacional Regional (CEIR), Campus Mare Nostrum (CMN), University of Murcia, 30120 Murcia, Spain; (J.S.-B.); (J.S.D.); (C.H.); (C.O.); (S.C.); (J.C.G.-B.)
| | - Cecilia Herraiz
- Department of Biochemistry, Molecular Biology and Immunology, School of Medicine, Campus de Excelencia Internacional Regional (CEIR), Campus Mare Nostrum (CMN), University of Murcia, 30120 Murcia, Spain; (J.S.-B.); (J.S.D.); (C.H.); (C.O.); (S.C.); (J.C.G.-B.)
- Biomedical Research Institute of Murcia (Instituto Murciano de Investigación Biosanitaria, IMIB), 30120 Murcia, Spain;
| | - Conchi Olivares
- Department of Biochemistry, Molecular Biology and Immunology, School of Medicine, Campus de Excelencia Internacional Regional (CEIR), Campus Mare Nostrum (CMN), University of Murcia, 30120 Murcia, Spain; (J.S.-B.); (J.S.D.); (C.H.); (C.O.); (S.C.); (J.C.G.-B.)
- Biomedical Research Institute of Murcia (Instituto Murciano de Investigación Biosanitaria, IMIB), 30120 Murcia, Spain;
| | - Sonia Cerdido
- Department of Biochemistry, Molecular Biology and Immunology, School of Medicine, Campus de Excelencia Internacional Regional (CEIR), Campus Mare Nostrum (CMN), University of Murcia, 30120 Murcia, Spain; (J.S.-B.); (J.S.D.); (C.H.); (C.O.); (S.C.); (J.C.G.-B.)
- Biomedical Research Institute of Murcia (Instituto Murciano de Investigación Biosanitaria, IMIB), 30120 Murcia, Spain;
| | - Pablo Cerezuela-Fuentes
- Biomedical Research Institute of Murcia (Instituto Murciano de Investigación Biosanitaria, IMIB), 30120 Murcia, Spain;
- Medical Oncology Department, Hospital Clínico Universitario Virgen de La Arrixaca, 30120 Murcia, Spain
| | - José Carlos García-Borrón
- Department of Biochemistry, Molecular Biology and Immunology, School of Medicine, Campus de Excelencia Internacional Regional (CEIR), Campus Mare Nostrum (CMN), University of Murcia, 30120 Murcia, Spain; (J.S.-B.); (J.S.D.); (C.H.); (C.O.); (S.C.); (J.C.G.-B.)
- Biomedical Research Institute of Murcia (Instituto Murciano de Investigación Biosanitaria, IMIB), 30120 Murcia, Spain;
| | - Celia Jiménez-Cervantes
- Department of Biochemistry, Molecular Biology and Immunology, School of Medicine, Campus de Excelencia Internacional Regional (CEIR), Campus Mare Nostrum (CMN), University of Murcia, 30120 Murcia, Spain; (J.S.-B.); (J.S.D.); (C.H.); (C.O.); (S.C.); (J.C.G.-B.)
- Biomedical Research Institute of Murcia (Instituto Murciano de Investigación Biosanitaria, IMIB), 30120 Murcia, Spain;
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22
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Todorovic N, Djurkovic P, Krstic A, Tomanovic N, Milanovic P, Kablar D, Rajkovic Pavlovic Z, Stevanovic M, Milanovic J, Arnaut A, Ljubisavljevic I, Selakovic D, Rosic G, Vasiljevic M. Primary Sinonasal Mucosal Melanoma: A Narrative Review. Diagnostics (Basel) 2025; 15:496. [PMID: 40002647 PMCID: PMC11854324 DOI: 10.3390/diagnostics15040496] [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: 12/05/2024] [Revised: 02/05/2025] [Accepted: 02/13/2025] [Indexed: 02/27/2025] Open
Abstract
Mucosal melanomas (MMs) are under-researched tumors with a poor prognosis that arise from melanocytes found in the mucous membranes at different anatomical locations throughout the body. MMs are an uncommon yet highly aggressive tumor that typically develops on mucosal surfaces, predominantly in the head and neck region. MM of the head and neck occurs in 8-10% of all head and neck melanomas. It most commonly affects the mucosa of the nasal cavity and paranasal sinuses (75%), followed by the oral cavity mucosa (25%). A family history and the presence of mucosal nevi are associated with the occurrence of MM. Inhaled and dietary carcinogens are also linked to the development of sinonasal melanoma, much like other malignancies of the nasal cavity. Overexpression of the C-KIT gene is found in more than 80% of all primary mucosal melanomas, with somatic mutations in 10-30% of cases. The presence of these genetic alterations is also reflected in recent clinical studies of specific gene inhibitors that have proven efficiency in the systemic therapy of melanoma. There are various treatment modalities for MM. Surgical therapy involves en bloc surgical resection with a macroscopically visible and palpable mucosal margin of 1.5-2 cm. Partial resection of the maxilla may be considered if it ensures adequate tumor-free margine. Because of its rarity, outcome data for locally advanced head and neck MM is limited and primarily derived from retrospective studies with small case numbers. This review aims to update and summarize findings from clinical trials, prospective observational studies, and retrospective studies, while also exploring future directions for multimodal treatment approaches in this area.
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Affiliation(s)
- Nikola Todorovic
- Clinic for Otorhinolaryngology and Maxillofacial Surgery, University Clinical Center of Serbia, 2 Pasterova Street, 11000 Belgrade, Serbia; (N.T.); (P.D.); (A.K.)
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Petar Djurkovic
- Clinic for Otorhinolaryngology and Maxillofacial Surgery, University Clinical Center of Serbia, 2 Pasterova Street, 11000 Belgrade, Serbia; (N.T.); (P.D.); (A.K.)
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Aleksandar Krstic
- Clinic for Otorhinolaryngology and Maxillofacial Surgery, University Clinical Center of Serbia, 2 Pasterova Street, 11000 Belgrade, Serbia; (N.T.); (P.D.); (A.K.)
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Nada Tomanovic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
- Institute of Pathology, 1 Dr. Subotica Street, 11000 Belgrade, Serbia
| | - Pavle Milanovic
- Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia; (P.M.); (Z.R.P.); (M.S.); (J.M.); (A.A.); (I.L.)
| | - Djurdjina Kablar
- Department for Pathology, Pathohistology and Medical Cytology, University Clinical Centre of Serbia, 11000 Belgrade, Serbia;
| | - Zlata Rajkovic Pavlovic
- Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia; (P.M.); (Z.R.P.); (M.S.); (J.M.); (A.A.); (I.L.)
| | - Momir Stevanovic
- Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia; (P.M.); (Z.R.P.); (M.S.); (J.M.); (A.A.); (I.L.)
| | - Jovana Milanovic
- Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia; (P.M.); (Z.R.P.); (M.S.); (J.M.); (A.A.); (I.L.)
| | - Aleksandra Arnaut
- Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia; (P.M.); (Z.R.P.); (M.S.); (J.M.); (A.A.); (I.L.)
| | - Ivan Ljubisavljevic
- Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia; (P.M.); (Z.R.P.); (M.S.); (J.M.); (A.A.); (I.L.)
| | - Dragica Selakovic
- Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia; (D.S.); (G.R.)
| | - Gvozden Rosic
- Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia; (D.S.); (G.R.)
| | - Milica Vasiljevic
- Department of Dentistry, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia; (P.M.); (Z.R.P.); (M.S.); (J.M.); (A.A.); (I.L.)
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23
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Ford CA, Koludrovic D, Centeno PP, Foth M, Tsonou E, Vlahov N, Sphyris N, Gilroy K, Bull C, Nixon C, Serrels B, Munro AF, Dawson JC, Carragher NO, Pavet V, Hornigold DC, Dunne PD, Downward J, Welch HC, Barry ST, Sansom OJ, Campbell AD. Targeting the PREX2/RAC1/PI3Kβ Signaling Axis Confers Sensitivity to Clinically Relevant Therapeutic Approaches in Melanoma. Cancer Res 2025; 85:808-824. [PMID: 39636745 PMCID: PMC11831108 DOI: 10.1158/0008-5472.can-23-2814] [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: 09/14/2023] [Revised: 10/04/2024] [Accepted: 11/27/2024] [Indexed: 12/07/2024]
Abstract
Metastatic melanoma remains a major clinical challenge. Large-scale genomic sequencing of melanoma has identified bona fide activating mutations in RAC1, which are associated with resistance to BRAF-targeting therapies. Targeting the RAC1-GTPase pathway, including the upstream activator PREX2 and the downstream effector PI3Kβ, could be a potential strategy for overcoming therapeutic resistance, limiting melanoma recurrence, and suppressing metastatic progression. Here, we used genetically engineered mouse models and patient-derived BRAFV600E-driven melanoma cell lines to dissect the role of PREX2 in melanomagenesis and response to therapy. Although PREX2 was dispensable for the initiation and progression of melanoma, its loss conferred sensitivity to clinically relevant therapeutics targeting the MAPK pathway. Importantly, genetic and pharmacologic targeting of PI3Kβ phenocopied PREX2 deficiency, sensitizing model systems to therapy. These data reveal a druggable PREX2/RAC1/PI3Kβ signaling axis in BRAF-mutant melanoma that could be exploited clinically. Significance: Cotargeting the MAPK and the PREX2/RAC1/PI3Kβ pathways has remarkable efficacy and outperforms monotherapy MAPK inhibition in BRAF-mutant melanoma, supporting the potential of this combination therapy for treating metastatic melanoma.
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Affiliation(s)
| | - Dana Koludrovic
- Cancer Research UK Scotland Institute, Glasgow, United Kingdom
| | | | - Mona Foth
- Cancer Research UK Scotland Institute, Glasgow, United Kingdom
- Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, Utah
| | - Elpida Tsonou
- Signalling Programme, Babraham Institute, Cambridge, United Kingdom
- Biopharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
| | - Nikola Vlahov
- Cancer Research UK Scotland Institute, Glasgow, United Kingdom
| | | | - Kathryn Gilroy
- Cancer Research UK Scotland Institute, Glasgow, United Kingdom
| | - Courtney Bull
- The Patrick G. Johnston Centre for Cancer Research, Queen’s University, Belfast, United Kingdom
| | - Colin Nixon
- Cancer Research UK Scotland Institute, Glasgow, United Kingdom
| | - Bryan Serrels
- Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - Alison F. Munro
- Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - John C. Dawson
- Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - Neil O. Carragher
- Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - Valeria Pavet
- Cancer Research UK Scotland Institute, Glasgow, United Kingdom
| | | | - Philip D. Dunne
- Cancer Research UK Scotland Institute, Glasgow, United Kingdom
- The Patrick G. Johnston Centre for Cancer Research, Queen’s University, Belfast, United Kingdom
| | - Julian Downward
- Oncogene Biology Laboratory, The Francis Crick Institute, London, United Kingdom
| | - Heidi C.E. Welch
- Signalling Programme, Babraham Institute, Cambridge, United Kingdom
| | - Simon T. Barry
- Bioscience, Early Oncology, AstraZeneca, Cambridge, United Kingdom
| | - Owen J. Sansom
- Cancer Research UK Scotland Institute, Glasgow, United Kingdom
- School of Cancer Sciences, University of Glasgow, United Kingdom
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24
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Morozova V, Pellegata D, Charles RP, Gertsch J. Carboxylesterase 1-mediated endocannabinoid metabolism in skin: role in melanoma progression in BRaf V600E/Pten -/- mice. Cancer Metab 2025; 13:8. [PMID: 39934865 DOI: 10.1186/s40170-025-00378-2] [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: 10/22/2024] [Accepted: 02/03/2025] [Indexed: 02/13/2025] Open
Abstract
BACKGROUND Melanoma is a highly aggressive skin cancer with a poor prognosis. The endocannabinoids 2-arachidonoylgylcerol (2-AG) and anandamide have been linked to melanoma progression, though their roles remain unclear. We hypothesized that the 2-AG-arachidonate-prostaglandin axis could drive aggressive melanoma progression. METHODS The genetically engineered melanoma mouse model B6-Tyr::CreERT2; BRafCA; PtenloxP was characterized by targeted metabolomics. Functionally expressed serine hydrolases in the tumor tissue were identified by chemoproteomics. Pharmacological inhibition of carboxylesterase 1 (CES1) was achieved through chronic in vivo i.p. treatment with JZL184 (10 mg/kg daily), confirmed by activity-based protein profiling (ABPP) and targeted lipidomics. CES1-mediated 2-AG hydrolysis was further confirmed in radiotracer-based assays using CES1-transfected cell lines. RESULTS The diacylglycerol and protein kinase C activator 1-stearoyl-2-arachidonoyl-sn-glycerol (SAG) was significantly elevated in the nodular-like melanoma tissues, along with 2-AG and arachidonic acid (ARA), compared to normal skin. AEA and other N-acylethanolamines were decreased, while, notably, prostaglandin levels remained unchanged. Significant changes in the levels of neuromodulators and neurotransmitters, including serotonin and adenosine, were observed. Pronounced differences between serine hydrolase activity in normal skin and melanoma tissue were identified by ABPP. Intriguingly, CES1 was identified as the only 2-AG-hydrolyzing enzyme in this melanoma tissue, as MAGL and ABHD6/12 were not expressed. The MAGL inhibitor JZL184 also efficiently inhibited CES1 in vitro and in vivo, increasing glycerol esters and reducing tumor progression. Additionally, scRNA-seq data from previous studies revealed divergent MAGL/CES1 expression patterns across different human melanoma subtypes. CONCLUSIONS A role of CES1 expression in skin is demonstrated for the first time. Our study suggests that 2-AG degradation to arachidonate favors melanoma progression, either reflecting the carcinogenic role of ARA or that monoacylglycerols like 2-AG and/or other CES1 substrates may exert antitumor effects, indicating that CES1 could be a potential therapeutic target. CES1 expression and high SAG, 2-AG, and ARA levels may be a signature of specific BRAF-driven malignant melanoma subtypes which are associated with discrete metabolic adaptations.
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Affiliation(s)
- Veronika Morozova
- Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, CH-3012, Switzerland
| | - Daniele Pellegata
- Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, CH-3012, Switzerland
| | - Roch-Philippe Charles
- Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, CH-3012, Switzerland
| | - Jürg Gertsch
- Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, CH-3012, Switzerland.
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25
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Tandukar B, Deivendran D, Chen L, Bahrani N, Weier B, Sharma H, Cruz-Pacheco N, Hu M, Marks K, Zitnay RG, Bandari AK, Nekoonam R, Yeh I, Judson-Torres R, Shain AH. Somatic mutations distinguish melanocyte subpopulations in human skin. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.07.637114. [PMID: 39975212 PMCID: PMC11839034 DOI: 10.1101/2025.02.07.637114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
To better understand the homeostatic mechanisms governing melanocytes, we performed deep phenotyping of clonal expansions of single melanocytes from human skin. In total, we interrogated the mutational landscapes, gene expression profiles, and morphological features of 297 melanocytes from 31 donors. To our surprise, a population of melanocytes with low mutation burden was maintained in sun damaged skin. These melanocytes were more stem-like, smaller, less dendritic and displayed distinct gene expression profiles compared to their counterparts with high mutation burdens. We used single-cell spatial transcriptomics (10X Xenium) to reveal the spatial distribution of melanocytes inferred to have low and high mutation burdens (LowMut and HighMut cells), based on their gene expression profiles. LowMut melanocytes were found in hair follicles as well as in the interfollicular epidermis, whereas HighMut melanocytes resided almost exclusively in the interfollicular epidermis. We propose that melanocytes in the hair follicle occupy a privileged niche, protected from UV radiation, but periodically migrate out of the hair follicle to replenish the interfollicular epidermis after waves of photodamage. More broadly, our study illustrates the advantages of a cell atlas that includes mutational information, as cells can change their cellular states and positional coordinates over time, but mutations are like scars, providing a historical record of the homeostatic processes that were operative on each cell.
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Affiliation(s)
- Bishal Tandukar
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
| | - Delahny Deivendran
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
| | - Limin Chen
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
| | - Neda Bahrani
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
- University of California Berkeley, Berkeley, CA, USA
| | - Beatrice Weier
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
- California Health Sciences University - College of Osteopathic Medicine (CHSU-COM), Clovis, CA, USA
| | - Harsh Sharma
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
| | - Noel Cruz-Pacheco
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
| | - Min Hu
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
- Department of Oncological Sciences, University of Utah, Salt Lake City, UT, USA
- Department of Dermatology, University of Utah, Salt Lake City, UT, USA
| | - Kayla Marks
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
| | - Rebecca G Zitnay
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA
| | - Aravind K. Bandari
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
| | - Rojina Nekoonam
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
| | - Iwei Yeh
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
- Department of Pathology, University of California, San Francisco, San Francisco, CA, USA
| | - Robert Judson-Torres
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
- Department of Oncological Sciences, University of Utah, Salt Lake City, UT, USA
- Department of Dermatology, University of Utah, Salt Lake City, UT, USA
| | - A. Hunter Shain
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
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26
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de Andrade CCN, de Oliveira Lopes AL, Sousa Duarte S, Assunção Araújo de Azevedo FDL, Araújo Loureiro PB, Wanderley Amorim GM, de Abreu Junior AR, Sobral da Silva M, Fechine Tavares J, Santos Golzio SD, Ramos Gonçalves JC, Vieira Sobral M. Potential In Vitro Antimelanoma Effect of the Essential Oil from Croton grewioides Baill. Chem Biodivers 2025; 22:e202401867. [PMID: 39375157 DOI: 10.1002/cbdv.202401867] [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: 07/31/2024] [Revised: 10/01/2024] [Accepted: 10/07/2024] [Indexed: 10/09/2024]
Abstract
Cancer is a group of diseases characterized by uncontrolled cell growth, invasive capacity, and metastatic potential. Despite the continual progress in cancer treatment, high toxicity and resistance to therapy remain recurring challenges. Croton grewioides Baill. is a plant from the brazilian semi-arid region with significant pharmacological potential due to its reported antidiarrheal, antioxidant, and antitumor properties. This study evaluated the antitumor activity of the essential oil from C. grewioides leaves (CgEO) by in vitro assays. CgEO showed higher cytotoxicity in human melanoma cells (SK-MEL-28), with a 50 % inhibitory concentration (IC50) of 70.0 μg/mL after 72 h, but with low toxicity in healthy keratinocytes (HaCaT). Additionally, it was suggested that the antitumor effect of CgEO is associated with the induction of apoptosis, cell cycle alterations, and combined antioxidant action mechanisms. In conclusion, CgEO exhibits antitumor activity with lower toxicity in non-tumor cells.
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Affiliation(s)
- Camyla Caroliny Neves de Andrade
- Post Graduation Program in Bioactive Natural and Synthetic Products, Federal University of Paraíba, CEP 58051-900, João Pessoa, PB, Brazil
| | - Ana Luiza de Oliveira Lopes
- Post Graduation Program in Bioactive Natural and Synthetic Products, Federal University of Paraíba, CEP 58051-900, João Pessoa, PB, Brazil
| | - Sâmia Sousa Duarte
- Post Graduation Program in Bioactive Natural and Synthetic Products, Federal University of Paraíba, CEP 58051-900, João Pessoa, PB, Brazil
| | | | - Paulo Bruno Araújo Loureiro
- Post Graduation Program in Bioactive Natural and Synthetic Products, Federal University of Paraíba, CEP 58051-900, João Pessoa, PB, Brazil
| | - Geraldo Moisés Wanderley Amorim
- Post Graduation Program in Bioactive Natural and Synthetic Products, Federal University of Paraíba, CEP 58051-900, João Pessoa, PB, Brazil
| | - Adegildo Rolim de Abreu Junior
- Post Graduation Program in Bioactive Natural and Synthetic Products, Federal University of Paraíba, CEP 58051-900, João Pessoa, PB, Brazil
| | - Marcelo Sobral da Silva
- Post Graduation Program in Bioactive Natural and Synthetic Products, Federal University of Paraíba, CEP 58051-900, João Pessoa, PB, Brazil
- Department of Pharmaceutical Sciences, Federal University of Paraíba, CEP 58051-900, João Pessoa, PB, Brazil
| | - Josean Fechine Tavares
- Post Graduation Program in Bioactive Natural and Synthetic Products, Federal University of Paraíba, CEP 58051-900, João Pessoa, PB, Brazil
- Department of Pharmaceutical Sciences, Federal University of Paraíba, CEP 58051-900, João Pessoa, PB, Brazil
| | - Sócrates Dos Santos Golzio
- Post Graduation Program in Bioactive Natural and Synthetic Products, Federal University of Paraíba, CEP 58051-900, João Pessoa, PB, Brazil
- Department of Pharmaceutical Sciences, Federal University of Paraíba, CEP 58051-900, João Pessoa, PB, Brazil
| | - Juan Carlos Ramos Gonçalves
- Post Graduation Program in Bioactive Natural and Synthetic Products, Federal University of Paraíba, CEP 58051-900, João Pessoa, PB, Brazil
- Department of Pharmaceutical Sciences, Federal University of Paraíba, CEP 58051-900, João Pessoa, PB, Brazil
| | - Marianna Vieira Sobral
- Post Graduation Program in Bioactive Natural and Synthetic Products, Federal University of Paraíba, CEP 58051-900, João Pessoa, PB, Brazil
- Department of Pharmaceutical Sciences, Federal University of Paraíba, CEP 58051-900, João Pessoa, PB, Brazil
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Deng M, Ren B, Zhao J, Guo X, Yang Y, Shi H, Bian X, Wu M, Xu C, Tao M, Liang R, Li Q. Temozolomide-Promoted MGMT Transcription Contributes to Chemoresistance by Activating the ERK Signalling Pathway in Malignant Melanoma. J Cell Mol Med 2025; 29:e70380. [PMID: 39873425 PMCID: PMC11773391 DOI: 10.1111/jcmm.70380] [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: 05/25/2024] [Revised: 01/10/2025] [Accepted: 01/15/2025] [Indexed: 01/30/2025] Open
Abstract
Tumour cells possess a multitude of chemoresistance mechanisms, which could plausibly contribute to the ineffectiveness of chemotherapy. O6-methylguanine-DNA methyltransferase (MGMT) is an important effector protein associated with Temozolomide (TMZ) resistance in various tumours. To some extent, the expression level of MGMT determines the sensitivity of cells to TMZ, but the mechanism of its expression regulation has not been fully elucidated. Cultured malignant melanoma cell lines A375 and Sk-MEL28 were employed. A luciferase assay was used to detect the transcriptional activity of the MGMT promoter. Western blotting was used to compare the expression levels of phosphorylated ERK1/2 (P-ERK1/2) after TMZ treatment. Immunofluorescent staining was used to detect TMZ-induced DNA damage protein levels. The sensitivity of melanoma cells to TMZ was detected by MTT assay and animal experiments. The expression of MGMT mRNA was tested by Quantitative real-time PCR (RT-qPCR). Flow cytometry was used to measure the apoptosis of TMZ-treated cells. TMZ enhanced the transcription of MGMT through activating the ERK pathway. ERK inhibitors U0126 and vemurafenib (vMF) inhibited the TMZ induced transcription of MGMT. The expression of MGMT and p-ERK1/2 was closely related in human MM tissues. vMF increased the sensitivity of melanoma (MM) to TMZ in vitro and in vivo through downregulating MGMT and promoting the TMZ induced DNA damage in MM. TMZ-promoted MGMT transcription contributed to instinctive chemoresistance by activating the ERK signalling pathway in malignant melanoma. Our study indicates that the use of the ERK inhibitor in combination with TMZ could potentially enhance the effectiveness of clinical treatment for malignant melanoma.
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Affiliation(s)
- Meiyi Deng
- Department of OncologyThe Fourth Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
- Division of Clinical OncologyMedical Center of Soochow UniversitySuzhouJiangsuChina
- Suzhou Sano Precision Medicine LtdSuzhouJiangsuChina
| | - Bingjie Ren
- Department of OncologyThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
- Department of OncologyNanyang Second General HospitalNanyangHenanChina
| | - Jing Zhao
- Department of Radiation OncologyThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Xia Guo
- Department of PathologyThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Yuanyuan Yang
- Department of OncologyThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Huiling Shi
- Department of OncologyThe Fourth Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
- Division of Clinical OncologyMedical Center of Soochow UniversitySuzhouJiangsuChina
| | - Xuyu Bian
- Department of OncologyThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Mengyao Wu
- Department of OncologyThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Caihua Xu
- Department of OncologyThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Min Tao
- Department of OncologyThe Fourth Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
- Division of Clinical OncologyMedical Center of Soochow UniversitySuzhouJiangsuChina
- Suzhou Sano Precision Medicine LtdSuzhouJiangsuChina
- Department of OncologyThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Rongrui Liang
- Department of OncologyThe Fourth Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
- Division of Clinical OncologyMedical Center of Soochow UniversitySuzhouJiangsuChina
- Department of OncologyThe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuChina
| | - Qiang Li
- Department of ChemotherapyJiangxi Cancer HospitalNanchangJiangxiChina
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28
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Leng D, Yang M, Miao X, Huang Z, Li M, Liu J, Wang T, Li D, Feng C. Dynamic changes in the skin transcriptome for the melanin pigmentation in embryonic chickens. Poult Sci 2025; 104:104210. [PMID: 39693959 PMCID: PMC11720608 DOI: 10.1016/j.psj.2024.104210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 07/12/2024] [Accepted: 08/08/2024] [Indexed: 12/20/2024] Open
Abstract
Dermal hyperpigmentation stands out among the various skin pigmentation phenotypes in chickens, where most other pigmentation variants affect feather color and patterning predominantly. Despite numerous black chicken breeds worldwide, only a select few exhibit comprehensive black pigmentation, which encompasses the skin, meat, flesh, and bones. The process of skin melanin pigmentation is intricate and develops successively. Historically, research has concentrated primarily on specific developmental points or stages, but fewer studies have examined the entire transcriptome across the timeline of the development of the embryo integument. In our investigation, we undertook the sequencing of chicken embryo skin samples from d 4 to d 13 of incubation. Our results showed that melanoblasts continued to migrate from E4 to the epidermis until E12. Beginning with E6, melanin was synthesized and transferred to epidermal cells and feather follicles in large quantities, and genes such as DCT, TYR, TYRP1, and MITF played a key role in this process, which is significantly different from that of white-skinned chickens. There were 854 differentially expressed genes between E7 and E8. At this stage, melanocytes formed dendritic forms and transferred melanin to keratinocytes, while the dorsal skin became visibly dark. In addition, CDH3, which is a core factor involved in a variety of biological processes, may have an important impact on skin melanin pigmentation. Collectively, our findings unveiled a phased relationship between the canonical pathway and the noncanonical pathway from E4 to E13. These analyses illuminated the gene regulatory mechanism and provided foundational data that pertained to pigmentation in chickens.
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Affiliation(s)
- Dong Leng
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; School of Pharmacy, Chengdu University, Chengdu 610106, China
| | - Maosen Yang
- School of Pharmacy, Chengdu University, Chengdu 610106, China; College of Animal Science and Technology, Guangxi University, Nanning 530004, China
| | - Xiaomeng Miao
- Institute of Animal Husbandry and Veterinary Medicine, Guizhou Academy of Agricultural Sciences, Guiyang 550005, China
| | - Zhiying Huang
- School of Pharmacy, Chengdu University, Chengdu 610106, China; College of Animal Science, Shanxi Agricultural University, Taiyuan 030031, China
| | - Mengmeng Li
- School of Pharmacy, Chengdu University, Chengdu 610106, China
| | - Jia Liu
- Guizhou Province Livestock and Poultry Genetic Resources Management Station, Guizhou Provincial Department of Agriculture and Rural Affairs, Guiyang 550001, China
| | - Tao Wang
- School of Pharmacy, Chengdu University, Chengdu 610106, China
| | - Diyan Li
- School of Pharmacy, Chengdu University, Chengdu 610106, China
| | - Chungang Feng
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.
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29
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Ren H, He J, Dong J, Jiang G, Hao J, Han L. Specific BCG-related gene expression levels correlate with immune cell infiltration and prognosis in melanoma. J Leukoc Biol 2024; 117:qiae064. [PMID: 38478636 DOI: 10.1093/jleuko/qiae064] [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: 01/30/2024] [Revised: 02/28/2024] [Accepted: 03/01/2024] [Indexed: 01/01/2025] Open
Abstract
Melanoma, caused by malignant melanocytes, is known for its invasiveness and poor prognosis. Therapies are often ineffective due to their heterogeneity and resistance. Bacillus Calmette-Guérin (BCG), primarily a tuberculosis vaccine, shows potential in treating melanoma by activating immune responses. In this study, data from The Cancer Genome Atlas and the National Center for Biotechnology Information Gene Expression Omnibus database were utilized to determine pivotal DEGs such as DSC2, CXCR1, BOK, and CSTB, which are significantly upregulated in BCG-treated blood samples and are strongly associated with the prognosis of melanoma. We employ tools like edgeR and ggplot2 for functional and pathway analysis and develop a prognostic model using LASSO Cox regression analysis to predict patient survival. A notable finding is the correlation between BCG-related genes and immune cell infiltration in melanoma, highlighting the potential of these genes as both biomarkers and therapeutic targets. Additionally, the study examines genetic alterations in these genes and their impact on the disease. This study highlights the necessity of further exploring BCG-related genes for insights into melanoma pathogenesis and treatment enhancement, suggesting that BCG's role in immune activation could offer novel therapeutic avenues in cancer treatment.
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Affiliation(s)
- He Ren
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, 150 Haping Rd, Harbin, 150081, Heilongjiang, China
| | - Jiacheng He
- College of Environment and Chemistry Engineering, Yanshan University, 438 W Hebei Rd, Qinhuangdao, 066004, Hebei, China
- Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, 601 W Huangpu Ave, Guangzhou, 510632, Guangdong, China
| | - Jie Dong
- Department of Clinical Laboratory, Guangzhou Twelfth People's Hospital, 1 Tianqiang Rd, Guangzhou, 510620, Guangdong, China
| | - Guoqian Jiang
- Key Laboratory of Measurement Technology and Instrumentation of Hebei Province, 438 W Hebei Rd, Qinhuangdao, 066004, Hebei, China
- School of Electrical Engineering, Yanshan University, 438 W Hebei Rd, Qinhuangdao, 066004, Hebei, China
| | - Jianlei Hao
- Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, 601 W Huangpu Ave, Guangzhou, 510632, Guangdong, China
- Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, 79 Kangning Rd, Zhuhai, 519000, Guangdong, China
| | - Liang Han
- School of Health, Guangdong Pharmaceutical University, 280 Daxuecheng Outer Ring East Rd, Guangzhou, 510006, Guangdong, China
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30
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Loos B, Salas-Bastos A, Nordin A, Debbache J, Stierli S, Cheng PF, Rufli S, Wyss C, Levesque MP, Dummer R, Wong WWL, Pascolo S, Cantù C, Sommer L. TGFβ signaling sensitizes MEKi-resistant human melanoma to targeted therapy-induced apoptosis. Cell Death Dis 2024; 15:925. [PMID: 39709491 DOI: 10.1038/s41419-024-07305-1] [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: 03/25/2024] [Revised: 11/29/2024] [Accepted: 12/11/2024] [Indexed: 12/23/2024]
Abstract
The TGFβ signaling pathway is known for its pleiotropic functions in a plethora of biological processes. In melanoma, TGFβ signaling promotes invasiveness and metastasis formation. However, its involvement in the response to therapy is controversial. While several studies have linked TGFβ signaling to elevated resistance to targeted therapy in melanoma, separate findings have indicated a favorable treatment response through TGFβ-mediated increase of cell death. We now found that the outcome of TGFβ signaling in the context of targeted therapy is dose dependent. Unlike low doses, high levels of TGFβ signal activation induce apoptosis upon simultaneous MAPK pathway inhibition, even in targeted therapy resistant melanoma cell lines. Using transcriptomic analyses, combined with genomic target identification of the critical TGFβ signaling effector SMAD4, we demonstrate that parallel activation of TGFβ signaling and MAPK pathway inhibition causes a complete switch of TGFβ target genes from promoting pro-invasive processes to fueling pro-apoptotic pathways. Investigations of underlying mechanisms identified a novel apoptosis-inducing gene signature. Functional validation of signature members highlighted a central role of the pro-apoptotic BCL2 family member BCL2L11 (BIM) in mediating apoptosis in this condition. Using a modified, synthetic version of the TGFB1 mRNA for intra-tumoral injections, we additionally showcase a potential therapeutic application of this treatment combination.
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Affiliation(s)
- Benjamin Loos
- University of Zürich, Institute of Anatomy, Winterthurerstrasse 190, 8057, Zürich, Switzerland
| | - Adrian Salas-Bastos
- University of Zürich, Institute of Anatomy, Winterthurerstrasse 190, 8057, Zürich, Switzerland
| | - Anna Nordin
- Wallenberg Centre for Molecular Medicine, Linköping University, 58185, Linköping, Sweden
- Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology; Faculty of Medicine and Health Sciences, Linköping University, 58185, Linköping, Sweden
| | - Julien Debbache
- University of Zürich, Institute of Anatomy, Winterthurerstrasse 190, 8057, Zürich, Switzerland
| | - Salome Stierli
- University of Zürich, Institute of Anatomy, Winterthurerstrasse 190, 8057, Zürich, Switzerland
| | - Phil F Cheng
- University of Zürich Hospital, University of Zürich, Department of Dermatology, Raemistrasse 100, 8091, Zürich, Switzerland
| | - Stefanie Rufli
- University of Zurich, Institute of Experimental Immunology, Winterthurerstrasse 190, 8057, Zürich, Switzerland
| | - Conrad Wyss
- University of Zürich Hospital, University of Zürich, Department of Dermatology, Raemistrasse 100, 8091, Zürich, Switzerland
| | - Mitchell P Levesque
- University of Zürich Hospital, University of Zürich, Department of Dermatology, Raemistrasse 100, 8091, Zürich, Switzerland
| | - Reinhard Dummer
- University of Zürich Hospital, University of Zürich, Department of Dermatology, Raemistrasse 100, 8091, Zürich, Switzerland
| | - Wendy Wei-Lynn Wong
- University of Zurich, Institute of Experimental Immunology, Winterthurerstrasse 190, 8057, Zürich, Switzerland
- Department of Molecular Life Sciences, University of Zürich, Zürich, Switzerland
| | - Steve Pascolo
- University of Zürich Hospital, University of Zürich, Department of Dermatology, Raemistrasse 100, 8091, Zürich, Switzerland
- Faculty of Medicine, University of Zürich, Zürich, Switzerland
| | - Claudio Cantù
- Wallenberg Centre for Molecular Medicine, Linköping University, 58185, Linköping, Sweden
- Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology; Faculty of Medicine and Health Sciences, Linköping University, 58185, Linköping, Sweden
| | - Lukas Sommer
- University of Zürich, Institute of Anatomy, Winterthurerstrasse 190, 8057, Zürich, Switzerland.
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31
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Gong R, Yang D, Zhang C, Abbas G, Miao B, Liang Y, Xu J, Fang X, Ding H. NIR-II Light-Driven Multifunctional Nanozymes PS@CS for Efficient Therapy against Melanoma and Post-tumor Surgery Infection. NANO LETTERS 2024; 24:16200-16207. [PMID: 39642288 DOI: 10.1021/acs.nanolett.4c05389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/08/2024]
Abstract
Melanoma, the most prevalent form of skin cancer, is primarily treated with surgical intervention. However, complete tumor cell removal is challenging, and surgical wounds are prone to infection, complicating treatment and increasing costs. The successful treatment of melanoma generally requires multifunctional agents that are coordinated in tumor therapy and wound healing. In this study, we developed platinum (Pt)- and selenium (Se)-based nanozymes, Pt-Se@Chitosan (PS@CS), which exhibit synergistic antitumor and bactericidal efficacy attributed to their multienzyme activity and strong photothermal conversion efficiency. Furthermore, we engineered PS@CS hydrogels capable of inhibiting tumor regrowth postsurgery and accelerating healing of infected wounds. The PS@CS and PS@CS hydrogels presented herein incorporate characteristics including catalytic therapy, photothermal therapy, antibacterial properties, and skin damage healing, providing an innovative and comprehensive therapeutic approach for melanoma treatment.
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Affiliation(s)
- Rui Gong
- Medical Innovation Technology Transformation Center, Shenzhen Key Laboratory of Nanozymes and Translational Cancer Research, Department of Otolaryngology, Shenzhen Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518039, China
- Faculty of Synthetic Biology, Shenzhen University of Advanced Technology, Shenzhen 518107, China
| | - Decai Yang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China
| | - Cuijuan Zhang
- Department of Cardiovascular Surgery, First Center of 301 Chinese PLA General Hospital, Beijing 100853, China
| | - Ghulam Abbas
- Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Beiping Miao
- Department of Otolaryngology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518039, China
| | - Yueyue Liang
- Department of Otolaryngology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518039, China
| | - Jianing Xu
- Department of Otorhinolaryngology, Qilu Hospital of Shandong University, NHC Key Laboratory of Otorhinolaryngology (Shandong University), Jinan, Shandong 250012, China
| | - Xueyang Fang
- Medical Innovation Technology Transformation Center, Shenzhen Key Laboratory of Nanozymes and Translational Cancer Research, Department of Otolaryngology, Shenzhen Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518039, China
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou 510631, China
| | - Hui Ding
- Medical Innovation Technology Transformation Center, Shenzhen Key Laboratory of Nanozymes and Translational Cancer Research, Department of Otolaryngology, Shenzhen Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518039, China
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32
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He YF. Malignant melanoma: An important differential diagnosis for clear cell sarcoma of the gastrointestinal tract. World J Clin Cases 2024; 12:6664-6668. [PMID: 39650811 PMCID: PMC11514356 DOI: 10.12998/wjcc.v12.i34.6664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 08/13/2024] [Accepted: 08/23/2024] [Indexed: 10/12/2024] Open
Abstract
A case report by Liu et al describes the characteristics of metastatic clear cell sarcoma (CCS) of the pancreas and provides valuable therapeutic insights for this rare malignancy. This case is interesting because of its rarity, suggesting that the pancreas may be a potential target organ for CCS, either primary or metastatic. At the same time, the authors also emphasize the importance of regular postoperative follow-up for timely detection of recurrent lesions, as CCS is characterized by a high degree of malignancy and a high rate of recurrent metastases. Considering that CCS of the gastrointestinal tract is easily confused with malignant melanoma (MM) of the gastrointestinal tract, here we compare the clinical features, histopathological and immunohistochemical characteristics, diagnosis, treatment, and prognosis of CCS and MM of the gastrointestinal tract, hoping to provide a reference for clinical work.
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Affiliation(s)
- Yan-Fei He
- Health Management Center, The Sixth Medical Center, Chinese PLA General Hospital, Beijing 100048, China
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33
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Gęgotek A, Mucha M, Skrzydlewska E. Skin cells protection against UVA radiation - The comparison of various antioxidants and viability tests. Biomed Pharmacother 2024; 181:117736. [PMID: 39647320 DOI: 10.1016/j.biopha.2024.117736] [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: 09/16/2024] [Revised: 11/21/2024] [Accepted: 12/03/2024] [Indexed: 12/10/2024] Open
Abstract
This study compares the effects of vitamins - including ascorbic acid, its derivative 3-O-ethyl-ascorbic acid (EAA), and tocopherol - as well as the main non-psychoactive phytocannabinoids on the viability of various skin cells, including healthy (keratinocytes/melanocytes/fibroblasts) and cancer cells (melanoma/SCC), under standard culture conditions and after the exposure to UVA radiation. All the conducted tests (MTT, SRB, and LDH) consistently indicate that the regenerative effect of EAA is stronger than that of ascorbic acid, while tocopherol acts selectively on healthy/cancer cells, inducing or inhibiting their proliferation, respectively. In the case of phytocannabinoids, only cannabidiol shows protective/regenerative properties for healthy cells. Moreover, the response of melanocytes to cannabigerol is divergent; however, only the LDH test indicates that cannabigerol strongly increases the membrane permeability of those cells. In summary it should be emphasized that various tests may give partially divergent results due to a variety of measured parameters. Nevertheless, despite the positive viability test results for the potential protective compound, caution should be taken as it may promote healthy skin cells but also protect cancer cells.
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Affiliation(s)
- Agnieszka Gęgotek
- Department of Analytical Chemistry, Medical University of Bialystok, Mickiewicza 2d, Bialystok 15-222, Poland.
| | - Magda Mucha
- Department of Analytical Chemistry, Medical University of Bialystok, Mickiewicza 2d, Bialystok 15-222, Poland
| | - Elżbieta Skrzydlewska
- Department of Analytical Chemistry, Medical University of Bialystok, Mickiewicza 2d, Bialystok 15-222, Poland
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34
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Zhang X, Deng J, Wu R, Hu J. Manganese improves anti-PD-L1 immunotherapy via eliciting type I interferon signaling in melanoma. Invest New Drugs 2024; 42:685-693. [PMID: 39592531 DOI: 10.1007/s10637-024-01484-6] [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] [Accepted: 11/18/2024] [Indexed: 11/28/2024]
Abstract
The immune checkpoint inhibitor therapy represented by blocking programmed cell death protein 1/ programmed cell death-ligand 1 (PD-1/PD-L1) has made significant progress in melanoma treatment. However, the response rate and therapeutic effect of immunotherapy alone are still not ideal for melanoma. In this study, we aimed to evaluate the defects of treating anti-PD-L1 alone and the therapeutic effect and molecular mechanism of combined therapy with anti-PD-L1 and MnCl2. We detected the changes of immune cell populations after anti-PD-L1 treatment in melanoma xenograft mouse model. Further, we evaluated the regulatory effect of MnCl2 on dendritic cells (DCs) maturation in vitro. Next, we tested the therapeutic effect and regulatory effect on the tumor microenvironment with anti-PD-L1 and MnCl2 via combining treatment with anti-PD-L1 and MnCl2. Anti-PD-L1 therapy has a certain tumor suppressive function, but the effect is not ideal. The results of flow cytometry showed that the number of CD4+ T cells and CD8+ T cells significantly increased after anti-PD-L1 treatment. However, the number of DCs remained basically unchanged after anti-PD-L1 treatment. In vitro, we confirmed that MnCl2 significantly promoted DCs maturation vis activating cGAS-STING signaling pathway. The combination of anti-PD-L1 and MnCl2 displayed the best tumor suppression effect in melanoma xenograft mouse model. In tumor microenvironment, the infiltration of T cells and the maturation of DCs were significantly promoted, demonstrating a strong anti-tumor immune response. In summary, we conclude that combining anti-PD-L1 with MnCl2 is a promising therapeutic strategy for melanoma.
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Affiliation(s)
- Xiaoxin Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Jianhua Deng
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Renjie Wu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Jian Hu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
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35
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Gęgotek A, Conde T, Domingues MR, Domingues P, Skrzydlewska E. Impact of Nannochloropsis oceanica and Chlorococcum amblystomatis Extracts on UVA-Irradiated on 3D Cultured Melanoma Cells: A Proteomic Insight. Cells 2024; 13:1934. [PMID: 39682683 PMCID: PMC11640244 DOI: 10.3390/cells13231934] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 11/12/2024] [Accepted: 11/20/2024] [Indexed: 12/18/2024] Open
Abstract
Melanoma is one of the most malignant forms of skin cancer, characterised by the highest mortality rate among affected patients. This study aims to analyse and compare the effects of lipid extracts from the microalgae Nannochloropsis oceanica (N.o.) and Chlorococcum amblystomatis (C.a.) on the intra and extracellular proteome of UVA-irradiated melanoma cells using a three-dimensional model. Proteomic analysis revealed that UVA radiation significantly increases the levels of pro-inflammatory proteins in melanoma cells. Treatment with algae extracts reduced these protein levels in both non-irradiated and irradiated cells. Furthermore, untreated cells released proteins responsible for cell growth and proliferation into the medium, a process hindered by UVA radiation through the promotion of pro-inflammatory molecules secretion. The treatment with algae extracts effectively mitigated UVA-induced alterations. Notably, UVA radiation significantly induced the formation of 4-HNE and 15-PGJ2 protein adducts in both cells and the medium, while treatment with algae extracts stimulated the formation of 4-HNE-protein adducts and reduced the level of 15-PGJ2-protein adducts. However, both algae extracts successfully prevented these UVA-induced modifications. In conclusion, lipid extracts from N.o. and C.a. appear to be promising agents in supporting anti-melanoma therapy. However, their potent protective capacity may limit their applicability, particularly following cells exposure to UVA.
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Affiliation(s)
- Agnieszka Gęgotek
- Department of Analytical Chemistry, Medical University of Bialystok, Mickiewicza 2D, 15-222 Bialystok, Poland;
| | - Tiago Conde
- Centre for Environmental and Marine Studies, Department of Chemistry, University of Aveiro, Santiago University Campus, 3810-193 Aveiro, Portugal; (T.C.); (M.R.D.)
| | - Maria Rosário Domingues
- Centre for Environmental and Marine Studies, Department of Chemistry, University of Aveiro, Santiago University Campus, 3810-193 Aveiro, Portugal; (T.C.); (M.R.D.)
| | - Pedro Domingues
- Mass Spectrometry Centre, LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Santiago University Campus, 3810-193 Aveiro, Portugal;
| | - Elżbieta Skrzydlewska
- Department of Analytical Chemistry, Medical University of Bialystok, Mickiewicza 2D, 15-222 Bialystok, Poland;
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Durgham RA, Nassar SI, Gun R, Nguyen SA, Asarkar AA, Nathan CAO. The Prognostic Value of the 31-Gene Expression Profile Test in Cutaneous Melanoma: A Systematic Review and Meta-Analysis. Cancers (Basel) 2024; 16:3714. [PMID: 39518150 PMCID: PMC11545106 DOI: 10.3390/cancers16213714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 10/30/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Cutaneous melanoma is an increasingly common and potentially lethal form of skin cancer. Current staging systems based on clinical and pathological features have limitations in accurately predicting outcomes, particularly for early-stage disease. The 31-gene expression profile (31-GEP) test has emerged as a promising tool for improving risk stratification in melanoma patients. METHODS We conducted a systematic review and meta-analysis of studies evaluating the prognostic performance of the 31-GEP test in cutaneous melanoma. A comprehensive literature search was performed in multiple databases. Studies reporting survival outcomes stratified by 31-GEP class were included. Random-effects models were used to determine survival estimates across studies. RESULTS Thirteen studies comprising 14,760 patients were included in the meta-analysis. The 31-GEP test consistently stratified patients into risk groups with significantly different outcomes. The 5-year melanoma-specific survival rates were 99.8% (95% CI: 98-100%) for Class 1A, 97.6% (95% CI: 92.4-99.3%) for Class 1B/2A, and 83.4% (95% CI: 66.5-92.7%) for Class 2B. Similar trends were observed for recurrence-free and distant metastasis-free survival. CONCLUSIONS This meta-analysis supports the prognostic utility of the 31-GEP test in cutaneous melanoma prognostication. The test consistently stratified patients into clinically meaningful risk groups across multiple survival metrics. These findings support the potential clinical utility of the 31-GEP test in enhancing current staging systems and informing personalized management strategies for melanoma patients.
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Affiliation(s)
- Ryan A. Durgham
- Department of Otolaryngology—Head and Neck Surgery, Medical University of South Carolina, Charleston, SC 29425, USA; (R.A.D.); (S.I.N.); (S.A.N.)
| | - Sami I. Nassar
- Department of Otolaryngology—Head and Neck Surgery, Medical University of South Carolina, Charleston, SC 29425, USA; (R.A.D.); (S.I.N.); (S.A.N.)
| | - Ramazan Gun
- Department of Otolaryngology—Head and Neck Surgery, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USA; (R.G.); (A.A.A.)
| | - Shaun A. Nguyen
- Department of Otolaryngology—Head and Neck Surgery, Medical University of South Carolina, Charleston, SC 29425, USA; (R.A.D.); (S.I.N.); (S.A.N.)
| | - Ameya A. Asarkar
- Department of Otolaryngology—Head and Neck Surgery, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USA; (R.G.); (A.A.A.)
| | - Cherie-Ann O. Nathan
- Department of Otolaryngology—Head and Neck Surgery, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USA; (R.G.); (A.A.A.)
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Yu ZW, Zheng M, Fan HY, Liang XH, Tang YL. Ultraviolet (UV) radiation: a double-edged sword in cancer development and therapy. MOLECULAR BIOMEDICINE 2024; 5:49. [PMID: 39417901 PMCID: PMC11486887 DOI: 10.1186/s43556-024-00209-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 09/18/2024] [Indexed: 10/19/2024] Open
Abstract
It has long been widely acknowledged that ultraviolet (UV) light is an environment risk factor that can lead to cancer, particularly skin cancer. However, it is worth noting that UV radiation holds potential for cancer treatment as a relatively high-energy electromagnetic wave. With the help of nanomaterials, the role of UV radiation has caught increasing attention in cancer treatment. In this review, we briefly summarized types of UV-induced cancers, including malignant melanoma, squamous cell carcinoma, basal cell carcinoma, Merkel cell carcinoma. Importantly, we discussed the primary mechanisms underlying UV carcinogenesis, including mutations by DNA damage, immunosuppression, inflammation and epigenetic alterations. Historically limited by its shallow penetration depth, the introduction of nanomaterials has dramatically transformed the utilization of UV light in cancer treatment. The direct effect of UV light itself generally leads to the suppression of cancer cell growth and the initiation of apoptosis and ferroptosis. It can also be utilized to activate photosensitizers for reactive oxygen species (ROS) production, sensitize radiotherapy and achieve controlled drug release. Finally, we comprehensively weigh the significant risks and limitations associated with the therapeutic use of UV radiation. And the contradictory effect of UV exposure in promoting and inhibiting tumor has been discussed. This review provides clues for potential clinical therapy as well as future study directions in the UV radiation field. The precise delivery and control of UV light or nanomaterials and the wavelength as well as dose effects of UV light are needed for a thorough understanding of UV radiation.
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Affiliation(s)
- Zhen-Wei Yu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, No.14, Sec.3, Renminnan Road, Chengdu, Sichuan, 610041, People's Republic of China
| | - Min Zheng
- Department of Stomatology, Zhoushan Hospital, Wenzhou Medical University, Zhoushan, Zhejiang, China
| | - Hua-Yang Fan
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, No.14, Sec.3, Renminnan Road, Chengdu, Sichuan, 610041, People's Republic of China
| | - Xin-Hua Liang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, No.14, Sec.3, Renminnan Road, Chengdu, Sichuan, 610041, People's Republic of China.
| | - Ya-Ling Tang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral Pathology, West China Hospital of Stomatology, Sichuan University, No.14, Sec.3, Renminnan Road, Chengdu, Sichuan, 610041, People's Republic of China.
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Stoyanova E, Mihaylova N, Ralchev N, Bradyanova S, Manoylov I, Raynova Y, Idakieva K, Tchorbanov A. Modified Hemocyanins from Rapana thomasiana and Helix aspersa Exhibit Strong Antitumor Activity in the B16F10 Mouse Melanoma Model. Mar Drugs 2024; 22:462. [PMID: 39452870 PMCID: PMC11509262 DOI: 10.3390/md22100462] [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: 09/07/2024] [Revised: 10/02/2024] [Accepted: 10/05/2024] [Indexed: 10/26/2024] Open
Abstract
Melanoma is one of the most common tumors worldwide, and new approaches and antitumor drugs for therapy are being investigated. Among the promising biomolecules of natural origin for antitumor research are gastropodan hemocyanins-highly immunogenic multimeric glycoproteins used as antitumor agents and components of therapeutic vaccines in human and mouse cancer models. A murine melanoma model established in C57BL/6 mice of the B16F10 cell line was used to study anticancer modified oxidized hemocyanins (Ox-Hcs) that were administered to experimental animals (100 μg/mouse) under different regimens: mild, intensive, and with sensitization. The solid tumor growth, antitumor response, cell infiltration in tumors, and survival were assessed using flow cytometry, ELISA, and cytotoxicity assays. Therapy with Ox-RtH or Ox-HaH resulted in the generation of enhanced specific immune response (increased levels of tumor-infiltrated mature NK cells (CD27+CD11b+) in sensitized groups and of macrophages in the intensively immunized animals) and tumor suppression. Beneficial effects such as delayed tumor incidence and growth as well as prolonged survival of tumor-bearing animals have been observed. High levels of melanoma-specific CTLs that mediate cytotoxic effects on tumor cells; tumor-infiltrating IgM antibodies expected to enhance antibody-dependent cellular cytotoxicity; type M1 macrophages, which stimulate the Th1 response and cytotoxic cells; and proinflammatory cytokines, were also observed after Ox-Hcs administration. The modified Hcs showed strong antitumor properties in different administration regimens in a murine model of melanoma with potential for future application in humans.
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Affiliation(s)
- Emiliya Stoyanova
- Department of Immunology, Stefan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria; (E.S.); (N.M.); (N.R.); (S.B.); (I.M.)
| | - Nikolina Mihaylova
- Department of Immunology, Stefan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria; (E.S.); (N.M.); (N.R.); (S.B.); (I.M.)
| | - Nikola Ralchev
- Department of Immunology, Stefan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria; (E.S.); (N.M.); (N.R.); (S.B.); (I.M.)
| | - Silviya Bradyanova
- Department of Immunology, Stefan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria; (E.S.); (N.M.); (N.R.); (S.B.); (I.M.)
| | - Iliyan Manoylov
- Department of Immunology, Stefan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria; (E.S.); (N.M.); (N.R.); (S.B.); (I.M.)
| | - Yuliana Raynova
- Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria; (Y.R.); (K.I.)
| | - Krassimira Idakieva
- Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria; (Y.R.); (K.I.)
| | - Andrey Tchorbanov
- Department of Immunology, Stefan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria; (E.S.); (N.M.); (N.R.); (S.B.); (I.M.)
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Rekler D, Ofek S, Kagan S, Friedlander G, Kalcheim C. Retinoic acid, an essential component of the roof plate organizer, promotes the spatiotemporal segregation of dorsal neural fates. Development 2024; 151:dev202973. [PMID: 39250350 PMCID: PMC11463963 DOI: 10.1242/dev.202973] [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: 04/18/2024] [Accepted: 08/26/2024] [Indexed: 09/11/2024]
Abstract
Dorsal neural tube-derived retinoic acid promotes the end of neural crest production and transition into a definitive roof plate. Here, we analyze how this impacts the segregation of central and peripheral lineages, a process essential for tissue patterning and function. Localized in ovo inhibition in quail embryos of retinoic acid activity followed by single-cell transcriptomics unraveled a comprehensive list of differentially expressed genes relevant to these processes. Importantly, progenitors co-expressed neural crest, roof plate and dI1 interneuron markers, indicating a failure in proper lineage segregation. Furthermore, separation between roof plate and dI1 interneurons is mediated by Notch activity downstream of retinoic acid, highlighting their crucial role in establishing the roof plate-dI1 boundary. Within the peripheral branch, where absence of retinoic acid resulted in neural crest production and emigration extending into the roof plate stage, sensory progenitors failed to separate from melanocytes, leading to formation of a common glia-melanocyte cell with aberrant migratory patterns. In summary, the implementation of single-cell RNA sequencing facilitated the discovery and characterization of a molecular mechanism responsible for the segregation of dorsal neural fates during development.
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Affiliation(s)
- Dina Rekler
- Department of Medical Neurobiology, Institute of Medical Research Israel-Canada (IMRIC) and the Edmond and Lily Safra Center for Brain Sciences (ELSC), Hebrew University of Jerusalem-Hadassah Medical School, Jerusalem 9112102, Israel
| | - Shai Ofek
- Department of Medical Neurobiology, Institute of Medical Research Israel-Canada (IMRIC) and the Edmond and Lily Safra Center for Brain Sciences (ELSC), Hebrew University of Jerusalem-Hadassah Medical School, Jerusalem 9112102, Israel
| | - Sarah Kagan
- Department of Medical Neurobiology, Institute of Medical Research Israel-Canada (IMRIC) and the Edmond and Lily Safra Center for Brain Sciences (ELSC), Hebrew University of Jerusalem-Hadassah Medical School, Jerusalem 9112102, Israel
| | - Gilgi Friedlander
- The Mantoux Bioinformatics Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Chaya Kalcheim
- Department of Medical Neurobiology, Institute of Medical Research Israel-Canada (IMRIC) and the Edmond and Lily Safra Center for Brain Sciences (ELSC), Hebrew University of Jerusalem-Hadassah Medical School, Jerusalem 9112102, Israel
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40
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Hu X, Ling D. Nanotechnology-based tumor metabolic reprogramming: Insights into nutrient-delivery and metabolism reactivation therapy. Acta Pharm Sin B 2024; 14:4619-4621. [PMID: 39525576 PMCID: PMC11544171 DOI: 10.1016/j.apsb.2024.07.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 07/13/2024] [Accepted: 07/14/2024] [Indexed: 11/16/2024] Open
Affiliation(s)
- Xi Hu
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230038, China
- Institute of Pharmaceutics, Anhui Academy of Chinese Medicine, Hefei 230038, China
- Anhui Province Key Laboratory of Pharmaceutical Preparation Technology and Application, Anhui University of Chinese Medicine, Hefei 230038, China
| | - Daishun Ling
- Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, National Center for Translational Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
- WLA Laboratories, Shanghai 201203, China
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41
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Kim B, Park YY, Lee JH. CXCL10 promotes melanoma angiogenesis and tumor growth. Anim Cells Syst (Seoul) 2024; 28:453-465. [PMID: 39268223 PMCID: PMC11391877 DOI: 10.1080/19768354.2024.2402024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 08/24/2024] [Accepted: 09/01/2024] [Indexed: 09/15/2024] Open
Abstract
Upregulation of CXC motif chemokine 10 (CXCL10) in melanoma patients has been found to be associated with melanoma progression. However, the role of endogenous CXCL10 from the host in melanoma tumor growth remains unclear. In the present study, we found that host-derived endogenous CXCL10 production was dramatically augmented during subcutaneous B16F10 melanoma tumor growth and that host ablation of CXCL10 in Cxcl10-/- mice showed a decrease in both angiogenesis and tumor growth of B16F10 melanoma in vivo. Several signaling pathways involved in production of pro-angiogenic factors and tumor growth were activated by CXCL10 in B16F10 melanoma cells. CXCL10 increased expression of pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor subunit-B (PDGF-B), fibroblast growth factor 2 (FGF2), hepatocyte growth factor (HGF), and angiopoietin 2 (Angpt2), in B16F10 melanoma cells, resulting in enhanced tube formation and proliferation of human umbilical vein endothelial cells in vitro. In addition, CXCL10 directly enhanced B16F10 melanoma tumor growth in an in vitro three-dimensional cell culture system. Together, our findings reveal that amplified host-derived endogenous CXCL10 is critical for B16F10 melanoma angiogenesis and tumor growth. Therefore, CXCL10 might represent a therapeutic target for melanoma.
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Affiliation(s)
- Bongjun Kim
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yun-Yong Park
- Department of life Science, Chung-Ang University, Seoul, Republic of Korea
| | - Jong-Ho Lee
- Department of Health Sciences, The Graduate School of Dong-A University, Busan, Republic of Korea
- Department of Biomedical Sciences, Dong-A University, Busan, Republic of Korea
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Zhang ZL, Xu HN, Gong CM, Li YZ, Li YM, Song XM, Wang R, Zhang DD. The Sources, Structures and Cytotoxicity of Animal-Derived Bisindole Compounds. Chem Biodivers 2024; 21:e202401165. [PMID: 38973453 DOI: 10.1002/cbdv.202401165] [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: 05/07/2024] [Revised: 07/07/2024] [Accepted: 07/08/2024] [Indexed: 07/09/2024]
Abstract
Bisindole compounds constitute a significant class of natural compounds distinguished by their characteristic bisindole structure and renowned for their anticancer properties. Over the past four decades, researchers have isolated 229 animal-derived bisindole compounds (ADBCs) from various animals. These compounds demonstrate a wide range of pharmacological properties, including cytotoxicity, antibacterial, antifungal, antiviral, and other activities. Notably, among these activities, cytotoxicity emerges as the most prominent characteristic of ADBCs. This review also summarizes the structureactivity relationship (SAR) studies associated with the cytotoxicity of these compounds and explores the druggability of these compounds. In summary, our objective is to provide an overview of the research progress concerning ADBCs, with the aim of fostering their continued development and utilization.
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Affiliation(s)
- Zi-Long Zhang
- School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, P.R. China
- School of Pharmacy, Shaanxi Key Laboratory of Research and Application of "Taibai Qi Yao", Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, 712046, P.R. China
| | - Hao-Nan Xu
- School of Pharmacy, Shaanxi Key Laboratory of Research and Application of "Taibai Qi Yao", Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, 712046, P.R. China
| | - Chuan-Ming Gong
- School of Pharmacy, Shaanxi Key Laboratory of Research and Application of "Taibai Qi Yao", Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, 712046, P.R. China
| | - Yu-Ze Li
- School of Pharmacy, Shaanxi Key Laboratory of Research and Application of "Taibai Qi Yao", Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, 712046, P.R. China
| | - Yi-Ming Li
- School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, P.R. China
| | - Xiao-Mei Song
- School of Pharmacy, Shaanxi Key Laboratory of Research and Application of "Taibai Qi Yao", Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, 712046, P.R. China
| | - Rui Wang
- School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, P.R. China
| | - Dong-Dong Zhang
- School of Pharmacy, Shaanxi Key Laboratory of Research and Application of "Taibai Qi Yao", Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, 712046, P.R. China
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Brito TLD, Edson EA, Dias Florêncio KG, Machado-Neto JA, Garnique ADMB, Mesquita Luiz JP, Cunha FDQ, Alves-Filho JC, Haygood M, Wilke DV. Tartrolon D induces immunogenic cell death in melanoma. Chem Biol Interact 2024; 400:111177. [PMID: 39097071 DOI: 10.1016/j.cbi.2024.111177] [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: 02/26/2024] [Revised: 07/23/2024] [Accepted: 07/29/2024] [Indexed: 08/05/2024]
Abstract
Tartrolon D (TRL) is produced by Teredinibacter turnerae, a symbiotic cellulose-degrading bacteria in shipworm gills. Immunogenic cell death (ICD) induction contributes to a better and longer-lasting response to anticancer treatment. Tumor cells undergoing ICD trigger activation of the immune system, as a vaccine. AIMS This study aimed to evaluate ICD induction by TRL. MAIN METHODS Cell viability was evaluated by SRB assay. Cell stress, cell death, ICD features and antigen-presenting molecules were evaluated by flow cytometry and immunoblot. KEY FINDINGS TRL showed antiproliferative activity on 7 tumor cell lines (L929, HCT 116, B16-F10, WM293A, SK-MEL-28, PC-3M, and MCF-7) and a non-tumor cell (HEK293A), with an inhibition concentration mean (IC50) ranging from 0.03 μM to 13 μM. Metastatic melanomas, SK-MEL-28, B16-F10, and WM293A, were more sensitive cell lines, with IC50 ranging from 0.07 to 1.2 μM. TRL induced apoptosis along with autophagy and endoplasmic reticulum stress and release of typical damage-associated molecular patterns (DAMPs) of ICD such calreticulin, ERp57, and HSP70 exposure, and HMGB1 release. Additionally, melanoma B16-F10 exposed to TRL increased expression of antigen-presenting molecules MHC II and CD1d and induced activation of splenocytes of C57BL/6 mice. SIGNIFICANCE In spite of recent advances provided by target therapy and immunotherapy, advanced metastatic melanoma is incurable for more than half of patients. ICD inducers yield better and long-lasting responses to anticancer treatment. Our findings shed light on an anticancer candidate of marine origin that induces ICD in melanoma.
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Affiliation(s)
- Thaís Lima de Brito
- Drug Research and Development Center, Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceara, Ceara, Brazil.
| | - Evelline Araújo Edson
- Drug Research and Development Center, Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceara, Ceara, Brazil.
| | - Katharine Gurgel Dias Florêncio
- Drug Research and Development Center, Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceara, Ceara, Brazil.
| | | | | | - João Paulo Mesquita Luiz
- Center for Research in Inflammatory Diseases (CRID), Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil.
| | - Fernando de Queiroz Cunha
- Center for Research in Inflammatory Diseases (CRID), Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil.
| | - José Carlos Alves-Filho
- Center for Research in Inflammatory Diseases (CRID), Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil.
| | | | - Diego Veras Wilke
- Drug Research and Development Center, Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceara, Ceara, Brazil.
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Colombino M, Casula M, Paliogiannis P, Manca A, Sini MC, Pisano M, Santeufemia DA, Cossu A, Palmieri G. Heterogeneous pathogenesis of melanoma: BRAF mutations and beyond. Crit Rev Oncol Hematol 2024; 201:104435. [PMID: 38977143 DOI: 10.1016/j.critrevonc.2024.104435] [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: 01/31/2024] [Revised: 05/22/2024] [Accepted: 06/29/2024] [Indexed: 07/10/2024] Open
Abstract
Melanoma pathogenesis, conventionally perceived as a linear accumulation of molecular changes, discloses substantial heterogeneity driven by non-linear biological processes, including the direct transformation of melanocyte stem cells. This heterogeneity manifests in diverse biological phenotypes and developmental states, influencing variable responses to treatments. Unveiling the aberrant mechanisms steering melanoma initiation, progression, and metastasis is imperative. Beyond mutations in oncogenic and tumor suppressor genes, the involvement of distinct molecular pathways assumes a pivotal role in melanoma pathogenesis. Ultraviolet (UV) radiations, a principal factor in melanoma etiology, categorizes melanomas based on cumulative sun damage (CSD). The genomic landscape of lesions correlates with UV exposure, impacting mutational load and spectrum of mutations. The World Health Organization's 2018 classification underscores the interplay between sun exposure and genomic characteristics, distinguishing melanomas associated with CSD from those unrelated to CSD. The classification elucidates molecular features such as tumor mutational burden and copy number alterations associated with different melanoma subtypes. The significance of the mutated BRAF gene and its pathway, notably BRAFV600 variants, in melanoma is paramount. BRAF mutations, prevalent across diverse cancer types, present therapeutic avenues, with clinical trials validating the efficacy of targeted therapies and immunotherapy. Additional driver mutations in oncogenes further characterize specific melanoma pathways, impacting tumor behavior. While histopathological examination remains pivotal, challenges persist in molecularly classifying melanocytic tumors. In this review, we went through all molecular characterization that aid in discriminating common and ambiguous lesions. Integration of highly sensitive molecular diagnostic tests into the diagnostic workflow becomes indispensable, particularly in instances where histology alone fails to achieve a conclusive diagnosis. A diagnostic algorithm based on different molecular features inferred by the various studies is here proposed.
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Affiliation(s)
- Maria Colombino
- Unit of Cancer Genetics, Institute of Genetic Biomedical Research (IRGB), National Research Council (CNR), Sassari, Italy.
| | - Milena Casula
- Unit of Cancer Genetics, Institute of Genetic Biomedical Research (IRGB), National Research Council (CNR), Sassari, Italy
| | | | - Antonella Manca
- Unit of Cancer Genetics, Institute of Genetic Biomedical Research (IRGB), National Research Council (CNR), Sassari, Italy
| | - Maria Cristina Sini
- Unit of Cancer Genetics, Institute of Genetic Biomedical Research (IRGB), National Research Council (CNR), Sassari, Italy
| | - Marina Pisano
- Unit of Cancer Genetics, Institute of Genetic Biomedical Research (IRGB), National Research Council (CNR), Sassari, Italy
| | | | - Antonio Cossu
- Department of Medicine, Surgery and Pharmacy, University of Sassari, Sassari, Italy
| | - Giuseppe Palmieri
- Unit of Cancer Genetics, Institute of Genetic Biomedical Research (IRGB), National Research Council (CNR), Sassari, Italy; Immuno-Oncology & Targeted Cancer Biotherapies, University of Sassari, Sassari, Italy
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Lu F, Wang L, Ma X, Li Y. A Mendelian randomization study of genetic liability to cutaneous melanoma and sunburns. Front Oncol 2024; 14:1393833. [PMID: 39281383 PMCID: PMC11392754 DOI: 10.3389/fonc.2024.1393833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 08/12/2024] [Indexed: 09/18/2024] Open
Abstract
Background Some studies have reported that sunburns and cutaneous melanoma (CM) risk is increasing, but a clear causal link has yet to be established. Methods This current study conducted a two-sample Mendelian randomization (MR) approach to clarify the association and causality between sunburn history and CM using large-scale genome-wide association study data. Results The inverse-variance weighted method result showed that sunburn might be associated with the risk of CM increasing (p = 2.21 × 10-23, OR = 1.034, 95% CI= 1.027-1.041), causally. The MR-Egger regression, weighted median method, simple mode method, and weighted mode method results showed similar results. Conclusion This study offers evidence of sunburn history and increased risk of CM, and it shows that there might be common genetic basics regarding sunburns and CM susceptibility in Caucasian, European, or British ethnic groups.
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Affiliation(s)
- Fengmin Lu
- Department of Dermatology, Clinical Medical Research Center of Dermatology and Venereal Disease in Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Ling Wang
- Department of Dermatology, Clinical Medical Research Center of Dermatology and Venereal Disease in Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xixing Ma
- Department of Dermatology, Clinical Medical Research Center of Dermatology and Venereal Disease in Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yanling Li
- Department of Dermatology, Clinical Medical Research Center of Dermatology and Venereal Disease in Hebei Province, The Second Hospital of Hebei Medical University, Shijiazhuang, China
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Du J, Yi X, Guo S, Wang H, Shi Q, Zhang J, Tian Y, Wang H, Zhang H, Zhang B, Gao T, Li C, Guo W, Yang Y. SIRT7 promotes mitochondrial biogenesis to render the adaptive resistance to MAPK inhibition in melanoma. Biochem Biophys Res Commun 2024; 722:150161. [PMID: 38797153 DOI: 10.1016/j.bbrc.2024.150161] [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: 04/14/2024] [Revised: 05/20/2024] [Accepted: 05/22/2024] [Indexed: 05/29/2024]
Abstract
Melanoma, arising from the malignant transformation of melanocytes, stands as the most lethal type of skin cancer. While significant strides have been made in targeted therapy and immunotherapy, substantially enhancing therapeutic efficacy, the prognosis for melanoma patients remains unoptimistic. SIRT7, a nuclear-localized deacetylase, plays a pivotal role in maintaining cellular homeostasis and adapting to external stressors in melanoma, with its activity closely tied to intracellular nicotinamide adenine dinucleotide (NAD+). However, its involvement in adaptive resistance to targeted therapy remains unclear. Herein, we unveil that up-regulated SIRT7 promotes mitochondrial biogenesis to render the adaptive resistance to MAPK inhibition in melanoma. Initially, we observed a significant increase of SIRT7 expression in publicly available datasets following targeted therapy within a short duration. In consistent, we found elevated SIRT7 expression in melanoma cells subjected to BRAF or MEK inhibitors in vitro. The up-regulation of SIRT7 expression was also confirmed in xenograft tumors in mice after targeted therapy in vivo. Furthermore, we proved that SIRT7 deficiency led to decreased cell viability upon prolonged exposure to BRAF or MEK inhibitors, accompanied by an increase in cell apoptosis. Mechanistically, SIRT7 deficiency restrained the upregulation of genes associated with mitochondrial biogenesis and intracellular ATP levels in response to targeted therapy treatment in melanoma cells. Ultimately, we proved that SIRT7 deficieny could sensitize BRAF-mutant melanoma cells to MAPK inhibition targeted therapy in vivo. In conclusion, our findings underscore the role of SIRT7 in fostering adaptive resistance to targeted therapy through the facilitation of mitochondrial biogenesis. Targeting SIRT7 emerges as a promising strategy to overcome MAPK inhibitor adaptive resistance in melanoma.
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Affiliation(s)
- Juan Du
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xiuli Yi
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Sen Guo
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Huina Wang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Qiong Shi
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Jianglin Zhang
- Department of Dermatology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China; Candidate Branch of National Clinical Research Center for Skin Diseases, Shenzhen, Guangdong, China
| | - Yangzi Tian
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Hao Wang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Hengxiang Zhang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Baolu Zhang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Tianwen Gao
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Chunying Li
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Weinan Guo
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
| | - Yuqi Yang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
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Wu X, Xu L, Zhang H, Zhu Y, Zhang Q, Zhang C, E G. Genome-Wide Selection Sweep Analysis to Identify Candidate Genes with Black and Brown Color in Tibetan Sibu Yaks. Animals (Basel) 2024; 14:2458. [PMID: 39272243 PMCID: PMC11394208 DOI: 10.3390/ani14172458] [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: 06/17/2024] [Revised: 08/21/2024] [Accepted: 08/22/2024] [Indexed: 09/15/2024] Open
Abstract
Although coat color is an important economic phenotype in domesticated yaks (Bos grunniens), its genetic basis is not yet fully understood. In this study, a genome-wide selective sweep and high-frequency runs of homozygosity (ROH) identification were performed on 50 yaks with different coat colors to investigate candidate genes (CDGs) related to coat color. The results suggested that 2263 CDGs were identified from the 5% interaction windows of the FST and θπ ratio, along with 2801 and 2834 CDGs from black and brown yaks with iHS, respectively. Furthermore, 648 and 691 CDGs from black and brown yaks, which were widely enriched in pathways related to melanogenesis, melanocyte differentiation, and melanosome organization via GO and KEGG functional enrichment, respectively, were confirmed on the basis of the intersection of three parameters. Additionally, the genome of brown yaks presented more ROH, longer ROH fragments, and higher inbreeding levels than those of black yaks. Specifically, a large number of genes related to melanin synthesis and regulation (e.g., UST, TCF25, and AHRR) from the ROH islands were confirmed to be under strong selection. In summary, the results of this study enhance the understanding of the genetic basis for determining yak coat color.
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Affiliation(s)
- Xinming Wu
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China
| | - Lu Xu
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China
| | - Haoyuan Zhang
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China
| | - Yong Zhu
- Institute of Animal Husbandry and Veterinary Medicine, Tibet Academy of Agriculture and Animal Husbandry Science, Lhasa 850009, China
| | - Qiang Zhang
- Institute of Animal Husbandry and Veterinary Medicine, Tibet Academy of Agriculture and Animal Husbandry Science, Lhasa 850009, China
| | - Chengfu Zhang
- Institute of Animal Husbandry and Veterinary Medicine, Tibet Academy of Agriculture and Animal Husbandry Science, Lhasa 850009, China
| | - Guangxin E
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China
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Londhe S, Tripathy S, Saha S, Patel A, Chandra Y, Patra CR. Therapeutic Potential of Silver Nitroprusside Nanoparticles for Melanoma. ACS APPLIED BIO MATERIALS 2024; 7:5057-5075. [PMID: 39115261 DOI: 10.1021/acsabm.4c00597] [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] [Indexed: 08/20/2024]
Abstract
Melanoma has gained considerable attention due to its high mortality and morbidity rate worldwide. The currently available treatment options are associated with several limitations such as nonspecificity, drug resistance, easy clearance, low efficacy, toxicity-related issues, etc. To this end, nanotechnology has garnered significant attention for the treatment of melanoma. In the present manuscript, we have demonstrated the in vitro and in vivo anticancer activity of silver nitroprusside nanoparticles (abbreviated as AgNNPs) against melanoma. The AgNNPs exhibit cytotoxicity against B16F10 cells, which has been investigated by several in vitro experiments including [methyl 3H]-thymidine incorporation assay, cell cycle and apoptosis analysis by flow cytometry, and ROS generation through DCFDA, DHE, and DAF2A reagents. Further, the internalization of nanoparticles was determined by ICPOES analysis, while their colocalization was analyzed by confocal microscopy. Additionally, JC-1 staining is performed to examine mitochondrial membrane potential (MMP). Cytoskeleton integrity was observed by phalloidin staining. Expression of different markers (Ki-67, cytochrome c, and E-cadherin) was checked using an immunofluorescence assay. The in vivo therapeutic efficacy of AgNNPs has been validated in the melanoma model established by inoculating B16F10 cells into the dorsal right abdomen of C57BL/6J mice. The intraperitoneal administration of AgNNPs reduced melanoma growth and increased the survivability of tumor-bearing mice. The in vivo immunofluorescence studies (Ki-67, CD31, and E-cadherin) and TUNEL assay support the inhibitory and apoptotic nature of AgNNPs toward melanoma, respectively. Furthermore, the various signaling pathways and molecular mechanisms involved in anticancer activity are evaluated by Western blot analysis. These findings altogether demonstrate the promising anticancer potential of AgNNPs toward melanoma.
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Affiliation(s)
- Swapnali Londhe
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, Telangana State, India
- Academy of Scientific and Innovative Research (AcSIR), CSIR-HRDC Campus, Kamala Nehru Nagar, Gaziabad 201002, U.P., India
| | - Sanchita Tripathy
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, Telangana State, India
- Academy of Scientific and Innovative Research (AcSIR), CSIR-HRDC Campus, Kamala Nehru Nagar, Gaziabad 201002, U.P., India
| | - Sudipta Saha
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, Telangana State, India
- Academy of Scientific and Innovative Research (AcSIR), CSIR-HRDC Campus, Kamala Nehru Nagar, Gaziabad 201002, U.P., India
| | - Arti Patel
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, Telangana State, India
| | - Yogesh Chandra
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, Telangana State, India
| | - Chitta Ranjan Patra
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, Telangana State, India
- Academy of Scientific and Innovative Research (AcSIR), CSIR-HRDC Campus, Kamala Nehru Nagar, Gaziabad 201002, U.P., India
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Limonta P, Chiaramonte R, Casati L. Unveiling the Dynamic Interplay between Cancer Stem Cells and the Tumor Microenvironment in Melanoma: Implications for Novel Therapeutic Strategies. Cancers (Basel) 2024; 16:2861. [PMID: 39199632 PMCID: PMC11352669 DOI: 10.3390/cancers16162861] [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: 06/28/2024] [Revised: 08/07/2024] [Accepted: 08/13/2024] [Indexed: 09/01/2024] Open
Abstract
Cutaneous melanoma still represents a significant health burden worldwide, being responsible for the majority of skin cancer deaths. Key advances in therapeutic strategies have significantly improved patient outcomes; however, most patients experience drug resistance and tumor relapse. Cancer stem cells (CSCs) are a small subpopulation of cells in different tumors, including melanoma, endowed with distinctive capacities of self-renewal and differentiation into bulk tumor cells. Melanoma CSCs are characterized by the expression of specific biomarkers and intracellular pathways; moreover, they play a pivotal role in tumor onset, progression and drug resistance. In recent years, great efforts have been made to dissect the molecular mechanisms underlying the protumor activities of melanoma CSCs to provide the basis for novel CSC-targeted therapies. Herein, we highlight the intricate crosstalk between melanoma CSCs and bystander cells in the tumor microenvironment (TME), including immune cells, endothelial cells and cancer-associated fibroblasts (CAFs), and its role in melanoma progression. Specifically, we discuss the peculiar capacities of melanoma CSCs to escape the host immune surveillance, to recruit immunosuppressive cells and to educate immune cells toward an immunosuppressive and protumor phenotype. We also address currently investigated CSC-targeted strategies that could pave the way for new promising therapeutic approaches for melanoma care.
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Affiliation(s)
- Patrizia Limonta
- Department of Pharmacological and Biomolecular Sciences “R. Paoletti”, Università degli Studi di Milano, 20133 Milan, Italy
| | - Raffaella Chiaramonte
- Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy;
| | - Lavinia Casati
- Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy;
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Azad M, Hosseini F, Hassanzade H, Gharedaghi S, Mahdipour E, Rassouli FB, Jamialahmadi K. Galbanic acid suppresses melanoma cell migration and invasion by reducing MMP activity and downregulating N-cadherin and fibronectin. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:5779-5788. [PMID: 38324091 DOI: 10.1007/s00210-024-02981-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 01/24/2024] [Indexed: 02/08/2024]
Abstract
High mortality rate of melanoma is due to the metastasis of malignant cells. Galbanic acid (GBA) is a natural sesquiterpene coumarin with valuable pharmaceutical activities. Our study aimed to investigate whether GBA can affect the migration, invasion, and adhesion of melanoma cells. The survival rate of B16F10 cells was measured using the alamarBlue assay. Scratch, adhesion, and invasion assays were performed to determine the effect of GBA on metastatic behavior of cells. Moreover, gelatin zymography was done to assess the activity of MMP-2 and MMP-9, and qRT-PCR was used to investigate the effect of GBA on the expression of candidate genes. Based on the results of alamarBlue assay, 40 µM GBA was chosen as the optimum concentration for all tests. Our findings indicated that GBA significantly decreased the invasion and migration of B16F10 cells while enhancing their adhesion ability. In addition, gelatin zymography demonstrated that GBA reduced the enzymatic activity of MMP-2 and MMP-9. Moreover, qRT-PCR revealed that GBA reduced the expression of N-cadherin and fibronectin. Current findings demonstrated, for the first time, that GBA inhibited the migration and invasion of melanoma cells via reducing the activity of MMP-2 and MMP-9 and downregulating N-cadherin and fibronectin expression. Accordingly, GBA could be suggested as a potential therapeutic agent for the treatment of melanoma.
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Affiliation(s)
- Masoumeh Azad
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemehsadat Hosseini
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Halimeh Hassanzade
- Stem Cell and Regenerative Medicine Research Group, Academic Center for Education, Culture and Research (ACECR)-Khorasan Razavi, Mashhad, Iran
| | - Shahin Gharedaghi
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Elahe Mahdipour
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh B Rassouli
- Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran.
| | - Khadijeh Jamialahmadi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
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