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Li Y, Zhou C, Sun J, Wang E, Wang C, Liu X, Zhou X, Bai J. Inhibition of DLK1 regulates AT2 differentiation and alleviates established pulmonary fibrosis by upregulating TTF-1/CLDN6. Respir Res 2025; 26:188. [PMID: 40380180 PMCID: PMC12085069 DOI: 10.1186/s12931-025-03264-z] [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: 07/17/2024] [Accepted: 04/29/2025] [Indexed: 05/19/2025] Open
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a devastating age-related disease with unknown causes and limited effective treatment. Dysregulation of Alveolar Type 2 (AT2) cells facilitates the initiation of IPF. While differentiation of AT2 into AT1 is necessary for restoring alveolar epithelium. Delta-like non-canonical Notch ligand 1 (DLK1) is a paternally imprinted gene that controls stem cell differentiation. However, the role of DLK1 on AT2 during lung fibrosis remains unclear. METHODS Lung specimens from 11 patients with IPF or contemporaneous non-IPF controls were collected to determine DLK1 expression. The murine model of bleomycin (BLM) -induced pulmonary fibrosis and cell models of transforming growth factor-beta (TGF-β)-treated A549, MRC5 or primary lung fibroblasts (PLFs) were established. Epithelial DLK1 knockdown mice were constructed by an alveolar epithelial -specific adeno-associated virus (AAV) 6 vector system. Besides, primary AT2 cells were isolated from SPC-EGFP mice and cultured in 2D and 3D organoids. RESULTS In the present study, we found that DLK1, predominantly expressed in AT2 cells, was upregulated in both IPF lungs and the murine fibrotic lung induced by BLM. AAV-mediated epithelial-specific knockdown of DLK1 promoted the proliferation and differentiation of AT2 into AT1 and alleviated the established lung fibrosis in murine BLM-induced models. In addition, recombinant DLK1 inhibited the renewal of AT2 and aggravated TGF-β-induced fibrosis in vitro, which can be rescued by si-DLK1 intervention. Mechanically, conditional knockdown of DLK1 upregulated TTF-1, a transcriptional factor that controls AT2 differentiation via CLDN6. CONCLUSION DLK1 inhibition regulates AT2 differentiation and contributes to the mitigation of established fibrosis via TTF-1/CLDN6 pathway, which suggests that DLK1 may be a therapeutic target for IPF.
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Affiliation(s)
- Yinzhen Li
- Department of Emergency Medicine and Critical Care, School of Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200092, China
- Research Center for Translational Medicine, School of Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200092, China
| | - Chen Zhou
- Research Center for Translational Medicine, School of Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200092, China
| | - Jiaxing Sun
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266071, China
| | - Enhao Wang
- Research Center for Translational Medicine, School of Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200092, China
| | - Chunmei Wang
- Department of Emergency Medicine and Critical Care, School of Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200092, China
| | - Xuan Liu
- Research Center for Translational Medicine, School of Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200092, China
- Shanghai Heart Failure Research Center, School of Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200092, China
| | - Xiaohui Zhou
- Research Center for Translational Medicine, School of Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200092, China.
- Shanghai Heart Failure Research Center, School of Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200092, China.
| | - Jianwen Bai
- Department of Emergency Medicine and Critical Care, School of Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200092, China.
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Wang W, Gao X, Niu W, Yin J, He K. Targeting Metabolism: Innovative Therapies for MASLD Unveiled. Int J Mol Sci 2025; 26:4077. [PMID: 40362316 PMCID: PMC12071536 DOI: 10.3390/ijms26094077] [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: 02/22/2025] [Revised: 04/01/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
The recent introduction of the term metabolic-dysfunction-associated steatotic liver disease (MASLD) has highlighted the critical role of metabolism in the disease's pathophysiology. This innovative nomenclature signifies a shift from the previous designation of non-alcoholic fatty liver disease (NAFLD), emphasizing the condition's progressive nature. Simultaneously, MASLD has become one of the most prevalent liver diseases worldwide, highlighting the urgent need for research to elucidate its etiology and develop effective treatment strategies. This review examines and delineates the revised definition of MASLD, exploring its epidemiology and the pathological changes occurring at various stages of the disease. Additionally, it identifies metabolically relevant targets within MASLD and provides a summary of the latest metabolically targeted drugs under development, including those in clinical and some preclinical stages. The review finishes with a look ahead to the future of targeted therapy for MASLD, with the goal of summarizing and providing fresh ideas and insights.
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Affiliation(s)
- Weixin Wang
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (W.W.); (W.N.)
| | - Xin Gao
- School of Public Health, Jilin University, Changchun 130021, China;
| | - Wentong Niu
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (W.W.); (W.N.)
| | - Jinping Yin
- NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun 130041, China;
| | - Kan He
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (W.W.); (W.N.)
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Ren X, Yang W, Yan X, Zhang H. Exploring RNA binding proteins in hepatocellular carcinoma: insights into mechanisms and therapeutic potential. J Exp Clin Cancer Res 2025; 44:130. [PMID: 40275278 PMCID: PMC12020288 DOI: 10.1186/s13046-025-03395-7] [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: 02/02/2025] [Accepted: 04/14/2025] [Indexed: 04/26/2025] Open
Abstract
Hepatocellular carcinoma (HCC), the most prevalent type of primary liver cancer, is linked to elevated global incidence and mortality rates. Elucidating the intricate molecular pathways that drive the progression of HCC is imperative for devising targeted and effective therapeutic interventions. RNA-binding proteins (RBPs) serve as pivotal regulators of post-transcriptional processes, influencing various cellular functions. This review endeavors to provide a comprehensive analysis of the expression, function, and potential implications of RBPs in HCC. We discuss the classification and diverse roles of RBPs, with a particular focus on key RBPs implicated in HCC and their association with disease progression. Additionally, we explore the mechanisms by which RBPs contribute to HCC, including their impact on gene expression, cell proliferation, cell metastasis, angiogenesis, signaling pathways, and post-transcriptional modifications. Importantly, we examine the potential of RBPs as therapeutic targets and prognostic biomarkers, offering insights into their relevance in HCC treatment. Finally, we outline future research directions, emphasizing the need for further investigation into the functional mechanisms of RBPs and their clinical translation for personalized HCC therapy. This comprehensive review highlights the pivotal role of RBPs in HCC and their potential as novel therapeutic avenues to improve patient outcomes.
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Affiliation(s)
- Xing Ren
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Wenna Yang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xiuli Yan
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China.
| | - Hui Zhang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Huang W, Zhong L, Shi Y, Ma Q, Yang X, Zhang H, Zhang J, Wang L, Wang K, Li J, Zou J, Yang X, Yang L, Zeng Q, Jing L, Chen Z, Zhao Y. An Anti-CD147 Antibody-Drug Conjugate Mehozumab-DM1 is Efficacious Against Hepatocellular Carcinoma in Cynomolgus Monkey. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2410438. [PMID: 39985225 PMCID: PMC12005782 DOI: 10.1002/advs.202410438] [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: 08/29/2024] [Revised: 01/21/2025] [Indexed: 02/24/2025]
Abstract
Effective treatment strategies are urgently needed for hepatocellular carcinoma (HCC) patients due to frequent therapeutic resistance and recurrence. Antibody-drug conjugate (ADC) is a specific antibody-drug conjugated with small molecular compounds, which has potent killing activity against cancer cells. However, few ADC candidates for HCC are undergoing clinical evaluation. CD147 is a tumor-associated antigen that is highly expressed on the surface of tumor cells. Here CD147 is found significantly upregulated in tumor tissues of HCC. Mehozumab-DM1, a humanized anti-CD147 monoclonal antibody conjugated with Mertansine (DM1) is developed. Mehozumab-DM1 is effectively internalized by cancer cells and demonstrated potent antitumor efficacy in HCC cells. In vivo evaluation of Mehozumab-DM1 is conducted in a CRISPR-mediated PTEN and TP53 mutation cynomolgus monkey liver cancer model, which is poorly responsive to sorafenib treatment. Mehozumab-DM1 demonstrated potent tumor inhibitory efficacy at doses of 0.2 and 1.0 mg kg-1 treatment groups in cynomolgus monkey. No treatment-related adverse reactions or body weight loss are observed. Interestingly, Mehozumab-DM1 treatment induced RIPK-dependent tumor cell necroptosis through inhibiting IκB kinase/NF-κB pathway. In conclusion, Mehozumab-DM1 potently inhibits hepatoma through effective internalization to release payload and inducing cell necroptosis to enhance the bystander effect, which is a promising treatment for refractory HCC.
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Affiliation(s)
- Wan Huang
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anShaanxi710032China
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesXi'anShaanxi710032China
| | - Liping Zhong
- State Key Laboratory of Targeting OncologyNational Center for International Research of Biotargeting TheranosticsGuangxi Key Laboratory of Biotargeting TheranosticsCollaborative Innovation Center for Targeting Tumor Diagnosis and TherapyGuangxi Medical UniversityNanningGuangxi530021China
| | - Ying Shi
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anShaanxi710032China
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesXi'anShaanxi710032China
| | - Qingzhi Ma
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anShaanxi710032China
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesXi'anShaanxi710032China
| | - Xiangmin Yang
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anShaanxi710032China
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesXi'anShaanxi710032China
| | - Hongmei Zhang
- Department of Clinical OncologyXijing HospitalFourth Military Medical UniversityXi'anShaanxi710032China
| | - Jing Zhang
- Department of PathologyXijing HospitalThe Fourth Military Medical UniversityXi'anShaanxi710032China
| | - Ling Wang
- Department of Health StatisticsSchool of Preventive MedicineFourth Military Medical UniversityXi'anShaanxi710032China
| | - Kun Wang
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anShaanxi710032China
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesXi'anShaanxi710032China
| | - Jingzhuo Li
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anShaanxi710032China
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesXi'anShaanxi710032China
| | - Jie Zou
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anShaanxi710032China
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesXi'anShaanxi710032China
| | - Xu Yang
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anShaanxi710032China
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesXi'anShaanxi710032China
| | - Liu Yang
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anShaanxi710032China
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesXi'anShaanxi710032China
| | - Qingmei Zeng
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anShaanxi710032China
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesXi'anShaanxi710032China
| | - Lin Jing
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anShaanxi710032China
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesXi'anShaanxi710032China
| | - Zhi‐Nan Chen
- Department of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'anShaanxi710032China
- State Key Laboratory of New Targets Discovery and Drug Development for Major DiseasesXi'anShaanxi710032China
| | - Yongxiang Zhao
- State Key Laboratory of Targeting OncologyNational Center for International Research of Biotargeting TheranosticsGuangxi Key Laboratory of Biotargeting TheranosticsCollaborative Innovation Center for Targeting Tumor Diagnosis and TherapyGuangxi Medical UniversityNanningGuangxi530021China
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Du H, Chen HB, Zhao Y. Exploring a new chapter in traditional Chinese medicine: The potential of Calculus bovis in liver cancer treatment. World J Clin Oncol 2024; 15:1520-1527. [PMID: 39720650 PMCID: PMC11514369 DOI: 10.5306/wjco.v15.i12.1520] [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: 07/23/2024] [Revised: 09/19/2024] [Accepted: 10/15/2024] [Indexed: 10/22/2024] Open
Abstract
In the ongoing quest for new treatments in medicine, traditional Chinese medicine offers unique insights and potential. Recently, studies on the ability of Calculus bovis to inhibit M2-type tumour-associated macrophage polarisation by modulating the Wnt/β-catenin signalling pathway to suppress liver cancer have undoubtedly revealed new benefits and hope for this field of research. The purpose of this article is to comment on this study and explore its strengths and weaknesses, thereby providing ideas for the future treatment of liver cancer.
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Affiliation(s)
- Huang Du
- Department of Gastroenterology, Minqing County General Hospital, Fuzhou 350800, Fujian Province, China
| | - Hong-Bin Chen
- Department of Gastroenterology I, Sanming First Hospital, Fujian Medical University, Sanming 365000, Fujian Province, China
| | - Yu Zhao
- Department of Gastroenterology, Hannover Medical School, Carl-Neuberg-Straße 1, Hannover 30625, Lower Saxony, Germany
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Kamikawa T, Kimura N, Ishii S, Muraoka M, Kodama T, Taniguchi K, Yoshimoto M, Miura-Okuda M, Uchikawa R, Kato C, Shinozuka J, Akai S, Naoi S, Tomioka N, Nagaya N, Pang CL, Garvita G, Feng S, Shimada M, Kamata-Sakurai M, Aburatani H, Kitazawa T, Igawa T. SAIL66, a next generation CLDN6-targeting T-cell engager, demonstrates potent antitumor efficacy through dual binding to CD3/CD137. J Immunother Cancer 2024; 12:e009563. [PMID: 39401967 PMCID: PMC11474890 DOI: 10.1136/jitc-2024-009563] [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: 04/26/2024] [Accepted: 09/26/2024] [Indexed: 10/17/2024] Open
Abstract
BACKGROUND Ovarian cancer remains a formidable challenge in oncology, necessitating innovative therapeutic approaches. Claudin-6 (CLDN6), a member of the tight junction molecule CLDN family, exhibits negligible expression in healthy tissues but displays aberrant upregulation in various malignancies, including ovarian cancer. Although several therapeutic modalities targeting CLDN6 are currently under investigation, there is still a need for more potent therapeutic options. While T-cell engagers (TCEs) hold substantial promise as potent immunotherapeutic agents, their current efficacy and safety in terms of target antigen selection and T-cell exhaustion due to only CD3 stimulation without co-stimulation must be improved, particularly against solid tumors. To provide an efficacious treatment option for ovarian cancer, we generated SAIL66, a tri-specific antibody against CLDN6/CD3/CD137. METHODS Using our proprietary next-generation TCE technology (Dual-Ig), SAIL66 was designed to bind to CLDN6 with one Fab and CD3/CD137 with the other, thereby activating T cells through CD3 activation and CD137 co-stimulation. The preclinical characterization of SAIL66 was performed in a series of in vitro and in vivo studies which included comparisons to a conventional TCE targeting CLDN6 and CD3. RESULTS Despite the high similarity between CLDN6 and other CLDN family members, SAIL66 demonstrated high specificity for CLDN6, reducing the risk of off-target toxicity. In an in vitro co-culture assay with CLDN6-positive cancer cells, we confirmed that SAIL66 strongly activated the CD137 signal in the Jurkat reporter system, and preferentially induced activation of both CD4+ and CD8+ T cells isolated from human peripheral blood mononuclear cells compared to conventional TCEs. In vivo studies demonstrated that SAIL66 led to a more pronounced increase in intratumor T-cell infiltration and a decrease in exhausted T cells compared with conventional CLDN6 TCE by contribution of CD137 co-stimulation, resulting in better antitumor efficacy in tumor-bearing mouse models. CONCLUSION Our data demonstrate that SAIL66, designed to engage CLDN6, CD3, and CD137, has the potential to enhance antitumor activity and provide a potent therapeutic option for patients with ovarian and other solid tumors expressing CLDN6. Clinical trials are currently underway to evaluate the safety and efficacy of SAIL66.
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Affiliation(s)
| | - Naoki Kimura
- Chugai Pharmaceutical Co Ltd, Yokohama, Kanagawa, Japan
| | - Shinya Ishii
- Chugai Pharmaceutical Co Ltd, Yokohama, Kanagawa, Japan
| | | | | | | | - Moe Yoshimoto
- Chugai Pharmaceutical Co Ltd, Yokohama, Kanagawa, Japan
| | | | - Ryo Uchikawa
- Chugai Pharmaceutical Co Ltd, Yokohama, Kanagawa, Japan
| | - Chie Kato
- Chugai Pharmaceutical Co Ltd, Yokohama, Kanagawa, Japan
| | | | - Sho Akai
- Chugai Pharmaceutical Co Ltd, Yokohama, Kanagawa, Japan
| | - Sotaro Naoi
- Chugai Pharmabody Research Pte Ltd, Singapore
| | | | | | | | | | - Shu Feng
- Chugai Pharmabody Research Pte Ltd, Singapore
| | - Mei Shimada
- Chugai Pharmaceutical Co Ltd, Yokohama, Kanagawa, Japan
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Tabariès S, Robert A, Marcil A, Ling B, Acchione M, Lippens J, Pagé M, Fortin A, Meury L, Coutu M, Annis MG, Girondel C, Navarre J, Jaramillo M, Moraitis AN, Siegel PM. Anti-Claudin-2 Antibody-Drug Conjugates for the Treatment of Colorectal Cancer Liver Metastasis. Mol Cancer Ther 2024; 23:1459-1470. [PMID: 38902871 DOI: 10.1158/1535-7163.mct-23-0393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 12/20/2023] [Accepted: 06/13/2024] [Indexed: 06/22/2024]
Abstract
We have previously demonstrated that Claudin-2 is required for colorectal cancer (CRC) liver metastasis. The expression of Claudin-2 in primary CRC is associated with poor survival and highly expressed in liver metastases. Claudin-2 also promotes breast cancer liver metastasis by enabling seeding and cancer cell survival. These observations support Claudin-2 as a potential therapeutic target for managing patients with liver metastases. Antibody-drug conjugates (ADC) are promising antitumor therapeutics, which combine the specific targeting ability of monoclonal antibodies with the potent cell killing activity of cytotoxic drugs. Herein, we report the generation of 28 anti-Claudin-2 antibodies for which the binding specificities, cross-reactivity with claudin family members, and cross-species reactivity were assessed by flow cytometry analysis. Multiple drug conjugates were tested, and PNU was selected for conjugation with anti-Claudin-2 antibodies binding either extracellular loop 1 or 2. Anti-Claudin-2 ADCs were efficiently internalized and were effective at killing Claudin-2-expressing CRC cancer cells in vitro. Importantly, PNU-conjugated-anti-Claudin-2 ADCs impaired the development of replacement-type CRC liver metastases in vivo, using established CRC cell lines and patient-derived xenograft (PDX) models of CRC liver metastases. Results suggest that the development of ADCs targeting Claudin-2 is a promising therapeutic strategy for managing patients with CRC liver-metastatic disease who present replacement-type liver metastases.
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Affiliation(s)
- Sébastien Tabariès
- Goodman Cancer Institute, McGill University, Montréal, Canada
- Department of Medicine, McGill University, Montréal, Canada
| | - Alma Robert
- National Research Council Canada, Montréal, Canada
| | - Anne Marcil
- National Research Council Canada, Montréal, Canada
| | - Binbing Ling
- National Research Council Canada, Ottawa, Canada
| | | | | | - Martine Pagé
- National Research Council Canada, Montréal, Canada
| | - Annie Fortin
- National Research Council Canada, Montréal, Canada
| | - Luc Meury
- National Research Council Canada, Montréal, Canada
| | | | - Matthew G Annis
- Goodman Cancer Institute, McGill University, Montréal, Canada
- Department of Medicine, McGill University, Montréal, Canada
| | - Charlotte Girondel
- Goodman Cancer Institute, McGill University, Montréal, Canada
- Department of Medicine, McGill University, Montréal, Canada
| | - Julie Navarre
- Goodman Cancer Institute, McGill University, Montréal, Canada
- Department of Medicine, McGill University, Montréal, Canada
| | | | | | - Peter M Siegel
- Goodman Cancer Institute, McGill University, Montréal, Canada
- Department of Medicine, McGill University, Montréal, Canada
- Department of Biochemistry, McGill University, Montréal, Canada
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Niu X, Liu W, Zhang Y, Liu J, Zhang J, Li B, Qiu Y, Zhao P, Wang Z, Wang Z. Cancer plasticity in therapy resistance: Mechanisms and novel strategies. Drug Resist Updat 2024; 76:101114. [PMID: 38924995 DOI: 10.1016/j.drup.2024.101114] [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: 04/17/2024] [Revised: 06/12/2024] [Accepted: 06/15/2024] [Indexed: 06/28/2024]
Abstract
Therapy resistance poses a significant obstacle to effective cancer treatment. Recent insights into cell plasticity as a new paradigm for understanding resistance to treatment: as cancer progresses, cancer cells experience phenotypic and molecular alterations, corporately known as cell plasticity. These alterations are caused by microenvironment factors, stochastic genetic and epigenetic changes, and/or selective pressure engendered by treatment, resulting in tumor heterogeneity and therapy resistance. Increasing evidence suggests that cancer cells display remarkable intrinsic plasticity and reversibly adapt to dynamic microenvironment conditions. Dynamic interactions between cell states and with the surrounding microenvironment form a flexible tumor ecosystem, which is able to quickly adapt to external pressure, especially treatment. Here, this review delineates the formation of cancer cell plasticity (CCP) as well as its manipulation of cancer escape from treatment. Furthermore, the intrinsic and extrinsic mechanisms driving CCP that promote the development of therapy resistance is summarized. Novel treatment strategies, e.g., inhibiting or reversing CCP is also proposed. Moreover, the review discusses the multiple lines of ongoing clinical trials globally aimed at ameliorating therapy resistance. Such advances provide directions for the development of new treatment modalities and combination therapies against CCP in the context of therapy resistance.
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Affiliation(s)
- Xing Niu
- China Medical University, Shenyang, Liaoning 110122, China; Experimental Center of BIOQGene, YuanDong International Academy Of Life Sciences, 999077, Hong Kong, China
| | - Wenjing Liu
- Medical Oncology Department of Thoracic Cancer (2), Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning 110042, China
| | - Yinling Zhang
- Department of Oncology Radiotherapy 1, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, Shandong 266042, China
| | - Jing Liu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
| | - Jianjun Zhang
- Department of Gastric Surgery, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning 110042, China
| | - Bo Li
- Department of Orthopedics, Beijing Luhe Hospital, Capital Medical University, Beijing 101149, China
| | - Yue Qiu
- Department of Digestive Diseases 1, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning 110042, China
| | - Peng Zhao
- Department of Medical Imaging, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning 110042, China
| | - Zhongmiao Wang
- Department of Digestive Diseases 1, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning 110042, China.
| | - Zhe Wang
- Department of Digestive Diseases 1, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning 110042, China.
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Hu X, Wei J, Liu P, Zheng Q, Zhang Y, Zhang Q, Yao J, Ni J. Organoid as a promising tool for primary liver cancer research: a comprehensive review. Cell Biosci 2024; 14:107. [PMID: 39192365 DOI: 10.1186/s13578-024-01287-5] [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: 04/07/2024] [Accepted: 08/15/2024] [Indexed: 08/29/2024] Open
Abstract
Primary liver cancer (PLC) is one of the most common malignant gastrointestinal tumors worldwide. Limited by the shortage of liver transplantation donors and the heterogeneity of tumors, patients with liver cancer lack effective treatment options, which leads to rapid progression and metastasis. Currently, preclinical models of PLC fall short of clinical reality and are limited in their response to disease progression and the effectiveness of drug therapy. Organoids are in vitro three-dimensional cultured preclinical models with a high degree of heterogeneity that preserve the histomorphological and genomic features of primary tumors. Liver cancer organoids have been widely used for drug screening, new target discovery, and precision medicine; thus representing a promising tool to study PLC. Here, we summarize the progress of research on liver cancer organoids and their potential application as disease models. This review provides a comprehensive introduction to this emerging technology and offers new ideas for researchers to explore in the field of precision medicine.
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Affiliation(s)
- Xuekai Hu
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China
| | - Jiayun Wei
- The First school of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
- The First Hospital of Lanzhou University, Lanzhou, 730000, China
| | - Pinyan Liu
- The First school of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
- The First Hospital of Lanzhou University, Lanzhou, 730000, China
| | - Qiuxia Zheng
- The First school of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Yue Zhang
- The First school of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Qichen Zhang
- The First school of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Jia Yao
- The First school of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China.
- The First Hospital of Lanzhou University, Lanzhou, 730000, China.
- Key Laboratory of Biotherapy and Regenerative Medicine, First Hospital of Lanzhou University, Lanzhou, 730000, China.
- The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, Gansu, 730000, P. R. China.
| | - Jingman Ni
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China.
- School of Basic Medical Sciences, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, Lanzhou, China.
- School of Pharmacy, Lanzhou University, No. 199 West Donggang Road, Lanzhou, Gansu, 730000, P. R. China.
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10
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Jamroze A, Liu X, Tang DG. Treatment-induced stemness and lineage plasticity in driving prostate cancer therapy resistance. CANCER HETEROGENEITY AND PLASTICITY 2024; 1:0005. [PMID: 39363904 PMCID: PMC11449474 DOI: 10.47248/chp2401010005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/05/2024]
Abstract
Most human cancers are heterogeneous consisting of cancer cells at different epigenetic and transcriptional states and with distinct phenotypes, functions, and drug sensitivities. This inherent cancer cell heterogeneity contributes to tumor resistance to clinical treatment, especially the molecularly targeted therapies such as tyrosine kinase inhibitors (TKIs) and androgen receptor signaling inhibitors (ARSIs). Therapeutic interventions, in turn, induce lineage plasticity (also called lineage infidelity) in cancer cells that also drives therapy resistance. In this Perspective, we focus our discussions on cancer cell lineage plasticity manifested as treatment-induced switching of epithelial cancer cells to basal/stem-like, mesenchymal, and neural lineages. We employ prostate cancer (PCa) as the prime example to highlight ARSI-induced lineage plasticity during and towards development of castration-resistant PCa (CRPC). We further discuss how the tumor microenvironment (TME) influences therapy-induced lineage plasticity. Finally, we offer an updated summary on the regulators and mechanisms driving cancer cell lineage infidelity, which should be therapeutically targeted to extend the therapeutic window and improve patients' survival.
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Affiliation(s)
- Anmbreen Jamroze
- Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Xiaozhuo Liu
- Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Dean G. Tang
- Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Experimental Therapeutics (ET) Graduate Program, University at Buffalo & Roswell Park Comprehensive Cancer Center, NY 14263, USA
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11
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Amadeo E, Foti S, Camera S, Rossari F, Persano M, Lo Prinzi F, Vitiello F, Casadei-Gardini A, Rimini M. Developing targeted therapeutics for hepatocellular carcinoma: a critical assessment of promising phase II agents. Expert Opin Investig Drugs 2024; 33:839-849. [PMID: 39039690 DOI: 10.1080/13543784.2024.2377321] [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: 05/03/2024] [Accepted: 07/03/2024] [Indexed: 07/24/2024]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the first for primary liver tumors. In recent years greater therapeutic advancement was represented by employment of tyrosine kinase inhibitors (TKIs) either in monotherapy or in combination with immune checkpoint inhibitors (ICIs). AREAS COVERED Major attention was given to target therapies in the last couple of years, especially in those currently under phase II trials. Priority was given either to combinations of novel ICI and TKIs or those targeting alternative mutations of major carcinogenic pathways. EXPERT OPINION As TKIs are playing a more crucial role in HCC therapeutic strategies, it is fundamental to further expand molecular testing and monitoring of acquired resistances. Despite the recent advancement in both laboratory and clinical studies, further research is necessary to face the discrepancy in clinical practice.
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Affiliation(s)
- Elisabeth Amadeo
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Silvia Foti
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Silvia Camera
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Federico Rossari
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Mara Persano
- Medical Oncology, University and University Hospital of Cagliari, Cagliari, Italy
| | - Federica Lo Prinzi
- Operative Research Unit of Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | - Francesco Vitiello
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Andrea Casadei-Gardini
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Margherita Rimini
- Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
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12
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Iavarone M, Nault JC, Cabibbo G, Torres F, Reig M. Indolent cancer and pattern of progression: Two missing parameters in trial design for hepatology. Hepatology 2024; 79:1452-1462. [PMID: 37399245 PMCID: PMC11095876 DOI: 10.1097/hep.0000000000000527] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 01/20/2023] [Indexed: 07/05/2023]
Abstract
The indolent and aggressive behaviors of HCC might have a role in clinical trial (CT) results; however, the indolent HCC is less analyzed compared to others cancer. Indolent profile could be characterized as follows: (1) patients with low risk of progression itself due to the HCC molecular profile and/or due to the interaction between cancer cell their microenvironment; (2) patients who achieve objective response or present spontaneous regression; and (3) patients who develop radiological progression with no consequence on either the liver function or general status, and without trigger a change in the tumor stage. Patients with "indolent HCC" generally never develop cancer-related symptoms neither die for HCC-related causes. Thus, we hypothesize that the imbalance in the proportion of "indolent" versus "aggressive HCC" between arms or the underestimation/overestimation of HCC behavior at baseline in single-arm CT could be associated with CT failure or under-overestimation of trial results. The "indolent progression" may also explain the discrepancy between radiological progression-based end points and survival. Moreover, we discuss the related causes that explain the indolent profile of HCC and propose (1) refining the progression-related end point by the pattern of progression to minimize the limitations of the current end points; (2) considering alternative statistical tools for survival analysis such as milestone survival, or restricted mean survival time to capture the value of indolent HCC. According to these considerations, we propose incorporating novel end points into the single arm of phase I/II CT as exploratory analysis or as a secondary end point in phase III CT.
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Affiliation(s)
- Massimo Iavarone
- Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico—Division of Gastroenterology and Hepatology, Milan, Italy
| | - Jean-Charles Nault
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris Cité, team « Functional Genomics of Solid Tumors », Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, Paris, France
- Service d’hépatologie, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bobigny, France
- Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris nord, Bobigny, France
| | - Giuseppe Cabibbo
- Section of Gastroenterology & Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy
| | - Ferran Torres
- Biostatistics Unit, Medical School, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Maria Reig
- Liver Oncology Unit. Liver Unit, Hospital Clínic Barcelona, Barcelona, Spain
- BCLC group, FUNDACIO/IDIBAPS, Barcelona, Spain
- CIBEREHD, Madrid, Spain
- Universitat de Barcelona, Barcelona, Spain
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13
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Heumann P, Albert A, Gülow K, Tümen D, Müller M, Kandulski A. Insights in Molecular Therapies for Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:1831. [PMID: 38791911 PMCID: PMC11120383 DOI: 10.3390/cancers16101831] [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: 04/03/2024] [Revised: 05/03/2024] [Accepted: 05/06/2024] [Indexed: 05/26/2024] Open
Abstract
We conducted a comprehensive review of the current literature of published data and clinical trials (MEDLINE), as well as published congress contributions and active recruiting clinical trials on targeted therapies in hepatocellular carcinoma. Combinations of different agents and medical therapy along with radiological interventions were analyzed for the setting of advanced HCC. Those settings were also analyzed in combination with adjuvant situations after resection or radiological treatments. We summarized the current knowledge for each therapeutic setting and combination that currently is or has been under clinical evaluation. We further discuss the results in the background of current treatment guidelines. In addition, we review the pathophysiological mechanisms and pathways for each of these investigated targets and drugs to further elucidate the molecular background and underlying mechanisms of action. Established and recommended targeted treatment options that already exist for patients are considered for systemic treatment: atezolizumab/bevacizumab, durvalumab/tremelimumab, sorafenib, lenvatinib, cabozantinib, regorafenib, and ramucirumab. Combination treatment for systemic treatment and local ablative treatment or transarterial chemoembolization and adjuvant and neoadjuvant treatment strategies are under clinical investigation.
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Affiliation(s)
- Philipp Heumann
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany (K.G.); (D.T.)
| | | | | | | | | | - Arne Kandulski
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany (K.G.); (D.T.)
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14
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Saviano A, Roehlen N, Baumert TF. Tight Junction Proteins as Therapeutic Targets to Treat Liver Fibrosis and Hepatocellular Carcinoma. Semin Liver Dis 2024; 44:180-190. [PMID: 38648796 DOI: 10.1055/s-0044-1785646] [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] [Indexed: 04/25/2024]
Abstract
In the last decade tight junction proteins exposed at the surface of liver or cancer cells have been uncovered as mediators of liver disease biology: Claudin-1 and Occludin are host factors for hepatitis C virus entry and Claudin-1 has been identified as a driver for liver fibrosis and hepatocellular carcinoma (HCC). Moreover, Claudins have emerged as therapeutic targets for liver disease and HCC. CLDN1 expression is upregulated in liver fibrosis and HCC. Monoclonal antibodies (mAbs) targeting Claudin-1 have completed preclinical proof-of-concept studies for treatment of liver fibrosis and HCC and are currently in clinical development for advanced liver fibrosis. Claudin-6 overexpression is associated with an HCC aggressive phenotype and treatment resistance. Claudin-6 mAbs or chimeric antigen receptor-T cells therapies are currently being clinically investigated for Claudin-6 overexpressing tumors. In conclusion, targeting Claudin proteins offers a novel clinical opportunity for the treatment of patients with advanced liver fibrosis and HCC.
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Affiliation(s)
- Antonio Saviano
- Inserm, U1110, Institute of Translational Medicine and Liver Disease, Strasbourg, France
- University of Strasbourg, Strasbourg, France
- Service d'hépato-gastroentérologie, Pôle Hépato-digestif, Institut-Hospitalo-Universitaire, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Natascha Roehlen
- Department of Medicine II, Gastroenterology, Hepatology, Endocrinology and Infectious Diseases, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Berta-Ottenstein-Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Thomas F Baumert
- Inserm, U1110, Institute of Translational Medicine and Liver Disease, Strasbourg, France
- University of Strasbourg, Strasbourg, France
- Service d'hépato-gastroentérologie, Pôle Hépato-digestif, Institut-Hospitalo-Universitaire, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
- Institut Universitaire de France, Paris, France
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15
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Coy S, Lee JS, Chan SJ, Woo T, Jones J, Alexandrescu S, Wen PY, Sorger PK, Ligon KL, Santagata S. Systematic characterization of antibody-drug conjugate targets in central nervous system tumors. Neuro Oncol 2024; 26:458-472. [PMID: 37870091 PMCID: PMC10912007 DOI: 10.1093/neuonc/noad205] [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: 06/10/2023] [Indexed: 10/24/2023] Open
Abstract
BACKGROUND Antibody-drug conjugates (ADCs) enhance the specificity of cytotoxic drugs by directing them to cells expressing target antigens. Multiple ADCs are FDA-approved for solid and hematologic malignancies, including those expressing HER2, TROP2, and NECTIN4. Recently, an ADC targeting HER2 (Trastuzumab-Deruxtecan) increased survival and reduced growth of brain metastases in treatment-refractory metastatic breast cancer, even in tumors with low HER2 expression. Thus, low-level expression of ADC targets may be sufficient for treatment responsiveness. However, ADC target expression is poorly characterized in many central nervous system (CNS) tumors. METHODS We analyzed publicly available RNA-sequencing and proteomic data from the children's brain tumor network (N = 188 tumors) and gene-expression-omnibus RNA-expression datasets (N = 356) to evaluate expression of 14 potential ADC targets that are FDA-approved or under investigation in solid cancers. We also used immunohistochemistry to measure the levels of HER2, HER3, NECTIN4, TROP2, CLDN6, CLDN18.2, and CD276/B7-H3 protein in glioblastoma, oligodendroglioma, meningioma, ependymoma, pilocytic astrocytoma, medulloblastoma, atypical teratoid/rhabdoid tumor (AT/RT), adamantinomatous craniopharyngioma (ACP), papillary craniopharyngioma (PCP), and primary CNS lymphoma (N = 575). RESULTS Pan-CNS analysis showed subtype-specific expression of ADC target proteins. Most tumors expressed HER3, B7-H3, and NECTIN4. Ependymomas strongly expressed HER2, while meningiomas showed weak-moderate HER2 expression. ACP and PCP strongly expressed B7-H3, with TROP2 expression in whorled ACP epithelium. AT/RT strongly expressed CLDN6. Glioblastoma showed little subtype-specific marker expression, suggesting a need for further target development. CONCLUSIONS CNS tumors exhibit subtype-specific expression of ADC targets including several FDA-approved for other indications. Clinical trials of ADCs in CNS tumors may therefore be warranted.
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Affiliation(s)
- Shannon Coy
- Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Boston, Massachusetts, USA
- Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts, USA
| | - Jong Suk Lee
- Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Boston, Massachusetts, USA
| | - Sabrina J Chan
- Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Boston, Massachusetts, USA
- Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Terri Woo
- Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Jacquelyn Jones
- Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Sanda Alexandrescu
- Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Patrick Y Wen
- Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Peter K Sorger
- Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Boston, Massachusetts, USA
- Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts, USA
| | - Keith L Ligon
- Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
- Department of Pediatric Oncology, Dana-Farber Boston Children’s Cancer and Blood Disorders Center, Boston, Massachusetts, USA
- Department of Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Sandro Santagata
- Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Boston, Massachusetts, USA
- Ludwig Center at Harvard, Harvard Medical School, Boston, Massachusetts, USA
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16
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Yang X, Yang C, Zhang S, Geng H, Zhu AX, Bernards R, Qin W, Fan J, Wang C, Gao Q. Precision treatment in advanced hepatocellular carcinoma. Cancer Cell 2024; 42:180-197. [PMID: 38350421 DOI: 10.1016/j.ccell.2024.01.007] [Citation(s) in RCA: 122] [Impact Index Per Article: 122.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 12/01/2023] [Accepted: 01/17/2024] [Indexed: 02/15/2024]
Abstract
The past decade has witnessed significant advances in the systemic treatment of advanced hepatocellular carcinoma (HCC). Nevertheless, the newly developed treatment strategies have not achieved universal success and HCC patients frequently exhibit therapeutic resistance to these therapies. Precision treatment represents a paradigm shift in cancer treatment in recent years. This approach utilizes the unique molecular characteristics of individual patient to personalize treatment modalities, aiming to maximize therapeutic efficacy while minimizing side effects. Although precision treatment has shown significant success in multiple cancer types, its application in HCC remains in its infancy. In this review, we discuss key aspects of precision treatment in HCC, including therapeutic biomarkers, molecular classifications, and the heterogeneity of the tumor microenvironment. We also propose future directions, ranging from revolutionizing current treatment methodologies to personalizing therapy through functional assays, which will accelerate the next phase of advancements in this area.
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Affiliation(s)
- Xupeng Yang
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Chen Yang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Immune Regulation in Cancer Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Shu Zhang
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Haigang Geng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Andrew X Zhu
- I-Mab Biopharma, Shanghai, China; Jiahui International Cancer Center, Jiahui Health, Shanghai, China
| | - René Bernards
- Division of Molecular Carcinogenesis, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Wenxin Qin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Cun Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Qiang Gao
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
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17
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Vonniessen B, Tabariès S, Siegel PM. Antibody-mediated targeting of Claudins in cancer. Front Oncol 2024; 14:1320766. [PMID: 38371623 PMCID: PMC10869466 DOI: 10.3389/fonc.2024.1320766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 01/09/2024] [Indexed: 02/20/2024] Open
Abstract
Tight junctions (TJs) are large intercellular adhesion complexes that maintain cell polarity in normal epithelia and endothelia. Claudins are critical components of TJs, forming homo- and heteromeric interaction between adjacent cells, which have emerged as key functional modulators of carcinogenesis and metastasis. Numerous epithelial-derived cancers display altered claudin expression patterns, and these aberrantly expressed claudins have been shown to regulate cancer cell proliferation/growth, metabolism, metastasis and cell stemness. Certain claudins can now be used as biomarkers to predict patient prognosis in a variety of solid cancers. Our understanding of the distinct roles played by claudins during the cancer progression has progressed significantly over the last decade and claudins are now being investigated as possible diagnostic markers and therapeutic targets. In this review, we will summarize recent progress in the use of antibody-based or related strategies for targeting claudins in cancer treatment. We first describe pre-clinical studies that have facilitated the development of neutralizing antibodies and antibody-drug-conjugates targeting Claudins (Claudins-1, -3, -4, -6 and 18.2). Next, we summarize clinical trials assessing the efficacy of antibodies targeting Claudin-6 or Claudin-18.2. Finally, emerging strategies for targeting Claudins, including Chimeric Antigen Receptor (CAR)-T cell therapy and Bi-specific T cell engagers (BiTEs), are also discussed.
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Affiliation(s)
- Benjamin Vonniessen
- Goodman Cancer Institute, McGill University, Montréal, QC, Canada
- Department of Medicine, McGill University, Montréal, QC, Canada
| | - Sébastien Tabariès
- Goodman Cancer Institute, McGill University, Montréal, QC, Canada
- Department of Medicine, McGill University, Montréal, QC, Canada
| | - Peter M. Siegel
- Goodman Cancer Institute, McGill University, Montréal, QC, Canada
- Department of Medicine, McGill University, Montréal, QC, Canada
- Department of Biochemistry, McGill University, Montréal, QC, Canada
- Department of Anatomy & Cell Biology, McGill University, Montréal, QC, Canada
- Department of Oncology, McGill University, Montréal, QC, Canada
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18
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Wang W, Zhou Y, Li W, Quan C, Li Y. Claudins and hepatocellular carcinoma. Biomed Pharmacother 2024; 171:116109. [PMID: 38185042 DOI: 10.1016/j.biopha.2023.116109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 12/23/2023] [Accepted: 12/28/2023] [Indexed: 01/09/2024] Open
Abstract
Hepatocellular carcinoma (HCC) has a high incidence and dismal prognosis, making it a significant global health burden. To change this, the development of new therapeutic strategies is imminent. The claudin (CLDN) family, as key components of tight junctions (TJs), plays an important role in the initiation and development of cancer. Dysregulated expression of CLDNs leads to loss of intercellular adhesion and aberrant cell signaling, which are closely related to cancer cell invasion, migration, and epithelial-mesenchymal transition (EMT). CLDN1, CLDN3, CLDN4, CLDN5, CLDN6, CLDN7, CLDN9, CLDN10, CLDN11, CLDN14, and CLDN17 are aberrantly expressed in HCC, which drives the progression of the disease. Consequently, they have tremendous potential as prognostic indicators and therapeutic targets. This article summarizes the aberrant expression, molecular mechanisms, and clinical application studies of different subtypes of CLDNs in HCC, with a particular emphasis on CLDN1.
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Affiliation(s)
- Wentao Wang
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, Jilin 130021, China; The Second Norman Bethune College of Clinical Medicine, Jilin University, Changchun 130021, China
| | - Yi Zhou
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, Jilin 130021, China; The First Norman Bethune College of Clinical Medicine, Jilin University, Changchun 130021, China
| | - Wei Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, Jilin 130021, China
| | - Chengshi Quan
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, Jilin 130021, China
| | - Yanru Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, Jilin 130021, China.
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19
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Man KF, Zhou L, Yu H, Lam KH, Cheng W, Yu J, Lee TK, Yun JP, Guan XY, Liu M, Ma S. SPINK1-induced tumor plasticity provides a therapeutic window for chemotherapy in hepatocellular carcinoma. Nat Commun 2023; 14:7863. [PMID: 38030644 PMCID: PMC10687140 DOI: 10.1038/s41467-023-43670-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 11/16/2023] [Indexed: 12/01/2023] Open
Abstract
Tumor lineage plasticity, considered a hallmark of cancer, denotes the phenomenon in which tumor cells co-opt developmental pathways to attain cellular plasticity, enabling them to evade targeted therapeutic interventions. However, the underlying molecular events remain largely elusive. Our recent study identified CD133/Prom1 in hepatocellular carcinoma (HCC) tumors to mark proliferative tumor-propagating cells with cancer stem cell-like properties, that follow a dedifferentiation trajectory towards a more embryonic state. Here we show SPINK1 to strongly associate with CD133 + HCC, and tumor dedifferentiation. Enhanced transcriptional activity of SPINK1 is mediated by promoter binding of ELF3, which like CD133, is found to increase following 5-FU and cisplatin treatment; while targeted depletion of CD133 will reduce both ELF3 and SPINK1. Functionally, SPINK1 overexpression promotes tumor initiation, self-renewal, and chemoresistance by driving a deregulated EGFR-ERK-CDK4/6-E2F2 signaling axis to induce dedifferentiation of HCC cells into their ancestral lineages. Depleting SPINK1 function by neutralizing antibody treatment or in vivo lentivirus-mediated Spink1 knockdown dampens HCC cancer growth and their ability to resist chemotherapy. Targeting oncofetal SPINK1 may represent a promising therapeutic option for HCC treatment.
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Affiliation(s)
- Ki-Fong Man
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Lei Zhou
- Department of Clinical Oncology, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, The University of Hong Kong - Shenzhen Hospital, Hong Kong, China
- Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Huajian Yu
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Ka-Hei Lam
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Wei Cheng
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, China
| | - Jun Yu
- Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Terence K Lee
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
| | - Jing-Ping Yun
- Department of Pathology, Sun Yat-Sen University Cancer Centre, Guangzhou, China
| | - Xin-Yuan Guan
- Department of Clinical Oncology, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, The University of Hong Kong - Shenzhen Hospital, Hong Kong, China
- Department of Clinical Oncology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Ming Liu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, China
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Stephanie Ma
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
- Department of Clinical Oncology, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, The University of Hong Kong - Shenzhen Hospital, Hong Kong, China.
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.
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20
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Jing S, Lian L, Hou Y, Li Z, Zheng Z, Li G, Tang G, Xie G, Xie M. Advances in volumetric bioprinting. Biofabrication 2023; 16:012004. [PMID: 37922535 DOI: 10.1088/1758-5090/ad0978] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 11/03/2023] [Indexed: 11/07/2023]
Abstract
The three-dimensional (3D) bioprinting technologies are suitable for biomedical applications owing to their ability to manufacture complex and high-precision tissue constructs. However, the slow printing speed of current layer-by-layer (bio)printing modality is the major limitation in biofabrication field. To overcome this issue, volumetric bioprinting (VBP) is developed. VBP changes the layer-wise operation of conventional devices, permitting the creation of geometrically complex, centimeter-scale constructs in tens of seconds. VBP is the next step onward from sequential biofabrication methods, opening new avenues for fast additive manufacturing in the fields of tissue engineering, regenerative medicine, personalized drug testing, and soft robotics, etc. Therefore, this review introduces the printing principles and hardware designs of VBP-based techniques; then focuses on the recent advances in VBP-based (bio)inks and their biomedical applications. Lastly, the current limitations of VBP are discussed together with future direction of research.
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Affiliation(s)
- Sibo Jing
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Biomedical Engineering, Guangzhou Medical University, Guangzhou 511436, People's Republic of China
| | - Liming Lian
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, United States of America
| | - Yingying Hou
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Biomedical Engineering, Guangzhou Medical University, Guangzhou 511436, People's Republic of China
| | - Zeqing Li
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Biomedical Engineering, Guangzhou Medical University, Guangzhou 511436, People's Republic of China
| | - Zihao Zheng
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Biomedical Engineering, Guangzhou Medical University, Guangzhou 511436, People's Republic of China
| | - Gang Li
- National Engineering Laboratory for Modern Silk, College of Textile and Clothing Engineering, Soochow University, Suzhou 215123, People's Republic of China
| | - Guosheng Tang
- 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 and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, People's Republic of China
| | - Guoxi Xie
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Biomedical Engineering, Guangzhou Medical University, Guangzhou 511436, People's Republic of China
| | - Maobin Xie
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Biomedical Engineering, Guangzhou Medical University, Guangzhou 511436, People's Republic of China
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21
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Li Z, Zhang Z, Fang L, Zhao J, Niu Z, Chen H, Cao G. Tumor Microenvironment Composition and Related Therapy in Hepatocellular Carcinoma. J Hepatocell Carcinoma 2023; 10:2083-2099. [PMID: 38022729 PMCID: PMC10676104 DOI: 10.2147/jhc.s436962] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 11/10/2023] [Indexed: 12/01/2023] Open
Abstract
Globally, primary liver cancer is the third leading cause of cancer death, and hepatocellular carcinoma (HCC) accounts for 75%-95%. The tumor microenvironment (TME), composed of the extracellular matrix, helper cells, immune cells, cytokines, chemokines, and growth factors, promotes the immune escape, invasion, and metastasis of HCC. Tumor metastasis and postoperative recurrence are the main threats to the long-term prognosis of HCC. TME-related therapies are increasingly recognized as effective treatments. Molecular-targeted therapy, immunotherapy, and their combined therapy are the main approaches. Immunotherapy, represented by immune checkpoint inhibitors (ICIs), and targeted therapy, highlighted by tyrosine kinase inhibitors (TKIs), have greatly improved the prognosis of HCC. This review focuses on the TME compositions and emerging therapeutic approaches to TME in HCC.
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Affiliation(s)
- Zishuai Li
- Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai, 200433, People’s Republic of China
- Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai, 200433, People’s Republic of China
- Department of Epidemiology, Second Military Medical University, Shanghai, 200433, People’s Republic of China
| | - Zihan Zhang
- Department of Epidemiology, Tongji University School of Medicine Tongji University, Shanghai, 200120, People’s Republic of China
| | - Letian Fang
- Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai, 200433, People’s Republic of China
- Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai, 200433, People’s Republic of China
- Department of Epidemiology, Second Military Medical University, Shanghai, 200433, People’s Republic of China
| | - Jiayi Zhao
- Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai, 200433, People’s Republic of China
- Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai, 200433, People’s Republic of China
- Department of Epidemiology, Second Military Medical University, Shanghai, 200433, People’s Republic of China
| | - Zheyun Niu
- Department of Epidemiology, Tongji University School of Medicine Tongji University, Shanghai, 200120, People’s Republic of China
| | - Hongsen Chen
- Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai, 200433, People’s Republic of China
- Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai, 200433, People’s Republic of China
- Department of Epidemiology, Second Military Medical University, Shanghai, 200433, People’s Republic of China
| | - Guangwen Cao
- Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai, 200433, People’s Republic of China
- Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai, 200433, People’s Republic of China
- Department of Epidemiology, Second Military Medical University, Shanghai, 200433, People’s Republic of China
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22
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Ren G, Zhou X, Long R, Xie M, Kankala RK, Wang S, Zhang YS, Liu Y. Biomedical applications of magnetosomes: State of the art and perspectives. Bioact Mater 2023; 28:27-49. [PMID: 37223277 PMCID: PMC10200801 DOI: 10.1016/j.bioactmat.2023.04.025] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 04/12/2023] [Accepted: 04/29/2023] [Indexed: 05/25/2023] Open
Abstract
Magnetosomes, synthesized by magnetotactic bacteria (MTB), have been used in nano- and biotechnological applications, owing to their unique properties such as superparamagnetism, uniform size distribution, excellent bioavailability, and easily modifiable functional groups. In this review, we first discuss the mechanisms of magnetosome formation and describe various modification methods. Subsequently, we focus on presenting the biomedical advancements of bacterial magnetosomes in biomedical imaging, drug delivery, anticancer therapy, biosensor. Finally, we discuss future applications and challenges. This review summarizes the application of magnetosomes in the biomedical field, highlighting the latest advancements and exploring the future development of magnetosomes.
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Affiliation(s)
- Gang Ren
- Institute of Pharmaceutical Engineering, Huaqiao University, Xiamen, Fujian, 361021, China
- College of Materials Science and Engineering, Huaqiao University, Xiamen, Fujian, 361021, China
| | - Xia Zhou
- Institute of Pharmaceutical Engineering, Huaqiao University, Xiamen, Fujian, 361021, China
- College of Chemical Engineering, Huaqiao University, Xiamen, Fujian, 361021, China
| | - Ruimin Long
- College of Chemical Engineering, Huaqiao University, Xiamen, Fujian, 361021, China
| | - Maobin Xie
- Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, 02139, USA
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, 511436, China
| | - Ranjith Kumar Kankala
- College of Chemical Engineering, Huaqiao University, Xiamen, Fujian, 361021, China
- Fujian Provincial Key Laboratory of Biochemical Technology, Xiamen, Fujian, 361021, China
| | - Shibin Wang
- Institute of Pharmaceutical Engineering, Huaqiao University, Xiamen, Fujian, 361021, China
- College of Materials Science and Engineering, Huaqiao University, Xiamen, Fujian, 361021, China
- Fujian Provincial Key Laboratory of Biochemical Technology, Xiamen, Fujian, 361021, China
| | - Yu Shrike Zhang
- Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, 02139, USA
| | - Yuangang Liu
- Institute of Pharmaceutical Engineering, Huaqiao University, Xiamen, Fujian, 361021, China
- College of Chemical Engineering, Huaqiao University, Xiamen, Fujian, 361021, China
- Fujian Provincial Key Laboratory of Biochemical Technology, Xiamen, Fujian, 361021, China
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23
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Ebrahimi SB, Hong X, Ludlow J, Doucet D, Thirumangalathu R. Studying Intermolecular Interactions in an Antibody-Drug Conjugate Through Chemical Screening and Computational Modeling. J Pharm Sci 2023; 112:2621-2628. [PMID: 37572780 DOI: 10.1016/j.xphs.2023.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 08/02/2023] [Accepted: 08/02/2023] [Indexed: 08/14/2023]
Abstract
Antibody-drug conjugates (ADCs) combine the selectivity of antibodies with the cytotoxicity of drug payloads to yield highly targeted and potent therapeutics. Owing to the need to chemically modify residues for attachment of the payload and their more complex structure compared to either component alone, ADCs can present additional challenges related to stability of the final drug product. Here, we report for the first time the use of high-throughput experimental screens and computational techniques to tune the conformational and colloidal behavior of a monomethyl auristatin F-based ADC. The ADC, which exhibits high opalescence with strongly attractive protein-protein interactions, is transformed into a more stable structure by experimentally traversing a library of more than ∼100 formulations. A significant reduction in turbidity and increase in diffusion interaction parameter is observed by varying properties such as pH and ionic strength. Computational modeling rationalized these changes and pointed to the presence of attractive electrostatic interactions between ADC molecules facilitated by the drug payload and histidine residues. Taken together, the experimental and computational work presented provides a general roadmap of studies to perform during ADC development to find stable formulations, while the mechanistic learnings can be applied towards the design and stabilization of other IgG1-based ADCs.
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Affiliation(s)
- Sasha B Ebrahimi
- Drug Product Development, Steriles, GlaxoSmithKline, Collegeville, PA 19426, United States.
| | - Xuan Hong
- Computational Sciences, GlaxoSmithKline, Collegeville, PA 19426, United States
| | - James Ludlow
- Drug Product Development, Steriles, GlaxoSmithKline, Collegeville, PA 19426, United States
| | - Dany Doucet
- Drug Product Development Packaging, Device and Design Solutions, GlaxoSmithKline, Collegeville, PA 19426, United States
| | - Renuka Thirumangalathu
- Drug Product Development, Steriles, GlaxoSmithKline, Collegeville, PA 19426, United States
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24
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Wang Y, Wan X, Du S. Integrated analysis revealing a novel stemness-metabolism-related gene signature for predicting prognosis and immunotherapy response in hepatocellular carcinoma. Front Immunol 2023; 14:1100100. [PMID: 37622118 PMCID: PMC10445950 DOI: 10.3389/fimmu.2023.1100100] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 07/10/2023] [Indexed: 08/26/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignant lethal tumor and both cancer stem cells (CSCs) and metabolism reprogramming have been proven to play indispensable roles in HCC. This study aimed to reveal the connection between metabolism reprogramming and the stemness characteristics of HCC, established a new gene signature related to stemness and metabolism and utilized it to assess HCC prognosis and immunotherapy response. The clinical information and gene expression profiles (GEPs) of 478 HCC patients came from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA). The one-class logistic regression (OCLR) algorithm was employed to calculate the messenger ribonucleic acid expression-based stemness index (mRNAsi), a new stemness index quantifying stemness features. Differentially expressed analyses were done between high- and low-mRNAsi groups and 74 differentially expressed metabolism-related genes (DEMRGs) were identified with the help of metabolism-related gene sets from Molecular Signatures Database (MSigDB). After integrated analysis, a risk score model based on the three most efficient prognostic DEMRGs, including Recombinant Phosphofructokinase Platelet (PFKP), phosphodiesterase 2A (PDE2A) and UDP-glucuronosyltransferase 1A5 (UGT1A5) was constructed and HCC patients were divided into high-risk and low-risk groups. Significant differences were found in pathway enrichment, immune cell infiltration patterns, and gene alterations between the two groups. High-risk group patients tended to have worse clinical outcomes and were more likely to respond to immunotherapy. A stemness-metabolism-related model composed of gender, age, the risk score model and tumor-node-metastasis (TNM) staging was generated and showed great discrimination and strong ability in predicting HCC prognosis and immunotherapy response.
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Affiliation(s)
| | | | - Shunda Du
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China
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25
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Ebrahimi SB, Samanta D. Engineering protein-based therapeutics through structural and chemical design. Nat Commun 2023; 14:2411. [PMID: 37105998 PMCID: PMC10132957 DOI: 10.1038/s41467-023-38039-x] [Citation(s) in RCA: 125] [Impact Index Per Article: 62.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 04/05/2023] [Indexed: 04/29/2023] Open
Abstract
Protein-based therapeutics have led to new paradigms in disease treatment. Projected to be half of the top ten selling drugs in 2023, proteins have emerged as rivaling and, in some cases, superior alternatives to historically used small molecule-based medicines. This review chronicles both well-established and emerging design strategies that have enabled this paradigm shift by transforming protein-based structures that are often prone to denaturation, degradation, and aggregation in vitro and in vivo into highly effective therapeutics. In particular, we discuss strategies for creating structures with increased affinity and targetability, enhanced in vivo stability and pharmacokinetics, improved cell permeability, and reduced amounts of undesired immunogenicity.
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Affiliation(s)
- Sasha B Ebrahimi
- Drug Product Development-Steriles, GlaxoSmithKline, Collegeville, PA, 19426, USA.
| | - Devleena Samanta
- Department of Chemistry, The University of Texas at Austin, Austin, TX, 78712, USA.
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Cherradi S, Garambois V, Marines J, Andrade AF, Fauvre A, Morand O, Fargal M, Mancouri F, Ayrolles-Torro A, Vezzo-Vié N, Jarlier M, Loussaint G, Huvelle S, Joubert N, Mazard T, Gongora C, Pourquier P, Boissière-Michot F, Rio MD. Improving the response to oxaliplatin by targeting chemotherapy-induced CLDN1 in resistant metastatic colorectal cancer cells. Cell Biosci 2023; 13:72. [PMID: 37041570 PMCID: PMC10091849 DOI: 10.1186/s13578-023-01015-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 03/15/2023] [Indexed: 04/13/2023] Open
Abstract
BACKGROUND Tumor resistance is a frequent cause of therapy failure and remains a major challenge for the long-term management of colorectal cancer (CRC). The aim of this study was to determine the implication of the tight junctional protein claudin 1 (CLDN1) in the acquired resistance to chemotherapy. METHODS Immunohistochemistry was used to determine CLDN1 expression in post-chemotherapy liver metastases from 58 CRC patients. The effects of oxaliplatin on membrane CLDN1 expression were evaluated by flow cytometry, immunofluorescence and western blotting experiments in vitro and in vivo. Phosphoproteome analyses, proximity ligation and luciferase reporter assays were used to unravel the mechanism of CLDN1 induction. RNAseq experiments were performed on oxaliplatin-resistant cell lines to investigate the role of CLDN1 in chemoresistance. The "one-two punch" sequential combination of oxaliplatin followed by an anti-CLDN1 antibody-drug conjugate (ADC) was tested in both CRC cell lines and murine models. RESULTS We found a significant correlation between CLDN1 expression level and histologic response to chemotherapy, CLDN1 expression being the highest in resistant metastatic residual cells of patients showing minor responses. Moreover, in both murine xenograft model and CRC cell lines, CLDN1 expression was upregulated after exposure to conventional chemotherapies used in CRC treatment. CLDN1 overexpression was, at least in part, functionally related to the activation of the MAPKp38/GSK3β/Wnt/β-catenin pathway. Overexpression of CLDN1 was also observed in oxaliplatin-resistant CRC cell lines and was associated with resistance to apoptosis, suggesting an anti-apoptotic role for CLDN1. Finally, we demonstrated that the sequential treatment with oxaliplatin followed by an anti-CLDN1 ADC displayed a synergistic effect in vitro and in in vivo. CONCLUSION Our study identifies CLDN1 as a new biomarker of acquired resistance to chemotherapy in CRC patients and suggests that a "one-two punch" approach targeting chemotherapy-induced CLDN1 expression may represent a therapeutic opportunity to circumvent resistance and to improve the outcome of patients with advanced CRC.
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Affiliation(s)
- Sara Cherradi
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut du Cancer de Montpellier, 208 rue des Apothicaires, Montpellier Cedex 5, F-34298, France
| | - Véronique Garambois
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut du Cancer de Montpellier, 208 rue des Apothicaires, Montpellier Cedex 5, F-34298, France
| | - Johanna Marines
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut du Cancer de Montpellier, 208 rue des Apothicaires, Montpellier Cedex 5, F-34298, France
| | - Augusto Faria Andrade
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut du Cancer de Montpellier, 208 rue des Apothicaires, Montpellier Cedex 5, F-34298, France
| | - Alexandra Fauvre
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut du Cancer de Montpellier, 208 rue des Apothicaires, Montpellier Cedex 5, F-34298, France
| | - Olivia Morand
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut du Cancer de Montpellier, 208 rue des Apothicaires, Montpellier Cedex 5, F-34298, France
| | - Manon Fargal
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut du Cancer de Montpellier, 208 rue des Apothicaires, Montpellier Cedex 5, F-34298, France
| | - Ferial Mancouri
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut du Cancer de Montpellier, 208 rue des Apothicaires, Montpellier Cedex 5, F-34298, France
| | - Adeline Ayrolles-Torro
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut du Cancer de Montpellier, 208 rue des Apothicaires, Montpellier Cedex 5, F-34298, France
| | - Nadia Vezzo-Vié
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut du Cancer de Montpellier, 208 rue des Apothicaires, Montpellier Cedex 5, F-34298, France
| | - Marta Jarlier
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut du Cancer de Montpellier, 208 rue des Apothicaires, Montpellier Cedex 5, F-34298, France
- Biometry Department, ICM, Montpellier, France
| | - Gerald Loussaint
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut du Cancer de Montpellier, 208 rue des Apothicaires, Montpellier Cedex 5, F-34298, France
| | - Steve Huvelle
- GICC, Team IMT, University of Tours, Tours, 7501, F-37032, France
| | - Nicolas Joubert
- GICC, Team IMT, University of Tours, Tours, 7501, F-37032, France
| | - Thibault Mazard
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut du Cancer de Montpellier, 208 rue des Apothicaires, Montpellier Cedex 5, F-34298, France
- Department of Medical Oncology, ICM, Montpellier, France
| | - Céline Gongora
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut du Cancer de Montpellier, 208 rue des Apothicaires, Montpellier Cedex 5, F-34298, France
| | - Philippe Pourquier
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut du Cancer de Montpellier, 208 rue des Apothicaires, Montpellier Cedex 5, F-34298, France
| | - Florence Boissière-Michot
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut du Cancer de Montpellier, 208 rue des Apothicaires, Montpellier Cedex 5, F-34298, France
- Translational Research Unit, ICM, Montpellier, France
| | - Maguy Del Rio
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut du Cancer de Montpellier, 208 rue des Apothicaires, Montpellier Cedex 5, F-34298, France.
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Wu Q, Peng M, Lv C, Chen L, Mao X, Lin T, Sun P, Wang Y. Claudin-6 enhances the malignant progression of gestational trophoblastic neoplasm by promoting proliferation and metastasis. Clin Transl Oncol 2023; 25:1114-1123. [PMID: 36471225 DOI: 10.1007/s12094-022-03021-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 11/20/2022] [Indexed: 12/12/2022]
Abstract
PURPOSE Choriocarcinoma (CC) is a rare and highly malignant epithelial tumour. However, the mechanism underlying its occurrence and development remains unknown. We aimed to reveal the biological significance and prognostic value of Claudin-6 (CLDN6) in gestational trophoblastic disease (GTD). PATIENTS AND METHODS We collected clinical GTD specimens from 2011 to 2019 and measured CLDN6 gene expression by immunohistochemistry (IHC). High-throughput mRNA sequencing (RNA-seq) revealed a GTD progression-associated gene. CCK-8, wound healing, and flow cytometry assays were used to assess the biological effects of CLDN6 overexpression and knockdown. The medical records of 118 GTD patients from 2011 to 2019 were retrospectively analysed to identify correlations between CLDN6 expression and GTD patient clinical-pathological parameters; these correlations were analysed using the chi-square test and one-way ANOVA. Univariate logistic regression was used to analyse various prognostic parameters of patients with post-molar GTN. RESULTS CLDN6 had the second highest fold change in gene expression between GTN and normal samples. CLDN6 was highly expressed in GTN tissues and CC cell lines, and silencing CLDN6 inhibited the proliferation and migration and promoted the apoptosis of CC cells. CLDN6 overexpression was significantly correlated with uterine size (p = 0.01) and ovarian cysts > 6 cm (p = 0.027), CLDN6 expression was significantly higher in HR-GTNs than in low-risk GTNs (LR-GTNs) (p = 0.008), and logistic regression analysis showed that CLDN6 expression in hydatidiform moles (HMs) was related to a high risk of developing post-molar GTN (OR = 2.393, p = 0.03). CONCLUSION We propose that CLDN6 participates in the development of GTD and may become a new therapeutic target for CC.
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Affiliation(s)
- Qibin Wu
- Department of Gynecology, Obstetrics and Gynecology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, People's Republic of China
- Department of Gynecology, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou, People's Republic of China
| | - Meilian Peng
- Department of Gynecology, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou, People's Republic of China
| | - Chengyu Lv
- Department of Gynecology, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou, People's Republic of China
| | - Lihua Chen
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing, People's Republic of China
| | - Xiaodan Mao
- Laboratory of Gynecologic Oncology, Department of Gynecology, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, People's Republic of China
- Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fuzhou, People's Republic of China
| | - Tianfu Lin
- Department of Gynecology, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou, People's Republic of China
| | - Pengming Sun
- Department of Gynecology, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou, People's Republic of China.
- Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fuzhou, People's Republic of China.
| | - Yifeng Wang
- Department of Gynecology, Obstetrics and Gynecology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, People's Republic of China.
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Fujiwara-Tani R, Mori S, Ogata R, Sasaki R, Ikemoto A, Kishi S, Kondoh M, Kuniyasu H. Claudin-4: A New Molecular Target for Epithelial Cancer Therapy. Int J Mol Sci 2023; 24:5494. [PMID: 36982569 PMCID: PMC10051602 DOI: 10.3390/ijms24065494] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 03/10/2023] [Accepted: 03/10/2023] [Indexed: 03/16/2023] Open
Abstract
Claudin-4 (CLDN4) is a key component of tight junctions (TJs) in epithelial cells. CLDN4 is overexpressed in many epithelial malignancies and correlates with cancer progression. Changes in CLDN4 expression have been associated with epigenetic factors (such as hypomethylation of promoter DNA), inflammation associated with infection and cytokines, and growth factor signaling. CLDN4 helps to maintain the tumor microenvironment by forming TJs and acts as a barrier to the entry of anticancer drugs into tumors. Decreased expression of CLDN4 is a potential marker of epithelial-mesenchymal transition (EMT), and decreased epithelial differentiation due to reduced CLDN4 activity is involved in EMT induction. Non-TJ CLDN4 also activates integrin beta 1 and YAP to promote proliferation, EMT, and stemness. These roles in cancer have led to investigations of molecular therapies targeting CLDN4 using anti-CLDN4 extracellular domain antibodies, gene knockdown, clostridium perfringens enterotoxin (CPE), and C-terminus domain of CPE (C-CPE), which have demonstrated the experimental efficacy of this approach. CLDN4 is strongly involved in promoting malignant phenotypes in many epithelial cancers and is regarded as a promising molecular therapeutic target.
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Affiliation(s)
- Rina Fujiwara-Tani
- Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan; (S.M.); (R.O.); (R.S.); (A.I.); (S.K.)
| | - Shiori Mori
- Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan; (S.M.); (R.O.); (R.S.); (A.I.); (S.K.)
| | - Ruiko Ogata
- Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan; (S.M.); (R.O.); (R.S.); (A.I.); (S.K.)
| | - Rika Sasaki
- Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan; (S.M.); (R.O.); (R.S.); (A.I.); (S.K.)
| | - Ayaka Ikemoto
- Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan; (S.M.); (R.O.); (R.S.); (A.I.); (S.K.)
| | - Shingo Kishi
- Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan; (S.M.); (R.O.); (R.S.); (A.I.); (S.K.)
| | - Masuo Kondoh
- Drug Innovation Center, Graduate School of Pharmaceutical Sciences, Osaka University, 6-1 Yamadaoka, Suita 565-0871, Japan;
| | - Hiroki Kuniyasu
- Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan; (S.M.); (R.O.); (R.S.); (A.I.); (S.K.)
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Shi ZD, Pang K, Wu ZX, Dong Y, Hao L, Qin JX, Wang W, Chen ZS, Han CH. Tumor cell plasticity in targeted therapy-induced resistance: mechanisms and new strategies. Signal Transduct Target Ther 2023; 8:113. [PMID: 36906600 PMCID: PMC10008648 DOI: 10.1038/s41392-023-01383-x] [Citation(s) in RCA: 82] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 12/07/2022] [Accepted: 02/20/2023] [Indexed: 03/13/2023] Open
Abstract
Despite the success of targeted therapies in cancer treatment, therapy-induced resistance remains a major obstacle to a complete cure. Tumor cells evade treatments and relapse via phenotypic switching driven by intrinsic or induced cell plasticity. Several reversible mechanisms have been proposed to circumvent tumor cell plasticity, including epigenetic modifications, regulation of transcription factors, activation or suppression of key signaling pathways, as well as modification of the tumor environment. Epithelial-to-mesenchymal transition, tumor cell and cancer stem cell formation also serve as roads towards tumor cell plasticity. Corresponding treatment strategies have recently been developed that either target plasticity-related mechanisms or employ combination treatments. In this review, we delineate the formation of tumor cell plasticity and its manipulation of tumor evasion from targeted therapy. We discuss the non-genetic mechanisms of targeted drug-induced tumor cell plasticity in various types of tumors and provide insights into the contribution of tumor cell plasticity to acquired drug resistance. New therapeutic strategies such as inhibition or reversal of tumor cell plasticity are also presented. We also discuss the multitude of clinical trials that are ongoing worldwide with the intention of improving clinical outcomes. These advances provide a direction for developing novel therapeutic strategies and combination therapy regimens that target tumor cell plasticity.
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Affiliation(s)
- Zhen-Duo Shi
- Department of Urology, Xuzhou Clinical School of Xuzhou Medical University, Jiangsu, China.,Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China.,School of Life Sciences, Jiangsu Normal University, Jiangsu, China.,Department of Urology, Heilongjiang Provincial Hospital, Heilongjiang, China
| | - Kun Pang
- Department of Urology, Xuzhou Clinical School of Xuzhou Medical University, Jiangsu, China.,Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Zhuo-Xun Wu
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Yang Dong
- Department of Urology, Xuzhou Clinical School of Xuzhou Medical University, Jiangsu, China.,Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Lin Hao
- Department of Urology, Xuzhou Clinical School of Xuzhou Medical University, Jiangsu, China.,Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Jia-Xin Qin
- Department of Urology, Xuzhou Clinical School of Xuzhou Medical University, Jiangsu, China.,Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Wei Wang
- Department of Medical College, Southeast University, Nanjing, China
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
| | - Cong-Hui Han
- Department of Urology, Xuzhou Clinical School of Xuzhou Medical University, Jiangsu, China. .,Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China. .,School of Life Sciences, Jiangsu Normal University, Jiangsu, China. .,Department of Urology, Heilongjiang Provincial Hospital, Heilongjiang, China.
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30
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Li MM, Kong FE, Li GM, He YT, Zhang XF, Zhang CY, Liang JK, Guan XY, Ma NF, Xie MB, Liu M. Identification and functional characterization of potential oncofetal targets in human hepatocellular carcinoma. STAR Protoc 2022; 3:101921. [PMID: 36595904 PMCID: PMC9763774 DOI: 10.1016/j.xpro.2022.101921] [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: 08/13/2022] [Revised: 10/09/2022] [Accepted: 11/18/2022] [Indexed: 12/13/2022] Open
Abstract
Here, we present a detailed protocol for the identification of potential oncofetal targets for hepatocellular carcinoma (HCC) patients through a hepatocyte differentiation model and a sorafenib refractory cell-line-derived xenograft model. We describe the procedures of tumor sphere formation, organoid generation, and subcutaneous tumor formation for functional studies. We then detail the procedures of immunohistochemistry and immunofluorescence for examination of changes in lineage-specific markers. Finally, we describe the development of antibody-based therapeutics targeting tumor lineage plasticity in HCC. For complete details on the use and execution of this protocol, please refer to Kong et al. (2021).1.
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Affiliation(s)
- Mei-Mei Li
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou 510095, China,Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Xinzao, Panyu District, Guangzhou 511436, China
| | - Fan-En Kong
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou 510095, China,Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Xinzao, Panyu District, Guangzhou 511436, China
| | - Guang-Meng Li
- The Second Affiliated Hospital, The State Key Laboratory of Respiratory Disease, Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou Medical University, Guangzhou 510260, China
| | - Yi-Ti He
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou 510095, China,Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Xinzao, Panyu District, Guangzhou 511436, China
| | - Xiao-Feng Zhang
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Cheng-Yang Zhang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou 510095, China,Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Xinzao, Panyu District, Guangzhou 511436, China
| | - Jie-Kai Liang
- The Third Clinical School of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 511436, China
| | - Xin-Yuan Guan
- Department of Clinical Oncology, State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
| | - Ning-Fang Ma
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou 510095, China,Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Xinzao, Panyu District, Guangzhou 511436, China
| | - Mao-Bin Xie
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Biomedical Engineering, Guangzhou Medical University, Guangzhou 511436, China,Correspondance:
| | - Ming Liu
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou 510095, China,Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Xinzao, Panyu District, Guangzhou 511436, China,Correspondance:
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Sun R, Gao Y, Shen F. Identification of subtypes of hepatocellular carcinoma and screening of prognostic molecular diagnostic markers based on cell adhesion molecule related genes. Front Genet 2022; 13:1042540. [PMID: 36482887 PMCID: PMC9723242 DOI: 10.3389/fgene.2022.1042540] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 11/09/2022] [Indexed: 10/03/2023] Open
Abstract
Cell adhesion molecules can predict liver hepatocellular carcinoma (LIHC) metastasis and determine prognosis, while the mechanism of the role of cell adhesion molecules in LIHC needs to be further explored. LIHC-related expression data were sourced from The Cancer Genome Atlas (TCGA) and the gene expression omnibus (GEO) databases, and genes related to cell adhesion were sourced from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. First, the TCGA-LIHC dataset was clustered by the nonnegative matrix factorization (NMF) algorithm to find different subtypes of LIHC. Then the difference of prognosis and immune microenvironment between patients of different subtypes was evaluated. In addition, a prognostic risk model was obtained by least shrinkage and selection operator (LASSO) and Cox analysis, while a nomogram was drawn. Furthermore, functional enrichment analysis between high and low risk groups was conducted. Finally, the expressions of model genes were explored by quantitative real-time polymerase chain reaction (qRT-PCR). The 371 LIHC patients were classified into four subtypes by NMF clustering, and survival analysis revealed that disease-free survival (DFS) of these four subtypes were clearly different. Cancer-related pathways and immune microenvironment among these four subtypes were dysregulated. Moreover, 58 common differentially expressed genes (DEGs) between four subtypes were identified and were mainly associated with PPAR signaling pathway and amino acid metabolism. Furthermore, a prognostic model consisting of IGSF11, CD8A, ALCAM, CLDN6, JAM2, ITGB7, SDC3, CNTNAP1, and MPZ was built. A nomogram consisting of pathologic T and riskScore was built, and the calibration curve illustrated that the nomogram could better forecast LIHC prognosis. Gene Set Enrichment Analysis (GSEA) demonstrated that DEGs between high and low risk groups were mainly involved in cell cycle. Finally, the qRT-PCR illustrated the expressions of nine model genes between normal and LIHC tissue. A prognostic model consisting of IGSF11, CD8A, ALCAM, CLDN6, JAM2, ITGB7, SDC3, CNTNAP1, and MPZ was obtained, which provides an important reference for the molecular diagnosis of patient prognosis.
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Affiliation(s)
- Ruge Sun
- College of Medicine, Shanxi Medical University, Taiyuan, China
- Department of Gastroenterology and Hepatoloy, The First Hospital of Shanxi Medical University, Taiyuan, China
| | - Yanchao Gao
- Department of Hepatobiliary Surgery, Liaocheng People’s Hospital, Liaocheng, China
| | - Fengjun Shen
- Department of Gastroenterology and Hepatoloy, The First Hospital of Shanxi Medical University, Taiyuan, China
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Tang H, Yuan J, Gong YF, Zhang CY, Liu M, Luo SX. Single-cell transcriptome sequencing reveals potential novel combination of biomarkers for antibody-based cancer therapeutics in hepatocellular carcinoma. Front Genet 2022; 13:928256. [PMID: 36186483 PMCID: PMC9515615 DOI: 10.3389/fgene.2022.928256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 08/12/2022] [Indexed: 11/23/2022] Open
Abstract
Background: Antibody-based cancer therapeutics is developing rapidly in recent years for its advantages in precisely targeting the tumor cells. However, tumor-specific cell surface antigens are still lacking, and the heterogeneity of tumor mass greatly impeded the development of effective drugs. Methods: In the present study, single-cell RNA sequencing was used to dissect tumor heterogeneity in human hepatocellular carcinoma (HCC). Tissues from different spatial regions including the tumor, para-tumor, and distant normal liver tissues were dissociated into single cells, and the gene expressions were compared in a different subpopulation of cells from these regions and validated in independent cohorts. Results: A total of 28 cell clusters with different distribution patterns and gene expression profiles were identified within a heterogenous tumor and its paired liver tissues. Differentially expressed genes encoding the plasma membrane in cells with hepatic lineage were further extracted from single-cell transcriptome sequencing and validated in TCGA database. A 3-gene signature was identified to be significantly upregulated in dominant HCC tumor cell subpopulations with prognostic significance and validated in multiple independent patient cohorts. Conclusion: The composition of the three plasma membrane proteins on the surface of HCC tumor cells within a heterogenous tumor might indicate poor prognostic tumor subpopulations during cancer evolution and potential therapeutic targets.
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Affiliation(s)
- Hong Tang
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Jun Yuan
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
- School of Basic Medical Science, Guangzhou Medical University, Guangzhou, China
| | - Yuan-Feng Gong
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Cheng-Yang Zhang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
- School of Basic Medical Science, Guangzhou Medical University, Guangzhou, China
| | - Ming Liu
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
- School of Basic Medical Science, Guangzhou Medical University, Guangzhou, China
| | - Su-Xia Luo
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
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Mranda GM, Xiang ZP, Liu JJ, Wei T, Ding Y. Advances in prognostic and therapeutic targets for hepatocellular carcinoma and intrahepatic cholangiocarcinoma: The hippo signaling pathway. Front Oncol 2022; 12:937957. [PMID: 36033517 PMCID: PMC9411807 DOI: 10.3389/fonc.2022.937957] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 07/13/2022] [Indexed: 01/07/2023] Open
Abstract
Primary liver cancer is the sixth most frequently diagnosed cancer worldwide and the third leading cause of cancer-related death. The majority of the primary liver cancer cases are hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Worldwide, there is an increasing incidence of primary liver cancer cases due to multiple risk factors ranging from parasites and viruses to metabolic diseases and lifestyles. Often, patients are diagnosed at advanced stages, depriving them of surgical curability benefits. Moreover, the efficacy of the available chemotherapeutics is limited in advanced stages. Furthermore, tumor metastases and recurrence make primary liver cancer management exceptionally challenging. Thus, exploring the molecular mechanisms for the development and progression of primary liver cancer is critical in improving diagnostic, treatment, prognostication, and surveillance modalities. These mechanisms facilitate the discovery of specific targets that are critical for novel and more efficient treatments. Consequently, the Hippo signaling pathway executing a pivotal role in organogenesis, hemostasis, and regeneration of tissues, regulates liver cells proliferation, and apoptosis. Cell polarity or adhesion molecules and cellular metabolic status are some of the biological activators of the pathway. Thus, understanding the mechanisms exhibited by the Hippo pathway is critical to the development of novel targeted therapies. This study reviews the advances in identifying therapeutic targets and prognostic markers of the Hippo pathway for primary liver cancer in the past six years.
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34
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Mechanisms of resistance to tyrosine kinase inhibitors in liver cancer stem cells and potential therapeutic approaches. Essays Biochem 2022; 66:371-386. [PMID: 35818992 DOI: 10.1042/ebc20220001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 06/13/2022] [Accepted: 06/17/2022] [Indexed: 12/24/2022]
Abstract
The administration of tyrosine kinase inhibitors (TKIs) for the treatment of advanced-stage patients is common in hepatocellular carcinoma (HCC). However, therapy resistance is often encountered, and its emergence eventually curtails long-term clinical benefits. Cancer stem cells (CSCs) are essential drivers of tumor recurrence and therapy resistance; thus, the elucidation of key hallmarks of resistance mechanisms of liver CSC-driven HCC may help improve patient outcomes and reduce relapse. The present review provides a comprehensive summary of the intrinsic and extrinsic mechanisms of TKI resistance in liver CSCs, which mediate treatment failure, and discusses potential strategies to overcome TKI resistance from a preclinical perspective.
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35
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Qu H, Wang M, Wang M, Liu Y, Quan C. The expression and the tumor suppressor role of CLDN6 in colon cancer. Mol Cell Biochem 2022; 477:2883-2893. [PMID: 35701678 DOI: 10.1007/s11010-022-04450-z] [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: 11/17/2021] [Accepted: 04/24/2022] [Indexed: 11/29/2022]
Abstract
As a member of the tight junction family, CLDN6 is a tumor suppressor in breast cancer, but its role in colon cancer is unknown. In this research, we aimed at revealing the function of CLDN6 in colon cancer. We found that colon cancer tissues lowly expressed CLDN6, and the expression of CLDN6 was negatively correlated with lymph node metastasis. Similarly, CLDN6 was lowly expressed in the colon cancer cell line SW1116, and overexpression of CLDN6 inhibited cell proliferation in vitro and in vivo. Consistently, the migration and invasion abilities of cells were significantly inhibited after CLDN6 overexpression. In addition, we demonstrated that CLDN6 may inhibit the migration and invasion abilities by activating the TYK2/STAT3 pathway. Therefore, our data indicated that CLDN6 acted as a tumor suppressor and had the potential to be regarded as a biomarker for the progression of colon cancer.
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Affiliation(s)
- Huinan Qu
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, 130021, Jilin, People's Republic of China
| | - Min Wang
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, 130021, Jilin, People's Republic of China
| | - Miaomiao Wang
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, 130021, Jilin, People's Republic of China
| | - Yuanyuan Liu
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, 130021, Jilin, People's Republic of China
| | - Chengshi Quan
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, 126 Xinmin Avenue, Changchun, 130021, Jilin, People's Republic of China.
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36
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Oncofetal proteins and cancer stem cells. Essays Biochem 2022; 66:423-433. [PMID: 35670043 DOI: 10.1042/ebc20220025] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/17/2022] [Accepted: 05/20/2022] [Indexed: 12/12/2022]
Abstract
Abstract
Cancer stem cells (CSCs) are considered as a small population of cells with stem-like properties within the tumor bulk, and are largely responsible for tumor recurrence, metastasis, and therapy resistance. CSCs share critical features with embryonic stem cells (ESCs). The pluripotent transcription factors (TFs) and developmental signaling pathways of ESCs are invariably hijacked by CSCs termed ‘oncofetal drivers’ in many cancers, which are rarely detectable in adult tissues. The unique expression pattern makes oncofetal proteins ideal therapeutic targets in cancer treatment. Therefore, elucidation of oncofetal drivers in cancers is critical for the development of effective CSCs-directed therapy. In this review, we summarize the common pluripotent TFs such as OCT4, SOX2, NANOG, KLF4, MYC, SALL4, and FOXM1, as well as the development signaling including Wnt/β-catenin, Hedgehog (Hh), Hippo, Notch, and TGF-β pathways of ESCs and CSCs. We also describe the newly identified oncofetal proteins that drive the self-renewal, plasticity, and therapy-resistance of CSCs. Finally, we explore how the clinical implementation of targeting oncofetal drivers, including small-molecule inhibitors, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) can facilitate the development of CSCs-directed therapy.
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Eroglu E, Yen CYT, Tsoi YL, Witman N, Elewa A, Joven Araus A, Wang H, Szattler T, Umeano CH, Sohlmér J, Goedel A, Simon A, Chien KR. Epicardium-derived cells organize through tight junctions to replenish cardiac muscle in salamanders. Nat Cell Biol 2022; 24:645-658. [PMID: 35550612 PMCID: PMC9106584 DOI: 10.1038/s41556-022-00902-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 03/21/2022] [Indexed: 12/13/2022]
Abstract
The contribution of the epicardium, the outermost layer of the heart, to cardiac regeneration has remained controversial due to a lack of suitable analytical tools. By combining genetic marker-independent lineage-tracing strategies with transcriptional profiling and loss-of-function methods, we report here that the epicardium of the highly regenerative salamander species Pleurodeles waltl has an intrinsic capacity to differentiate into cardiomyocytes. Following cryoinjury, CLDN6+ epicardium-derived cells appear at the lesion site, organize into honeycomb-like structures connected via focal tight junctions and undergo transcriptional reprogramming that results in concomitant differentiation into de novo cardiomyocytes. Ablation of CLDN6+ differentiation intermediates as well as disruption of their tight junctions impairs cardiac regeneration. Salamanders constitute the evolutionarily closest species to mammals with an extensive ability to regenerate heart muscle and our results highlight the epicardium and tight junctions as key targets in efforts to promote cardiac regeneration.
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Affiliation(s)
- Elif Eroglu
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
| | - Christopher Y T Yen
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Yat-Long Tsoi
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Nevin Witman
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Ahmed Elewa
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
- Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, Barcelona, Spain
| | - Alberto Joven Araus
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Heng Wang
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
- College of Animal Sciences and Technology, Huazhong Agricultural University, Wuhan, China
| | - Tamara Szattler
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Chimezie H Umeano
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
- Department of Molecular Medicine and Gene Therapy, Lunds Universitet, Lund, Sweden
| | - Jesper Sohlmér
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Alexander Goedel
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
- Klinik und Poliklinik für Innere Medizin I, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany
| | - András Simon
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
| | - Kenneth R Chien
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
- Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
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Matsuzaki J, Lele S, Odunsi K, Tsuji T. Identification of Claudin 6-specific HLA class I- and HLA class II-restricted T cell receptors for cellular immunotherapy in ovarian cancer. Oncoimmunology 2022; 11:2020983. [PMID: 35003898 PMCID: PMC8741298 DOI: 10.1080/2162402x.2021.2020983] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Adoptive cell therapy (ACT) is one of promising immunotherapies for cancer patients by providing a large amount of cancer antigen-specific effector T cells that can be manufactured rapidly by ex vivo gene engineering. To provide antigen-specificity to patients’ autologous T cells in a short-term culture, T-cell receptors (TCRs) or chimeric antigen receptors (CARs) are transduced to bulk T cells. Because of intra- and inter-tumoral heterogeneity in tumor antigen expression, a repertoire of TCR or CAR genes targeting a wide range of tumor antigens are required for a broad and effective treatment by ACT. Here, we characterized immunogenicity of claudin 6 (CLDN6) in ovarian cancer patients and identified specific TCR genes from CD8+ and CD4+ T cells. CLDN6 protein was frequently expressed on EpCAM+ ovarian cancer cells but not CD45+ lymphocytes in tumor ascites of ovarian cancer patients. Spontaneous CLDN6-specific CD4+ and CD8+ T-cell response was detected in peripheral blood mononuclear cells (PBMCs) from 1 out of 17 ovarian cancer patients. HLA-A*02:01 (A2) and DR*04:04 (DR4)-restricted TCR genes were isolated from CLDN6-specific CD8+ and CD4+ T cells, respectively. T cells that were engineered with A2-restricted TCR gene recognized and killed A2+CLDN6+ cancer cells. DR4-restricted TCR-transduced T cells directly recognized DR4+CLDN6+-overexpressed cancer cells. Our results demonstrate that these CLDN6-specific TCR genes are useful as therapeutic genes for ACT to patients with ovarian and other solid tumors expressing CLDN6.
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Affiliation(s)
- Junko Matsuzaki
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.,Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA.,University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA
| | - Shashikant Lele
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Kunle Odunsi
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.,Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA.,University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA.,Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Takemasa Tsuji
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.,Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA.,University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA
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Zhang H, Zhang W, Jiang L, Chen Y. Recent advances in systemic therapy for hepatocellular carcinoma. Biomark Res 2022; 10:3. [PMID: 35000616 PMCID: PMC8744248 DOI: 10.1186/s40364-021-00350-4] [Citation(s) in RCA: 133] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 09/26/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumors in the world. Therapeutic options for advanced HCC are limited. Systemic treatment, especially with conventional cytotoxic drugs, is usually ineffective. For more than a decade, sorafenib has been the only systemic drug that has been proven to be clinically effective for treating advanced HCC. However, over the past three years, the rapid progress of molecular targeted therapies has dramatically changed the treatment landscape for advanced HCC. Immune checkpoint therapies are now being incorporated into HCC therapies, and their combination with molecular targeted therapy is emerging as a tool to enhance the immune response. In this review, we summarize the development and progress of molecular targeted agents and immunotherapies in HCC.
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Affiliation(s)
- Huajun Zhang
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Wuyang Zhang
- Clinical skills training center, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Longying Jiang
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
| | - Yongheng Chen
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
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Qu H, Qi D, Wang X, Dong Y, Jin Q, Wei J, Quan C. CLDN6 Suppresses c-MYC-Mediated Aerobic Glycolysis to Inhibit Proliferation by TAZ in Breast Cancer. Int J Mol Sci 2021; 23:ijms23010129. [PMID: 35008557 PMCID: PMC8745066 DOI: 10.3390/ijms23010129] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/08/2021] [Accepted: 12/20/2021] [Indexed: 12/22/2022] Open
Abstract
Claudin 6 (CLDN6) was found to be a breast cancer suppressor gene, which is lowly expressed in breast cancer and inhibits breast cancer cell proliferation upon overexpression. However, the mechanism by which CLDN6 inhibits breast cancer proliferation is unclear. Here, we investigated this issue and elucidated the molecular mechanisms by which CLDN6 inhibits breast cancer proliferation. First, we verified that CLDN6 was lowly expressed in breast cancer tissues and that patients with lower CLDN6 expression had a worse prognosis. Next, we confirmed that CLDN6 inhibited breast cancer proliferation through in vitro and in vivo experiments. As for the mechanism, we found that CLDN6 inhibited c-MYC-mediated aerobic glycolysis based on a metabolomic analysis of CLDN6 affecting cellular lactate levels. CLDN6 interacted with a transcriptional co-activator with PDZ-binding motif (TAZ) and reduced the level of TAZ, thereby suppressing c-MYC transcription, which led to a reduction in glucose uptake and lactate production. Considered together, our results suggested that CLDN6 suppressed c-MYC-mediated aerobic glycolysis to inhibit the proliferation of breast cancer by TAZ, which indicated that CLDN6 acted as a novel regulator of aerobic glycolysis and provided a theoretical basis for CLDN6 as a biomarker of progression in breast cancer.
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Qu H, Jin Q, Quan C. CLDN6: From Traditional Barrier Function to Emerging Roles in Cancers. Int J Mol Sci 2021; 22:ijms222413416. [PMID: 34948213 PMCID: PMC8705207 DOI: 10.3390/ijms222413416] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/06/2021] [Accepted: 12/12/2021] [Indexed: 02/07/2023] Open
Abstract
Claudins (CLDNs) are the most important tight junction proteins, which are mainly expressed in endothelial cells or epithelial cells in a tissue-specific manner. As a member of the CLDNs family, CLDN6 is highly expressed in fetal tissues such as the stomach, pancreas, lung, and kidney, but is not expressed in corresponding adult tissues. The expression of CLDN6 is regulated by a variety of factors, including but not limited to stimuli and transcription factors, DNA methylation, and post-translational modifications. CLDN6 has been found to have a key role in the formation of barriers, especially the lung epithelial barrier and the epidermal permeability barrier (EPB). Importantly, the roles of CLDN6 in cancers have gained focus and are being investigated in recent years. Strong evidence indicates that the altered expression of CLDN6 is linked to the development of various cancers. Malignant phenotypes of tumors affected by CLDN6 include proliferation and apoptosis, migration and invasion, and drug resistance, which are regulated by CLDN6-mediated key signaling pathways. Given the important role in tumors and its low or no expression in normal tissues, CLDN6 is an ideal target for tumor therapy. This review aims to provide an overview of the structure and regulation of CLDN6, and its traditional barrier function, with a special emphasis on its emerging roles in cancers, including its impact on the malignant phenotypes, signal-modulating effects, the prognosis of tumor patients, and clinical applications in cancers.
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Li MM, Yuan J, Guan XY, Ma NF, Liu M. Molecular subclassification of gastrointestinal cancers based on cancer stem cell traits. Exp Hematol Oncol 2021; 10:53. [PMID: 34774101 PMCID: PMC8590337 DOI: 10.1186/s40164-021-00246-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 11/05/2021] [Indexed: 12/18/2022] Open
Abstract
Human gastrointestinal malignancies are highly heterogeneous cancers. Clinically, heterogeneity largely contributes to tumor progression and resistance to therapy. Heterogeneity within gastrointestinal cancers is defined by molecular subtypes in genomic and transcriptomic analyses. Cancer stem cells (CSCs) have been demonstrated to be a major source of tumor heterogeneity; therefore, assessing tumor heterogeneity by CSC trait-guided classification of gastrointestinal cancers is essential for the development of effective therapies. CSCs share critical features with embryonic stem cells (ESCs). Molecular investigations have revealed that embryonic genes and developmental signaling pathways regulating the properties of ESCs or cell lineage differentiation are abnormally active and might be oncofetal drivers in certain tumor subtypes. Currently, multiple strategies allow comprehensive identification of tumor subtype-specific oncofetal signatures and evaluation of subtype-specific therapies. In this review, we summarize current knowledge concerning the molecular classification of gastrointestinal malignancies based on CSC features and elucidate their clinical relevance. We also outline strategies for molecular subtype identification and subtype-based therapies. Finally, we explore how clinical implementation of tumor classification by CSC subtype might facilitate the development of more effective personalized therapies for gastrointestinal cancers.
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Affiliation(s)
- Mei-Mei Li
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510095, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Science, Guangzhou Medical University, Xinzao, Panyu District, Guangzhou, 511436, China
| | - Jun Yuan
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510095, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Science, Guangzhou Medical University, Xinzao, Panyu District, Guangzhou, 511436, China
| | - Xin-Yuan Guan
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
- Department of Clinical Oncology, State Key Laboratory of Liver Research, University of Hong Kong, Hong Kong, China
| | - Ning-Fang Ma
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510095, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Science, Guangzhou Medical University, Xinzao, Panyu District, Guangzhou, 511436, China
| | - Ming Liu
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510095, China.
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Science, Guangzhou Medical University, Xinzao, Panyu District, Guangzhou, 511436, China.
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Thankamony AP, Subbalakshmi AR, Jolly MK, Nair R. Lineage Plasticity in Cancer: The Tale of a Skin-Walker. Cancers (Basel) 2021; 13:3602. [PMID: 34298815 PMCID: PMC8306016 DOI: 10.3390/cancers13143602] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 07/04/2021] [Accepted: 07/14/2021] [Indexed: 12/11/2022] Open
Abstract
Lineage plasticity, the switching of cells from one lineage to another, has been recognized as a cardinal property essential for embryonic development, tissue repair and homeostasis. However, such a highly regulated process goes awry when cancer cells exploit this inherent ability to their advantage, resulting in tumorigenesis, relapse, metastasis and therapy resistance. In this review, we summarize our current understanding on the role of lineage plasticity in tumor progression and therapeutic resistance in multiple cancers. Lineage plasticity can be triggered by treatment itself and is reported across various solid as well as liquid tumors. Here, we focus on the importance of lineage switching in tumor progression and therapeutic resistance of solid tumors such as the prostate, lung, hepatocellular and colorectal carcinoma and the myeloid and lymphoid lineage switch observed in leukemias. Besides this, we also discuss the role of epithelial-mesenchymal transition (EMT) in facilitating the lineage switch in biphasic cancers such as aggressive carcinosarcomas. We also discuss the mechanisms involved, current therapeutic approaches and challenges that lie ahead in taming the scourge of lineage plasticity in cancer.
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Affiliation(s)
- Archana P. Thankamony
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Kerala 695014, India;
- Manipal Academy of Higher Education (MAHE), Manipal 576104, India
| | - Ayalur Raghu Subbalakshmi
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India;
| | - Mohit Kumar Jolly
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India;
| | - Radhika Nair
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Kerala 695014, India;
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A comprehensive transcriptomic landscape of cholangiocarcinoma based on bioinformatics analysis from large cohort of patients. Sci Rep 2021; 11:13713. [PMID: 34211100 PMCID: PMC8249535 DOI: 10.1038/s41598-021-93250-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Accepted: 06/22/2021] [Indexed: 02/07/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a group of malignancies emerging in the biliary tree and is associated with a poor patient prognosis. Although the anatomical location is the only worldwide accepted classification basis, it still has bias. The current study integrates the whole-genome expression data from several big cohorts in the literature, to screen and provide a comprehensive bioinformatic analysis, in order to better classify molecular subtypes and explore an underlying cluster mechanism related to anatomy and geographical regions. Differentially expressed protein-coding genes (DEGs) were identified for CCA as well as subtypes. Biological function enrichment analysis-Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis-was applied and identified different DEGs enriched signaling pathways in CCA subtypes. A co-expression network was presented by Weighted gene co-expression network analysis package and modules related to specific phenotypes were identified. Combined with DEGs, hub genes in the given module were demonstrated through protein-protein interaction network analysis. Finally, DEGs which significantly related to patient overall survival and disease-free survival time were selected, including ARHGAP21, SCP2, UBIAD1, TJP2, RAP1A and HDAC9.
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Jin W, Liang Y, Li S, Lin G, Liang H, Zhang Z, Zhang W, Nie R. MiR-513b-5p represses autophagy during the malignant progression of hepatocellular carcinoma by targeting PIK3R3. Aging (Albany NY) 2021; 13:16072-16087. [PMID: 34120890 PMCID: PMC8266330 DOI: 10.18632/aging.203135] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 05/18/2021] [Indexed: 12/20/2022]
Abstract
Hepatocellular carcinoma (HCC) serves as a prevailing global malignancy with severe mortality and extremely unsatisfactory prognosis, in which autophagy is a fundamental process in liver cancer pathogenesis, but the mechanisms are poorly understood. MicroRNAs (miRNAs) serve as a type of well-recognized non-coding regulators and contribute to the modulation of liver cancer development, from the aspects of diagnosis, progression, and therapy. Here, we aimed to investigate the function of hsa_microRNA-513b-5p (miR-513b-5p) in regulating autophagy during HCC progression. Specifically, our data showed that miR-513b-5p mimic reduced the LC3-II and beclin1 expression but enhanced p62 expression in HCC cells. MiR-513b-5p repressed liver cancer cell proliferation, migration/invasion, and induced apoptosis in vitro. Crucially, miR-513b-5p attenuated tumor growth of liver cancer cells in vivo. In the mechanical investigation, we identified that PIK3R3 mRNA 3′UTR was targeted by miR-513b-5p and miR-513b-5p suppressed PIK3R3 expression. PIK3R3 overexpression partly reversed miR-513b-5p-mediated autophagy, proliferation, and apoptosis of liver cancer cells. Consequently, we concluded that miR-513b-5p repressed autophagy during the malignant progression of HCC by targeting PIK3R3. MiR-513b-5p may be applied as a therapeutic target for HCC.
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Affiliation(s)
- Wei Jin
- Department of Hepatobiliary Surgery, Affiliated Wuming Hospital, Guangxi Medical University, Nanning, Guangxi Province, China
| | - Yilei Liang
- Department of Maxillofacial Surgery, Affiliated Wuming Hospital, Guangxi Medical University, Nanning, Guangxi Province, China
| | - Shuyou Li
- Department of Oncology and Intervention, Affiliated Wuming Hospital, Guangxi Medical University, Nanning, Guangxi Province, China
| | - Guoxiang Lin
- Department of Oncology and Intervention, Affiliated Wuming Hospital, Guangxi Medical University, Nanning, Guangxi Province, China
| | - Haiying Liang
- Department of Gynecology, Affiliated Wuming Hospital, Guangxi Medical University, Nanning, Guangxi Province, China
| | - Zhenni Zhang
- Department of Oncology and Intervention, Affiliated Wuming Hospital, Guangxi Medical University, Nanning, Guangxi Province, China
| | - Weiming Zhang
- Department of Oncology and Intervention, Affiliated Wuming Hospital, Guangxi Medical University, Nanning, Guangxi Province, China
| | - Rongjun Nie
- Department of Oncology and Intervention, Affiliated Wuming Hospital, Guangxi Medical University, Nanning, Guangxi Province, China
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