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Catozzi A, Peiris Pagès M, Humphrey S, Revill M, Morgan D, Roebuck J, Chen Y, Davies-Williams B, Brennan K, Mukarram Hossain ASM, Makeev VJ, Satia K, Sfyri PP, Galvin M, Coles D, Lallo A, Pearce SP, Kerr A, Priest L, Foy V, Carter M, Caeser R, Chan JM, Rudin CM, Blackhall F, Frese KK, Dive C, Simpson KL. Functional characterization of the ATOH1 molecular subtype indicates a pro-metastatic role in small cell lung cancer. Cell Rep 2025; 44:115603. [PMID: 40305287 PMCID: PMC12116416 DOI: 10.1016/j.celrep.2025.115603] [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: 05/24/2024] [Revised: 12/09/2024] [Accepted: 03/31/2025] [Indexed: 05/02/2025] Open
Abstract
Molecular subtypes of small cell lung cancer (SCLC) have been described based on differential expression of the transcription factors (TFs) ASCL1, NEUROD1, and POU2F3 and immune-related genes. We previously reported an additional subtype based on expression of the neurogenic TF ATOH1 within our SCLC circulating tumor cell-derived explant (CDX) model biobank. Here, we show that ATOH1 protein is detected in 7 of 81 preclinical models and 16 of 102 clinical samples of SCLC. In CDX models, ATOH1 directly regulates neurogenesis and differentiation programs, consistent with roles in normal tissues. In ex vivo cultures of ATOH1+ CDXs, ATOH1 is required for cell survival. In vivo, ATOH1 depletion slows tumor growth and suppresses liver metastasis. Our data validate ATOH1 as a bona fide lineage-defining TF of SCLC with cell survival and pro-metastatic functions. Further investigation exploring ATOH1-driven vulnerabilities for targeted treatment with predictive biomarkers is warranted.
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Affiliation(s)
- Alessia Catozzi
- SCLC Biology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK; Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK
| | - Maria Peiris Pagès
- SCLC Biology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK; Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK
| | - Sam Humphrey
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK; Cancer Research UK National Biomarker Centre, University of Manchester, Manchester M20 4BX, UK
| | - Mitchell Revill
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK; Cancer Research UK National Biomarker Centre, University of Manchester, Manchester M20 4BX, UK
| | - Derrick Morgan
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK; Cancer Research UK National Biomarker Centre, University of Manchester, Manchester M20 4BX, UK
| | - Jordan Roebuck
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK; Cancer Research UK National Biomarker Centre, University of Manchester, Manchester M20 4BX, UK
| | - Yitao Chen
- SCLC Biology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK; Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK
| | - Bethan Davies-Williams
- SCLC Biology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK; Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK
| | - Kevin Brennan
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK; Cancer Research UK National Biomarker Centre, University of Manchester, Manchester M20 4BX, UK
| | - A S Md Mukarram Hossain
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester M20 4BX, UK
| | - Vsevolod J Makeev
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK; Cancer Research UK National Biomarker Centre, University of Manchester, Manchester M20 4BX, UK
| | - Karishma Satia
- SCLC Biology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK; Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK
| | - Pagona P Sfyri
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester M20 4BX, UK
| | - Melanie Galvin
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK; Cancer Research UK National Biomarker Centre, University of Manchester, Manchester M20 4BX, UK
| | - Darryl Coles
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester M20 4BX, UK
| | - Alice Lallo
- SCLC Biology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK; Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK
| | - Simon P Pearce
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK; Cancer Research UK National Biomarker Centre, University of Manchester, Manchester M20 4BX, UK
| | - Alastair Kerr
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK; Cancer Research UK National Biomarker Centre, University of Manchester, Manchester M20 4BX, UK
| | - Lynsey Priest
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK; Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK
| | - Victoria Foy
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK; Cancer Research UK National Biomarker Centre, University of Manchester, Manchester M20 4BX, UK; Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK
| | - Mathew Carter
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK; Cancer Research UK National Biomarker Centre, University of Manchester, Manchester M20 4BX, UK; Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK
| | - Rebecca Caeser
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Joseph M Chan
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Charles M Rudin
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Fiona Blackhall
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK; Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M20 4BX, UK
| | - Kristopher K Frese
- SCLC Biology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK; Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK; Cancer Research UK National Biomarker Centre, University of Manchester, Manchester M20 4BX, UK
| | - Caroline Dive
- SCLC Biology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK; Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK; Cancer Research UK National Biomarker Centre, University of Manchester, Manchester M20 4BX, UK.
| | - Kathryn L Simpson
- SCLC Biology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK; Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK; Cancer Research UK National Biomarker Centre, University of Manchester, Manchester M20 4BX, UK
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Chen S, Qin Z, Zhou S, Xu Y, Zhu Y. The emerging role of intestinal stem cells in ulcerative colitis. Front Med (Lausanne) 2025; 12:1569328. [PMID: 40201327 PMCID: PMC11975877 DOI: 10.3389/fmed.2025.1569328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Accepted: 03/14/2025] [Indexed: 04/10/2025] Open
Abstract
Ulcerative colitis (UC) is a chronic idiopathic inflammatory disease affecting the colon and rectum. Characterized by recurrent attacks, UC is often resistant to traditional anti-inflammatory therapies, imposing significant physiological, psychological, and economic burdens on patients. In light of these challenges, innovative targeted therapies have become a new expectation for patients with UC. A crucial pathological feature of UC is the impairment of the intestinal mucosal barrier, which underlies aberrant immune responses and inflammation. Intestinal stem cells (ISCs), which differentiate into intestinal epithelial cells, play a central role in maintaining this barrier. Growing studies have proved that regulating the regeneration and differentiation of ISC is a promising approach to treating UC. Despite this progress, there is a dearth of comprehensive articles describing the role of ISCs in UC. This review focuses on the importance of ISCs in maintaining the intestinal mucosal barrier in UC and discusses the latest findings on ISC functions, markers, and their regulatory mechanisms. Key pathways involved in ISC regulation, including the Wnt, Notch, Hedgehog (HH), Hippo/Yap, and autophagy pathways, are explored in detail. Additionally, this review examines recent advances in ISC-targeted therapies for UC, such as natural or synthetic compounds, microbial preparations, traditional Chinese medicine (TCM) extracts and compounds, and transplantation therapy. This review aims to offer novel therapeutic insights and strategies for patients who have long struggled with UC.
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Affiliation(s)
- Siqing Chen
- Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Zhang Qin
- The Fourth Hospital of Changsha (Changsha Hospital Affiliated with Hunan Normal University), Changsha, Hunan, China
| | - Sainan Zhou
- Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Yin Xu
- Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Ying Zhu
- Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
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Campos F, Kasper B. Examining nirogacestat for adults with progressing desmoid tumors who require systemic treatment. Expert Opin Pharmacother 2024; 25:2115-2124. [PMID: 39414771 DOI: 10.1080/14656566.2024.2418416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 10/10/2024] [Accepted: 10/15/2024] [Indexed: 10/18/2024]
Abstract
INTRODUCTION Desmoid tumor (DT) is a rare, locally aggressive, mesenchymal neoplasm that can arise at any site in the body. Medical therapies play a major role for DT's patients requiring treatment. A novel systemic approach has recently emerged with Nirogacestat, a γ-secretase inhibitor targeting the NOTCH signaling pathway. AREAS COVERED Nirogacestat is the first drug in its class to receive approval from the Food and Drug Administration (FDA) and is the first FDA-approved treatment specifically for DTs. We reviewed the data leading to its discovery, including its mechanism of action, pharmacological properties, clinical efficacy, and its positioning within the current treatment armamentarium for DTs. EXPERT OPINION High-quality evidence for systemic therapies in the management of DTs remains an unmet need. Nirogacestat now joins sorafenib as the only drugs with efficacy in DTs demonstrated by randomized phase 3 studies. Currently, there are no comparative trials of the available systemic therapies. Therefore, physicians should consider factors such as drug accessibility, cost, toxicity profile, comorbidities, and patient preferences when selecting treatment. Long-term efficacy and safety data will be essential for evaluating the duration of treatment response and monitoring late-onset side effects of Nirogacestat.
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Affiliation(s)
- Fernando Campos
- Sarcoma Reference Center, A.C.Camargo Cancer Center (ACCCC), Sao Paulo, Brazil
| | - Bernd Kasper
- Sarcoma Unit, Mannheim Cancer Center (MCC), Mannheim University Medical Center, University of Heidelberg, Mannheim, Germany
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Huang H, Jin H, Lei R, He Z, He S, Chen J, Saw PE, Qiu Z, Ren G, Nie Y. lncRNA-WAL Promotes Triple-Negative Breast Cancer Aggression by Inducing β-Catenin Nuclear Translocation. Mol Cancer Res 2024; 22:1036-1050. [PMID: 38949521 PMCID: PMC11528204 DOI: 10.1158/1541-7786.mcr-23-0334] [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: 05/06/2023] [Revised: 09/28/2023] [Accepted: 06/27/2024] [Indexed: 07/02/2024]
Abstract
Because of its insensitivity to existing radiotherapy, namely, chemotherapy and targeted treatments, triple-negative breast cancer (TNBC) remains a great challenge to overcome. Increasing evidence has indicated abnormal Wnt/β-catenin pathway activation in TNBC but not luminal or HER2+ breast cancer, and lncRNAs play a key role in a variety of cancers. Through lncRNA microarray profiling between activated and inactivated Wnt/β-catenin pathway of TNBC tissues, lnc-WAL (Wnt/β-catenin-associated lncRNA; WAL) was selected as the top upregulated lncRNA in Wnt/β-catenin pathway activation compared with the inactivation group. RNA immunoprecipitation sequencing was used to compare the β-catenin and IgG groups, in which lnc-WAL could interact with β-catenin. Clinically, increased lnc-WAL in TNBC tumor tissue was associated with shorter survival. lnc-WAL promoted epithelial-mesenchymal transition, the proliferation, migration, and invasion of breast cancer stem cells and TNBC cells. Mechanistically, lnc-WAL inhibited β-catenin protein degradation via AXIN-mediated phosphorylation at serine 45. Subsequently, β-catenin accumulated in the nucleus and activated the target genes. Importantly, Wnt/β-catenin pathway activation stimulated the transcription of lnc-WAL. These results pointed to a master regulatory role of lnc-WAL/AXIN/β-catenin in the malignant progression of TNBC. Our findings provide important clinical translational evidence that lnc-WAL may be a potential therapeutic target against TNBC. Implications: The positive feedback between lnc-WAL and the Wnt/β-catenin pathway promotes TNBC progression, and lnc-WAL could be a potential prognostic marker for patients with TNBC.
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Affiliation(s)
- Hongyan Huang
- Department of Breast Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Haiyun Jin
- Department of Gynecology and Obstetrics, Southern Hospital TaiHe Branch, Southern Medical University, Guangzhou, China
| | - Rong Lei
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhanghai He
- Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shishi He
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiewen Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Phei E. Saw
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhu Qiu
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Guosheng Ren
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yan Nie
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
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5
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Sfeir N, Kajdan M, Jalaguier S, Bonnet S, Teyssier C, Pyrdziak S, Yuan R, Bousquet E, Maraver A, Bernex F, Pirot N, Boissière‐Michot F, Castet‐Nicolas A, Lapierre M, Cavaillès V. RIP140 regulates transcription factor HES1 oscillatory expression and mitogenic activity in colon cancer cells. Mol Oncol 2024; 18:1510-1530. [PMID: 38459621 PMCID: PMC11161732 DOI: 10.1002/1878-0261.13626] [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: 06/28/2023] [Revised: 01/17/2024] [Accepted: 02/23/2024] [Indexed: 03/10/2024] Open
Abstract
The transcription factor receptor-interacting protein 140 (RIP140) regulates intestinal homeostasis and tumorigenesis through Wnt signaling. In this study, we investigated its effect on the Notch/HES1 signaling pathway. In colorectal cancer (CRC) cell lines, RIP140 positively regulated HES1 gene expression at the transcriptional level via a recombining binding protein suppressor of hairless (RBPJ)/neurogenic locus notch homolog protein 1 (NICD)-mediated mechanism. In support of these in vitro data, RIP140 and HES1 expression significantly correlated in mouse intestine and in a cohort of CRC samples, thus supporting the positive regulation of HES1 gene expression by RIP140. Interestingly, when the Notch pathway is fully activated, RIP140 exerted a strong inhibition of HES1 gene transcription controlled by the level of HES1 itself. Moreover, RIP140 directly interacts with HES1 and reversed its mitogenic activity in human CRC cells. In line with this observation, HES1 levels were associated with a better patient survival only when tumors expressed high levels of RIP140. Our data identify RIP140 as a key regulator of the Notch/HES1 signaling pathway, with a dual effect on HES1 gene expression at the transcriptional level and a strong impact on colon cancer cell proliferation.
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Affiliation(s)
- Nour Sfeir
- IRCM, Institut de Recherche en Cancérologie de MontpellierFrance
- INSERM, U1194France
- Université de MontpellierFrance
- Institut régional du Cancer de MontpellierFrance
| | - Marilyn Kajdan
- IRCM, Institut de Recherche en Cancérologie de MontpellierFrance
- INSERM, U1194France
- Université de MontpellierFrance
- Institut régional du Cancer de MontpellierFrance
| | - Stéphan Jalaguier
- IRCM, Institut de Recherche en Cancérologie de MontpellierFrance
- INSERM, U1194France
- Université de MontpellierFrance
- Institut régional du Cancer de MontpellierFrance
| | - Sandrine Bonnet
- IRCM, Institut de Recherche en Cancérologie de MontpellierFrance
- INSERM, U1194France
- Université de MontpellierFrance
- Institut régional du Cancer de MontpellierFrance
| | - Catherine Teyssier
- IRCM, Institut de Recherche en Cancérologie de MontpellierFrance
- INSERM, U1194France
- Université de MontpellierFrance
- Institut régional du Cancer de MontpellierFrance
| | - Samuel Pyrdziak
- IRCM, Institut de Recherche en Cancérologie de MontpellierFrance
- INSERM, U1194France
- Université de MontpellierFrance
- Institut régional du Cancer de MontpellierFrance
| | - Rong Yuan
- Department of Medical Microbiology, Immunology and Cell Biology, School of MedicineSouthern Illinois UniversitySpringfieldILUSA
| | - Emilie Bousquet
- IRCM, Institut de Recherche en Cancérologie de MontpellierFrance
- INSERM, U1194France
- Université de MontpellierFrance
- Institut régional du Cancer de MontpellierFrance
| | - Antonio Maraver
- IRCM, Institut de Recherche en Cancérologie de MontpellierFrance
- INSERM, U1194France
- Université de MontpellierFrance
- Institut régional du Cancer de MontpellierFrance
| | - Florence Bernex
- IRCM, Institut de Recherche en Cancérologie de MontpellierFrance
- INSERM, U1194France
- Université de MontpellierFrance
- Institut régional du Cancer de MontpellierFrance
| | - Nelly Pirot
- IRCM, Institut de Recherche en Cancérologie de MontpellierFrance
- INSERM, U1194France
- Université de MontpellierFrance
- Institut régional du Cancer de MontpellierFrance
| | - Florence Boissière‐Michot
- IRCM, Institut de Recherche en Cancérologie de MontpellierFrance
- INSERM, U1194France
- Université de MontpellierFrance
- Institut régional du Cancer de MontpellierFrance
- Translational Research UnitMontpellier Cancer Institute Val d'AurelleFrance
| | - Audrey Castet‐Nicolas
- IRCM, Institut de Recherche en Cancérologie de MontpellierFrance
- INSERM, U1194France
- Université de MontpellierFrance
- Institut régional du Cancer de MontpellierFrance
| | - Marion Lapierre
- IRCM, Institut de Recherche en Cancérologie de MontpellierFrance
- INSERM, U1194France
- Université de MontpellierFrance
- Institut régional du Cancer de MontpellierFrance
| | - Vincent Cavaillès
- IRCM, Institut de Recherche en Cancérologie de MontpellierFrance
- INSERM, U1194France
- Université de MontpellierFrance
- Institut régional du Cancer de MontpellierFrance
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6
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Yokoi A, Murayama A, Hashimura M, Oguri Y, Harada Y, Fukagawa N, Hayashi M, Ono M, Ohhigata K, Saegusa M. A Complex Interplay between Notch Effectors and β-Catenin Signaling in Morular Differentiation of Endometrial Carcinoma Cells. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:459-470. [PMID: 38096983 DOI: 10.1016/j.ajpath.2023.11.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 11/02/2023] [Accepted: 11/28/2023] [Indexed: 12/24/2023]
Abstract
Notch signaling contributes to tissue development and homeostasis, but little is known about its role in morular differentiation of endometrial carcinoma (Em Ca) cells. The current study focused on crosstalk between Notch and β-catenin signaling in Em Ca with morules. Promoters of hairy and enhancer of split 1 (Hes1) and mastermind-like 2 (MAML2) were activated by Notch intracellular domain 1 but not β-catenin, and a positive feedback loop between Hes1 and MAML2 was observed. Immunoreactivities for nuclear β-catenin, Hes1, and MAML2, as well as the interaction between β-catenin and Hes1 or MAML2, were significantly higher in morular lesions compared with surrounding carcinoma in Em Ca. Inhibition of glycogen synthase kinase-3β (GSK-3β) increased expression of total nuclear and cytoplasmic GSK-3β and its phosphorylated forms, as well as Notch intracellular domain 1, Hes1, and active β-catenin. GSK-3β inhibition also decreased proliferation and migration, consistent with the response of cells stably overexpressing Hes1. Finally, the nuclear/cytoplasmic GSK-3β score was significantly higher in morules compared with surrounding carcinoma in Em Ca, and it was positively correlated with nuclear β-catenin, Hes1, and MAML2 scores. This complex interplay between Notch effectors and β-catenin signaling through GSK-3β inhibition contributes to the establishment and maintenance of β-catenin-mediated morular differentiation, which is, in turn, associated with reduced proliferation and inhibition of migration in Em Ca.
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Affiliation(s)
- Ako Yokoi
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Akari Murayama
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Miki Hashimura
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Yasuko Oguri
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Yohei Harada
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Naomi Fukagawa
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Misato Hayashi
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Mototsugu Ono
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Kensuke Ohhigata
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Makoto Saegusa
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan.
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7
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Catozzi A, Peiris-Pagès M, Humphrey S, Revill M, Morgan D, Roebuck J, Chen Y, Davies-Williams B, Lallo A, Galvin M, Pearce SP, Kerr A, Priest L, Foy V, Carter M, Caeser R, Chan J, Rudin CM, Blackhall F, Frese KK, Dive C, Simpson KL. Functional Characterisation of the ATOH1 Molecular Subtype Indicates a Pro-Metastatic Role in Small Cell Lung Cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.16.580247. [PMID: 38405859 PMCID: PMC10888785 DOI: 10.1101/2024.02.16.580247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/27/2024]
Abstract
Molecular subtypes of Small Cell Lung Cancer (SCLC) have been described based on differential expression of transcription factors (TFs) ASCL1, NEUROD1, POU2F3 and immune-related genes. We previously reported an additional subtype based on expression of the neurogenic TF ATOH1 within our SCLC Circulating tumour cell-Derived eXplant (CDX) model biobank. Here we show that ATOH1 protein was detected in 7/81 preclinical models and 16/102 clinical samples of SCLC. In CDX models, ATOH1 directly regulated neurogenesis and differentiation programs consistent with roles in normal tissues. In ex vivo cultures of ATOH1-positive CDX, ATOH1 was required for cell survival. In vivo, ATOH1 depletion slowed tumour growth and suppressed liver metastasis. Our data validate ATOH1 as a bona fide oncogenic driver of SCLC with tumour cell survival and pro-metastatic functions. Further investigation to explore ATOH1 driven vulnerabilities for targeted treatment with predictive biomarkers is warranted.
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Affiliation(s)
- Alessia Catozzi
- Cancer Research UK Manchester Institute, University of Manchester, Manchester, United Kingdom
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester, United Kingdom
| | - Maria Peiris-Pagès
- Cancer Research UK Manchester Institute, University of Manchester, Manchester, United Kingdom
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester, United Kingdom
| | - Sam Humphrey
- Cancer Research UK Manchester Institute, University of Manchester, Manchester, United Kingdom
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester, United Kingdom
| | - Mitchell Revill
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester, United Kingdom
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester, United Kingdom
| | - Derrick Morgan
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester, United Kingdom
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester, United Kingdom
| | - Jordan Roebuck
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester, United Kingdom
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester, United Kingdom
| | - Yitao Chen
- Cancer Research UK Manchester Institute, University of Manchester, Manchester, United Kingdom
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester, United Kingdom
| | - Bethan Davies-Williams
- Cancer Research UK Manchester Institute, University of Manchester, Manchester, United Kingdom
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester, United Kingdom
| | - Alice Lallo
- Cancer Research UK Manchester Institute, University of Manchester, Manchester, United Kingdom
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester, United Kingdom
| | - Melanie Galvin
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester, United Kingdom
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester, United Kingdom
| | - Simon P Pearce
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester, United Kingdom
| | - Alastair Kerr
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester, United Kingdom
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester, United Kingdom
| | - Lynsey Priest
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester, United Kingdom
- Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Victoria Foy
- Cancer Research UK Manchester Institute, University of Manchester, Manchester, United Kingdom
- Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Mathew Carter
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester, United Kingdom
- Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Rebecca Caeser
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Joseph Chan
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Charles M. Rudin
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Fiona Blackhall
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester, United Kingdom
- Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Kristopher K Frese
- Cancer Research UK Manchester Institute, University of Manchester, Manchester, United Kingdom
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester, United Kingdom
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester, United Kingdom
| | - Caroline Dive
- Cancer Research UK Manchester Institute, University of Manchester, Manchester, United Kingdom
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester, United Kingdom
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester, United Kingdom
| | - Kathryn L Simpson
- Cancer Research UK Manchester Institute, University of Manchester, Manchester, United Kingdom
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester, United Kingdom
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester, United Kingdom
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8
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Ibrahim R, Assi T, Khoury R, Ngo C, Faron M, Verret B, Lévy A, Honoré C, Hénon C, Le Péchoux C, Bahleda R, Le Cesne A. Desmoid-type fibromatosis: Current therapeutic strategies and future perspectives. Cancer Treat Rev 2024; 123:102675. [PMID: 38159438 DOI: 10.1016/j.ctrv.2023.102675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 12/18/2023] [Accepted: 12/21/2023] [Indexed: 01/03/2024]
Abstract
Desmoid tumors (DT) are rare, slow-growing, locally invasive soft tissue tumors that often pose significant therapeutic challenges. Traditional management strategies including active surveillance, surgery, radiotherapy, and systemic therapy which are associated with varying recurrence rates and high morbidity. Given the challenging nature of DT and the modest outcomes associated with current treatment strategies, there has been a growing interest in the field of γ-secretase inhibitors as a result of its action on the Wnt/β-catenin signaling pathway. In this review article, we will shed the light on the pathogenesis and molecular biology of DT, discuss its symptoms and diagnosis, and provide a comprehensive review of the traditional therapeutic approaches. We will also delve into the mechanisms of action of γ-secretase inhibitors, its efficacy, and the existing preclinical and clinical data available to date on the use of these agents, as well as the potential challenges and future prospects in the treatment landscape of these tumors.
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Affiliation(s)
- Rebecca Ibrahim
- Division of International Patients Care, Gustave Roussy Cancer Campus, Villejuif, France
| | - Tarek Assi
- Division of International Patients Care, Gustave Roussy Cancer Campus, Villejuif, France; Sarcoma Unit, Gustave Roussy Cancer Campus, Villejuif, France.
| | - Rita Khoury
- Division of International Patients Care, Gustave Roussy Cancer Campus, Villejuif, France
| | - Carine Ngo
- Sarcoma Unit, Gustave Roussy Cancer Campus, Villejuif, France
| | - Matthieu Faron
- Sarcoma Unit, Gustave Roussy Cancer Campus, Villejuif, France
| | - Benjamin Verret
- Sarcoma Unit, Gustave Roussy Cancer Campus, Villejuif, France
| | - Antonin Lévy
- Sarcoma Unit, Gustave Roussy Cancer Campus, Villejuif, France
| | - Charles Honoré
- Sarcoma Unit, Gustave Roussy Cancer Campus, Villejuif, France
| | - Clémence Hénon
- Sarcoma Unit, Gustave Roussy Cancer Campus, Villejuif, France
| | | | | | - Axel Le Cesne
- Division of International Patients Care, Gustave Roussy Cancer Campus, Villejuif, France; Sarcoma Unit, Gustave Roussy Cancer Campus, Villejuif, France
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9
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Yue J, Zhang J, Huan R, Zeng Y, Tan Y, Cheng Y. Dishevelled-associated antagonist of β-catenin homolog 3 (DACT3) suppresses glioma progression though Notch1 signaling pathway in β-catenin-dependent manner. Heliyon 2024; 10:e23511. [PMID: 38230242 PMCID: PMC10789601 DOI: 10.1016/j.heliyon.2023.e23511] [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: 09/19/2023] [Revised: 11/16/2023] [Accepted: 12/05/2023] [Indexed: 01/18/2024] Open
Abstract
The disheveled-associated antagonist of β-catenin homolog 3 (DACT3) has been recognized as a tumor suppressor in various cancers. However, the function of DACT3 on glioma malignant progression along with potential molecular mechanisms is poorly clarified. This research aimed to investigate how DACT3 contributes to suppressing the progression of glioma. In our investigation, a pronounced decrease in DACT3 expression was observed in glioma tissues. Through the overexpression of DACT3, we noted a significant suppression in the proliferation, invasion, and migration of glioma cells, while concurrently observing an increase in cell adhesion. Our exploration into the molecular mechanisms revealed that DACT3 executes its tumor-suppressive role by impeding the expression of notch 1 intracellular domain (NICD) and translocating into the nucleus by downregulating the expression of β-catenin. Consequently, this process leads to the suppression of Notch1 signaling. To summarize, our findings reveal the function of DACT3 to inhibit glioma progression via the Notch1 signaling pathway in β-catenin dependent manner. This study stands as the pioneer in examining the role of DACT3 in glioma progression and comprehensively elucidating its molecular mechanisms in glioma development. Therefore, our results suggest that DACT3 holds promise as both a prognostic factor and a potential biomarker for guiding treatment strategies in glioma patients (Graphical Abstract).
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Affiliation(s)
- Jianhe Yue
- Department of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jiqin Zhang
- Department of Anesthesiology, Guizhou Provincial People's Hospital, Guiyang, China
| | - Renzheng Huan
- Department of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yu Zeng
- Department of Neurosurgery, Guizhou Provincial People's Hospital, Guiyang, China
| | - Ying Tan
- Department of Neurosurgery, Guizhou Provincial People's Hospital, Guiyang, China
| | - Yuan Cheng
- Department of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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10
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Zheng C, Huang J, Xu G, Li W, Weng X, Zhang S. The Notch signaling pathway in desmoid tumor: Recent advances and the therapeutic prospects. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166907. [PMID: 37793461 DOI: 10.1016/j.bbadis.2023.166907] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 09/27/2023] [Accepted: 09/28/2023] [Indexed: 10/06/2023]
Abstract
Desmoid tumor (DT) is a rare fibroblastic soft-tissue neoplasm that is characterized by local aggressiveness but no metastatic potential. Although the prognosis is relatively favorable, the unpredictable disease course and infiltrative growth lead to significant impairments and morbidity. Aberrant activation of Wnt/β-catenin signaling has been well-established in the pathogenesis of sporadic DT and familial adenomatous polyposis (FAP) or Gardners syndrome-associated DT, suggesting therapy targeting this pathway is an appealing treatment strategy. However, agents against this pathway are currently in their preliminary stages and have not yet been implemented in clinical practice. Increasing studies demonstrate activation of the Notch pathway is closely associated with the development and progression of DT, which provides a potential alternative therapeutic target against DT. Early-stage clinical trials and preclinical models have indicated that inhibition of Notch pathway might be a promising treatment approach for DT. The Notch signaling activation is mainly dependent on the activity of the γ-secretase enzyme, which is responsible for cleaving the Notch intracellular domain and facilitating its nuclear translocation to promote gene transcription. Two γ-secretase inhibitors called nirogacestat and AL102 are currently under extensive investigation in the advanced stage of clinical development. The updated findings from the phase III randomized controlled trial (DeFi trial) demonstrated that nirogacestat exerts significant benefits in terms of disease control and symptom resolution in patients with progressive DT. Therefore, this review provides a comprehensive overview of the present understanding of Notch signaling in the pathogenesis of DT, with a particular emphasis on the prospective therapeutic application of γ-secretase inhibitors in the management of DT.
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Affiliation(s)
- Chuanxi Zheng
- Department of Musculoskeletal Tumor Surgery, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China
| | - Jianghong Huang
- Department of Spine Surgery and Orthopedics, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen 518035, China
| | - Gang Xu
- Department of Musculoskeletal Tumor Surgery, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China
| | - Wei Li
- Department of Musculoskeletal Tumor Surgery, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China
| | - Xin Weng
- Department of Pathology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China
| | - Shiquan Zhang
- Department of Musculoskeletal Tumor Surgery, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
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11
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Costa AVD, Rattes IC, Goes CP, Lobo LHG, Barreto LBE, Gama P. Breastfeeding lifespan control of growth, maintenance, and metabolism of small intestinal epithelium. J Cell Physiol 2023; 238:2304-2315. [PMID: 37555566 DOI: 10.1002/jcp.31089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 07/08/2023] [Accepted: 07/12/2023] [Indexed: 08/10/2023]
Abstract
Gastrointestinal epithelial cells respond to milk-born molecules throughout breastfeeding, influencing growth, and development. The rapid renewal of the small intestine depends on the proliferation in the crypt that drives cell fates. We used early weaning model to investigate immediate and late effects of breastfeeding on proliferation, differentiation of jejunal epithelial cells. Wistar rats were either allowed to suckle (S) until 21 postnatal days or submitted to early weaning (EW) at 15 days. By comparing ages (18, 60, and 120 days), we found that EW decreased Ki67 indices and villi height at 18 and 60 days (p < 0.05), and at 120 days they were similar between diets. Proliferative reduction and augmented expression of Cdkn1b (p27 gene) were parallel. In the stem cell niche, EW increased the number and activity (Defa24) of Paneth cells at 18 and 60 days (p < 0.05), and Lgr5 and Ascl2 genes showed inverted responses between ages. Among target cells, EW decreased goblet cell number at 18 and 60 days (p < 0.05) and increased it at 120 days (p < 0.05), whereas enteroendocrine marker genes were differentially altered. EW reduced enterocytes density at 18 days (p < 0.05), and at 120 days this population was decreased (vs. 60 days). Among cell fate crypt-controlling genes, Notch and Atoh1 were the main targets of EW. Metabolically, intraperitoneal glucose tolerance was immediately reduced (18 days), being reverted until 120 days (p < 0.05). Currently, we showed that breastfeeding has a lifespan influence on intestinal mucosa and on its stem cell compartment. We suggest that, although jejunum absorptive function is granted after early weaning, the long lasting changes in gene expression might prime the mucosa with a different sensitivity to gut disorders that still have to be further explored.
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Affiliation(s)
- Aline Vasques da Costa
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Isadora Campos Rattes
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Carolina Purcell Goes
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Larissa Honda Greco Lobo
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Laylla Barreto E Barreto
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Patricia Gama
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
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12
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Bektas M, Bell T, Khan S, Tumminello B, Fernandez MM, Heyes C, Oton AB. Desmoid Tumors: A Comprehensive Review. Adv Ther 2023; 40:3697-3722. [PMID: 37436594 PMCID: PMC10427533 DOI: 10.1007/s12325-023-02592-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 06/21/2023] [Indexed: 07/13/2023]
Abstract
Desmoid tumors (DT) are rare, locally aggressive, fibroblastic soft-tissue tumors that are characterized by infiltrative growth and can affect organs and adjacent structures, resulting in substantial clinical burden impacting patients' health-related quality of life. Searches of PubMed, Embase, Cochrane, and key conferences were conducted in November 2021 and updated periodically through March 2023 to identify articles describing the burden of DT. Of 651 publications identified, 96 relevant ones were retained. Diagnosis of DT is challenging because of its morphologic heterogeneity and variable clinical presentation. Patients visit multiple healthcare providers, often facing delays in correct diagnosis. The low incidence of DT (estimated 3-5 cases per million person-years) limits disease awareness. Patients with DT experience a high symptom burden: up to 63% of patients experience chronic pain, which leads to sleep disturbance (73% of cases), irritability (46% of cases), and anxiety/depression (15% of cases). Frequently mentioned symptoms are pain, limited function and mobility, fatigue, muscle weakness, and swelling around the tumor. Overall, quality of life in patients with DT is lower than in healthy controls. There is no treatment approved by the US Food and Drug Administration for DT; however, treatment guidelines reference available options, such as active surveillance, surgery, systemic therapy, and locoregional therapy. Choice of active treatment may depend on tumor location, symptoms, and risk of morbidity. The substantial burden of illness of DT is related to difficulties in timely and accurate diagnosis, high symptom burden (pain and functional limitations), and decreased quality of life. There is a high unmet need for treatments that specifically target DT and improve quality of life.
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Affiliation(s)
- Meryem Bektas
- RTI Health Solutions, Research Triangle Park, NC, USA
| | - Timothy Bell
- SpringWorks Therapeutics, Inc., Stamford, CT, USA.
| | - Shahnaz Khan
- RTI Health Solutions, Research Triangle Park, NC, USA
| | | | | | | | - Ana B Oton
- SpringWorks Therapeutics, Inc., Stamford, CT, USA
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13
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Liu B, Sun Z, Zhou R, Shen D, Zhu S, Chen L, Huang G. Novel insights into biomarkers of progression in Desmoid tumor. Front Oncol 2023; 13:1206800. [PMID: 37601698 PMCID: PMC10434506 DOI: 10.3389/fonc.2023.1206800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Accepted: 07/19/2023] [Indexed: 08/22/2023] Open
Abstract
Desmoid tumor (DT) is a rare neoplasm characterized by the proliferation of myofibroblastic cells that infiltrates and invades adjacent tissues. Due to its locally aggressive and recurrent nature, DT often causes local symptoms and can be challenging to manage clinically. Therefore, identifying biomarkers that can predict the progression of DT and guide treatment decisions is critical. This review summarizes several biomarkers that have been implicated in active surveillance (AS) and the prediction of postoperative recurrence and attempts to elucidate their underlying mechanisms. Some of these novel markers could provide prognostic value for clinicians, and ultimately help facilitate optimal and accurate therapeutic decisions for DT.
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Affiliation(s)
- Baiqi Liu
- Department of Hernia and Abdominal Wall Surgery, General Surgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Zefang Sun
- Department of Hernia and Abdominal Wall Surgery, General Surgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Rui Zhou
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Dingcheng Shen
- Department of Hernia and Abdominal Wall Surgery, General Surgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Shuai Zhu
- Department of Hernia and Abdominal Wall Surgery, General Surgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Lu Chen
- Department of Hernia and Abdominal Wall Surgery, General Surgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Gengwen Huang
- Department of Hernia and Abdominal Wall Surgery, General Surgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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14
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Zinina VV, Sauer M, Nigmatullina L, Kreim N, Soshnikova N. TCF7L1 Controls the Differentiation of Tuft Cells in Mouse Small Intestine. Cells 2023; 12:1452. [PMID: 37296573 PMCID: PMC10253002 DOI: 10.3390/cells12111452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 05/10/2023] [Accepted: 05/18/2023] [Indexed: 06/12/2023] Open
Abstract
Continuous and rapid renewal of the intestinal epithelium depends on intestinal stem cells (ISCs). A large repertoire of transcription factors mediates the correct maintenance and differentiation of ISCs along either absorptive or secretory lineages. In the present study, we addressed the role of TCF7L1, a negative regulator of WNT signalling, in embryonic and adult intestinal epithelium using conditional mouse mutants. We found that TCF7L1 prevents precocious differentiation of the embryonic intestinal epithelial progenitors towards enterocytes and ISCs. We show that Tcf7l1 deficiency leads to upregulation of the Notch effector Rbp-J, resulting in a subsequent loss of embryonic secretory progenitors. In the adult small intestine, TCF7L1 is required for the differentiation of secretory epithelial progenitors along the tuft cell lineage. Furthermore, we show that Tcf7l1 promotes the differentiation of enteroendocrine D- and L-cells in the anterior small intestine. We conclude that TCF7L1-mediated repression of both Notch and WNT pathways is essential for the correct differentiation of intestinal secretory progenitors.
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Affiliation(s)
- Valeriya V. Zinina
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany; (V.V.Z.); (M.S.)
| | - Melanie Sauer
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany; (V.V.Z.); (M.S.)
| | | | - Nastasja Kreim
- Institute of Molecular Biology gGmbH, 55128 Mainz, Germany (N.K.)
| | - Natalia Soshnikova
- Institute for Molecular Medicine and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany
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15
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Lei Y, Shen HF, Li QW, Yang S, Xie HT, Li XF, Chen ML, Xia JW, Wang SC, Dai GQ, Zhou Y, Li YC, Huang SH, He DH, Zhou ZH, Cong JG, Lin XL, Lin TY, Wu AB, Xiao D, Xiao SJ, Zhang XK, Jia JS. Hairy gene homolog increases nasopharyngeal carcinoma cell stemness by upregulating Bmi-1. Aging (Albany NY) 2023; 15:204742. [PMID: 37219449 DOI: 10.18632/aging.204742] [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: 11/24/2022] [Accepted: 05/09/2023] [Indexed: 05/24/2023]
Abstract
B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) is overexpressed in various cancer types. We found that Bmi-1 mRNA levels were elevated in nasopharyngeal carcinoma (NPC) cell lines. In immunohistochemical analyses, high Bmi-1 levels were observed in not only 5 of 38 non-cancerous nasopharyngeal squamous epithelial biopsies, but also in 66 of 98 NPC specimens (67.3%). High Bmi-1 levels were detected more frequently in T3-T4, N2-N3 and stage III-IV NPC biopsies than in T1-T2, N0-N1 and stage I-II NPC samples, indicating that Bmi-1 is upregulated in advanced NPC. In 5-8F and SUNE1 NPC cells, stable depletion of Bmi-1 using lentiviral RNA interference greatly suppressed cell proliferation, induced G1-phase cell cycle arrest, reduced cell stemness and suppressed cell migration and invasion. Likewise, knocking down Bmi-1 inhibited NPC cell growth in nude mice. Both chromatin immunoprecipitation and Western blotting assays demonstrated that Hairy gene homolog (HRY) upregulated Bmi-1 by binding to its promoter, thereby increasing the stemness of NPC cells. Immunohistochemistry and quantitative real-time PCR analyses revealed that HRY expression correlated positively with Bmi-1 expression in a cohort of NPC biopsies. These findings suggested that HRY promotes NPC cell stemness by upregulating Bmi-1, and that silencing Bmi-1 can suppress NPC progression.
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Affiliation(s)
- Ye Lei
- School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
- Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China
- Guangzhou Southern Medical Laboratory Animal Sci and Tech Co. Ltd., Guangzhou 510515, China
| | - Hong-Fen Shen
- School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Qi-Wen Li
- School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Sheng Yang
- School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Hong-Ting Xie
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Xu-Feng Li
- School of Basic Medical Sciences, Guangxi Medical University, Nanning 530000, China
| | - Mei-Ling Chen
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Jia-Wei Xia
- The Third People’s Hospital of Kunming (The Sixth Affiliated Hospital of Dali University), Kunming 650041, China
| | - Sheng-Chun Wang
- Department of Pathology, School of Basic Medicine, Guangdong Medical University, Dongguan 523808, China
| | - Guan-Qi Dai
- School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Ying Zhou
- School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Ying-Chun Li
- School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Shi-Hao Huang
- School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Dan-Hua He
- School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Zhi-Hao Zhou
- School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Jin-Ge Cong
- School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
- Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China
- Guangzhou Southern Medical Laboratory Animal Sci and Tech Co. Ltd., Guangzhou 510515, China
| | - Xiao-Lin Lin
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
| | - Tao-Yan Lin
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Ai-Bing Wu
- Central People’s Hospital of Zhanjiang, Zhanjiang 524000, China
| | - Dong Xiao
- School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
- Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China
- Guangzhou Southern Medical Laboratory Animal Sci and Tech Co. Ltd., Guangzhou 510515, China
- National Demonstration Center for Experimental Education of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Sheng-Jun Xiao
- Department of Pathology, The Second Affiliated Hospital, Guilin Medical University, Guilin 541199, China
| | - Xin-Ke Zhang
- Department of Pathology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Jun-Shuang Jia
- School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
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16
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Notch Signaling in Acute Inflammation and Sepsis. Int J Mol Sci 2023; 24:ijms24043458. [PMID: 36834869 PMCID: PMC9967996 DOI: 10.3390/ijms24043458] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/27/2023] [Accepted: 02/07/2023] [Indexed: 02/11/2023] Open
Abstract
Notch signaling, a highly conserved pathway in mammals, is crucial for differentiation and homeostasis of immune cells. Besides, this pathway is also directly involved in the transmission of immune signals. Notch signaling per se does not have a clear pro- or anti-inflammatory effect, but rather its impact is highly dependent on the immune cell type and the cellular environment, modulating several inflammatory conditions including sepsis, and therefore significantly impacts the course of disease. In this review, we will discuss the contribution of Notch signaling on the clinical picture of systemic inflammatory diseases, especially sepsis. Specifically, we will review its role during immune cell development and its contribution to the modulation of organ-specific immune responses. Finally, we will evaluate to what extent manipulation of the Notch signaling pathway could be a future therapeutic strategy.
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17
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Low HES-1 and positive DLL4 expression predicts poor prognosis of colorectal cancers. Pathology 2023; 55:52-57. [PMID: 36167746 DOI: 10.1016/j.pathol.2022.07.008] [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: 03/24/2022] [Revised: 06/14/2022] [Accepted: 07/06/2022] [Indexed: 01/27/2023]
Abstract
Hairy and enhancer of split-1 (HES-1) is a downstream transcription factor and delta-like 4 (DLL4) is a ligand of the Notch signalling pathway. HES-1 and DLL4 expression are known to have an association with the progression and metastasis of cancers. We evaluated HES-1 and DLL4 expression and assessed their correlation with biological behaviour and prognostic significance of 327 colorectal cancers. Low HES-1 expression was identified in 210 (64.2%) cases and was significantly correlated with large tumour size, lymphovascular invasion, and distant metastasis. DLL4 was positive in 132 (40.4%) cases and significantly correlated with perineural invasion, distant metastasis, and involved resection margin. Patients with low HES-1 expression showed significantly worse overall survival than patients with high HES-1 expression [hazard ratio (HR)=3.017; 95% confidence interval (CI) 1.880-4.841; p<0.001]. The overall survival of patients with positive DLL4 expression was significantly worse than that of patients with negative DLL4 expression (HR=2.922; 95% CI 1.976-4.322; p<0.001). Furthermore, the combined HES-1lowDLL4positive expression group showed the worst overall survival compared to other groups (p<0.001) and was an independent poor prognostic factor of colorectal cancer patients. Thus, low HES-1 and positive DLL4 expression are associated with aggressive biological behaviour and can be used as prognostic factors in colorectal cancer patients.
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18
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Giolito MV, La Rosa T, Farhat D, Bodoirat S, Guardia GDA, Domon‐Dell C, Galante PAF, Freund J, Plateroti M. Regulation of the THRA gene, encoding the thyroid hormone nuclear receptor TRα1, in intestinal lesions. Mol Oncol 2022; 16:3975-3993. [PMID: 36217307 PMCID: PMC9718118 DOI: 10.1002/1878-0261.13298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 07/05/2022] [Accepted: 07/29/2022] [Indexed: 12/24/2022] Open
Abstract
The THRA gene, encoding the thyroid hormone nuclear receptor TRα1, is expressed in an increasing gradient at the bottom of intestinal crypts, overlapping with high Wnt and Notch activities. Importantly, THRA is upregulated in colorectal cancers, particularly in the high-Wnt molecular subtype. The basis of this specific and/or altered expression pattern has remained unknown. To define the mechanisms controlling THRA transcription and TRα1 expression, we used multiple in vitro and ex vivo approaches. Promoter analysis demonstrated that transcription factors important for crypt homeostasis and altered in colorectal cancers, such as transcription factor 7-like 2 (TCF7L2; Wnt pathway), recombining binding protein suppressor of hairless (RBPJ; Notch pathway), and homeobox protein CDX2 (epithelial cell identity), modulate THRA activity. Specifically, although TCF7L2 and CDX2 stimulated THRA, RBPJ induced its repression. In-depth analysis of the Wnt-dependent increase showed direct regulation of the THRA promoter in cells and of TRα1 expression in murine enteroids. Given our previous results on the control of the Wnt pathway by TRα1, our new results unveil a complex regulatory loop and synergy between these endocrine and epithelial-cell-intrinsic signals. Our work describes, for the first time, the regulation of the THRA gene in specific cell and tumor contexts.
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Affiliation(s)
- Maria Virginia Giolito
- Inserm, IRFAC/UMR‐S1113, FMTS, Université de StrasbourgFrance,INSERM U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de LyonFrance
| | - Théo La Rosa
- INSERM U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de LyonFrance,Present address:
Stem‐Cell and Brain Research Institute, U1208 INSERM, USC1361 INRABronFrance
| | - Diana Farhat
- Inserm, IRFAC/UMR‐S1113, FMTS, Université de StrasbourgFrance,INSERM U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de LyonFrance
| | | | | | | | | | | | - Michelina Plateroti
- Inserm, IRFAC/UMR‐S1113, FMTS, Université de StrasbourgFrance,INSERM U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de LyonFrance
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19
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SOX8 Knockdown Overcomes Enzalutamide Resistance in Castration-Resistant Prostate Cancer by Inhibiting the Notch Signaling Pathway. BIOMED RESEARCH INTERNATIONAL 2022; 2022:9235837. [PMID: 36246971 PMCID: PMC9560839 DOI: 10.1155/2022/9235837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 09/14/2022] [Indexed: 11/17/2022]
Abstract
Castration-resistant prostate cancer (CRPC) is still challenging to treat. Dissatisfaction with androgen signal-targeted therapy forces people to look for other treatment strategies. Therefore, this study is aimed at exploring the role of SOX8/Notch signaling in CRPC. The upregulation of SOX8, Notch4, and Hes5 indicated a poor progression-free survival (PFS) in CRPC patients. The expression of these proteins was also upregulated in enzalutamide-resistant LNCaP cells (Enza-R). Moreover, knocking down SOX8 inhibited malignant biological behaviors and decreased the activation of Notch signaling in Enza-R cells. Importantly, knocking down SOX8 obviously reversed the enzalutamide resistance in Enza-R cells, while RO0429097 (a γ secretase inhibitor inactivates Notch signaling) exerted similar effects. At last, we found that both SOX8 knockdown and/or RO0429097 suppressed tumor growth and bone metastasis in vivo. Altogether, our study indicated that the SOX8/Notch signaling is involved in CRPC and that these enzymes are possible targets to develop novel treatment for CRPC.
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20
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Molecular pathogenesis of desmoid tumor and the role of γ-secretase inhibition. NPJ Precis Oncol 2022; 6:62. [PMID: 36068332 PMCID: PMC9448813 DOI: 10.1038/s41698-022-00308-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 08/23/2022] [Indexed: 11/08/2022] Open
Abstract
Desmoid tumor (DT) is a rare, soft tissue neoplasm associated with an unpredictable clinical course. Although lacking metastatic potential, DT is often locally aggressive and invasive, causing significant morbidity. Both sporadic DT and familial adenomatous polyposis (FAP)-associated DT are linked to constitutive activation of the Wnt signaling pathway with mutations in the β-catenin oncogene CTNNB1 or the tumor suppressor gene APC, respectively. Cross-talk between the Notch and Wnt pathways, as well as activation of the Notch pathway resulting from dysregulation of the Wnt pathway, suggest a possible therapeutic target for DT. Due to the role γ-secretase plays in Notch signaling through cleavage of the Notch intracellular domain (with subsequent translocation to the nucleus to activate gene transcription), γ-secretase inhibitors (GSIs) have emerged as a potential treatment for DT. Two GSIs, nirogacestat (PF-03084014) and AL102 are in later-stage clinical development; nirogacestat is being evaluated in a phase 3, randomized, placebo-controlled trial while AL102 is being evaluated in a phase 2/3, dose-finding (part A) and placebo-controlled (part B) trial. This review summarizes current understanding of the molecular pathogenesis of DT focusing on dysregulation of the Wnt signaling pathway, crosstalk with the Notch pathway, and the potential therapeutic role for GSIs in DT.
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21
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Luo H, Li M, Wang F, Yang Y, Wang Q, Zhao Y, Du F, Chen Y, Shen J, Zhao Q, Zeng J, Wang S, Chen M, Li X, Li W, Sun Y, Gu L, Wen Q, Xiao Z, Wu X. The role of intestinal stem cell within gut homeostasis: Focusing on its interplay with gut microbiota and the regulating pathways. Int J Biol Sci 2022; 18:5185-5206. [PMID: 35982910 PMCID: PMC9379405 DOI: 10.7150/ijbs.72600] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 07/29/2022] [Indexed: 12/05/2022] Open
Abstract
Intestinal stem cells (ISCs) play an important role in maintaining intestinal homeostasis via promoting a healthy gut barrier. Within the stem cell niche, gut microbiota linking the crosstalk of dietary influence and host response has been identified as a key regulator of ISCs. Emerging insights from recent research reveal that ISC and gut microbiota interplay regulates epithelial self-renewal. This article reviews the recent knowledge on the key role of ISC in their local environment (stem cell niche) associating with gut microbiota and their metabolites as well as the signaling pathways. The current progress of intestinal organoid culture is further summarized. Subsequently, the key challenges and future directions are discussed.
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Affiliation(s)
- Haoming Luo
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Fang Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Yifei Yang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Qin Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Qianyun Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Jiuping Zeng
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Shengpeng Wang
- State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
| | - Meijuan Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Xiaobing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Wanping Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Yuhong Sun
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Li Gu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Qinglian Wen
- Department of Oncology, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Zhangang Xiao
- Department of Oncology, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China.,Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
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22
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McLean TD, Duchi S, Di Bella C. Molecular Pathogenesis of Sporadic Desmoid Tumours and Its Implications for Novel Therapies: A Systematised Narrative Review. Target Oncol 2022; 17:223-252. [PMID: 35446005 PMCID: PMC9217905 DOI: 10.1007/s11523-022-00876-z] [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] [Accepted: 03/15/2022] [Indexed: 12/22/2022]
Abstract
Sporadic desmoid-type fibromatosis is a rare, fibroblastic soft-tissue neoplasm with local aggressiveness but no metastatic potential. Aberrant Wnt/β-catenin signalling has been extensively linked to desmoid pathogenesis, although little is known about other molecular drivers and no established treatment approach exists. We aimed to summarise the current literature regarding the molecular pathogenesis of sporadic desmoid-type fibromatosis and to discuss the effects of both current and emerging novel therapies targeting these mechanisms. A literature search was conducted of MEDLINE® ALL and EMBASE databases for published studies (2000–August 2021) using keywords related to ‘fibromatosis aggressive’, ‘immunohistochemistry’, ‘polymerase chain reaction’ and ‘mutation’. Articles were included if they examined the role of proteins in sporadic or extra-abdominal human desmoid-type fibromatosis pathogenesis. Searching identified 1684 articles. Following duplicate removal and eligibility screening, 36 were identified. After a full-text screen, 22 were included in the final review. At least 47% of desmoid-type fibromatosis cases displayed aberrant β-catenin immunoreactivity amongst ten studies. Cyclin D1 overexpression occurred in at least 40% of cases across five studies. Six studies reported oestrogen receptor-β expression with a range of 7.4–90%. Three studies implicated matrix metalloproteinases, with one study demonstrating vascular endothelial growth factor overexpression. One study explored the positive relationship between cyclooxygenase-2 and platelet-derived growth factor receptor-β. Aberrant Wnt/β-catenin signalling is a well-established pathogenic driver that may be targeted via downstream modulation. Growth factor signalling is best appreciated through the clinical trial effects of multi-targeted tyrosine kinase inhibitors, whilst oestrogen receptor expression data may only offer a superficial insight into oestrogen signalling. Finally, the tumour microenvironment presents multiple potential novel therapeutic targets. Sporadic desmoid tumours are rare soft-tissue neoplasms that arise from connective tissues in the chest wall, head, neck and limbs. Whilst lacking metastatic potential, uncertainty surrounding their locally aggressive growth and unpredictable recurrence complicates treatment approaches. At the molecular level, alterations in the Wnt/β-catenin signalling pathway, a fundamental coordinator of cell growth and development, have been strongly linked to desmoid tumour development. Beyond this, however, little is known about other molecular drivers. In the case of progressive or life-threatening disease, complex treatment decisions are made regarding the use of surgery, radiotherapy or systemic treatment modalities. Of the targeted systemic therapies, a lack of comparative clinical studies further complicates medical treatment decision making as no definitive treatment approach exists. Therefore, this review aimed to summarise the literature regarding the molecular drivers of desmoid tumour pathogenesis and to discuss the current and emerging novel therapies targeting such mechanisms. Utilising findings from human desmoid tissue samples, we present the rationale for targeting downstream mediators of the central Wnt/β-catenin pathway and outline potential treatment targets in the tumour microenvironment. We also highlight the knowledge gained from clinical drug trials targeting desmoid growth factor signalling and present the potentially superficial insight provided by oestrogen receptor expression profiles on the role of oestrogen signalling in desmoid pathogenesis. In doing so, this work may assist in the eventual development of an evidence-based treatment approach for sporadic desmoid tumours.
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Affiliation(s)
- Thomas D McLean
- Melbourne Medical School, The University of Melbourne, Melbourne, VIC, Australia.
| | - Serena Duchi
- Department of Surgery, The University of Melbourne, Melbourne, VIC, Australia.,Biofab 3D, Aikenhead Centre for Medical Discovery, Melbourne, VIC, Australia
| | - Claudia Di Bella
- Department of Surgery, The University of Melbourne, Melbourne, VIC, Australia.,Department of Orthopaedics, St Vincent's Hospital Melbourne, VIC, Australia
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23
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Yu F, Yu C, Li F, Zuo Y, Wang Y, Yao L, Wu C, Wang C, Ye L. Wnt/β-catenin signaling in cancers and targeted therapies. Signal Transduct Target Ther 2021; 6:307. [PMID: 34456337 PMCID: PMC8403677 DOI: 10.1038/s41392-021-00701-5] [Citation(s) in RCA: 395] [Impact Index Per Article: 98.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 06/19/2021] [Accepted: 06/28/2021] [Indexed: 02/07/2023] Open
Abstract
Wnt/β-catenin signaling has been broadly implicated in human cancers and experimental cancer models of animals. Aberrant activation of Wnt/β-catenin signaling is tightly linked with the increment of prevalence, advancement of malignant progression, development of poor prognostics, and even ascendence of the cancer-associated mortality. Early experimental investigations have proposed the theoretical potential that efficient repression of this signaling might provide promising therapeutic choices in managing various types of cancers. Up to date, many therapies targeting Wnt/β-catenin signaling in cancers have been developed, which is assumed to endow clinicians with new opportunities of developing more satisfactory and precise remedies for cancer patients with aberrant Wnt/β-catenin signaling. However, current facts indicate that the clinical translations of Wnt/β-catenin signaling-dependent targeted therapies have faced un-neglectable crises and challenges. Therefore, in this study, we systematically reviewed the most updated knowledge of Wnt/β-catenin signaling in cancers and relatively targeted therapies to generate a clearer and more accurate awareness of both the developmental stage and underlying limitations of Wnt/β-catenin-targeted therapies in cancers. Insights of this study will help readers better understand the roles of Wnt/β-catenin signaling in cancers and provide insights to acknowledge the current opportunities and challenges of targeting this signaling in cancers.
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Affiliation(s)
- Fanyuan Yu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Endodontics, West China Stomatology Hospital, Sichuan University, Chengdu, China
| | - Changhao Yu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Endodontics, West China Stomatology Hospital, Sichuan University, Chengdu, China
| | - Feifei Li
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yanqin Zuo
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Endodontics, West China Stomatology Hospital, Sichuan University, Chengdu, China
| | - Yitian Wang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Lin Yao
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Endodontics, West China Stomatology Hospital, Sichuan University, Chengdu, China
| | - Chenzhou Wu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Chenglin Wang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Endodontics, West China Stomatology Hospital, Sichuan University, Chengdu, China
| | - Ling Ye
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
- Department of Endodontics, West China Stomatology Hospital, Sichuan University, Chengdu, China.
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24
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Soldi R, Halder TG, Sampson S, Vankayalapati H, Weston A, Thode T, Bhalla KN, Ng S, Rodriguez Del Villar R, Drenner K, Kaadige MR, Horrigan SK, Batra SK, Salgia R, Sharma S. The Small Molecule BC-2059 Inhibits Wingless/Integrated (Wnt)-Dependent Gene Transcription in Cancer through Disruption of the Transducin β-Like 1- β-Catenin Protein Complex. J Pharmacol Exp Ther 2021; 378:77-86. [PMID: 34006586 DOI: 10.1124/jpet.121.000634] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 05/04/2021] [Indexed: 12/26/2022] Open
Abstract
The central role of β-catenin in the Wnt pathway makes it an attractive therapeutic target for cancers driven by aberrant Wnt signaling. We recently developed a small-molecule inhibitor, BC-2059, that promotes apoptosis by disrupting the β-catenin/transducin β-like 1 (TBL1) complex through an unknown mechanism of action. In this study, we show that BC-2059 directly interacts with high affinity for TBL1 when in complex with β-catenin. We identified two amino acids in a hydrophobic pocket of TBL1 that are required for binding with β-catenin, and computational modeling predicted that BC-2059 interacts at the same hydrophobic pocket. Although this pocket in TBL1 is involved in binding with NCoR/SMRT complex members G Protein Pathway Suppressor 2 (GSP2) and SMRT and p65 NFκB subunit, BC-2059 failed to disrupt the interaction of TBL1 with either NCoR/SMRT or NFκB. Together, our results show that BC-2059 selectively targets TBL1/β-catenin protein complex, suggesting BC-2059 as a therapeutic for tumors with deregulated Wnt signaling pathway. SIGNIFICANCE STATEMENT: This study reports the mechanism of action of a novel Wnt pathway inhibitor, characterizing the selective disruption of the transducin β-like 1/β-catenin protein complex. As Wnt signaling is dysregulated across cancer types, this study suggests BC-2059 has the potential to benefit patients with tumors reliant on this pathway.
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Affiliation(s)
- Raffaella Soldi
- Applied Cancer Research and Drug Discovery, Translational Genomics Research Institute (TGen), Phoenix, Arizona (R.S., T.G.H., S.S., A.W., T.T., R.R.d.V., K.D., M.R.K., S.S.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.V.); MD Anderson Cancer Center, University of Texas, Department of Leukemia, Division of Cancer Medicine, Houston, Texas (K.N.B.); Iterion Therapeutics, Inc., Houston, Texas (S.K.H.); College of Medicine, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska (S.K.B.); City of Hope Comprehensive Cancer Center, Duarte, California (R.S.)
| | - Tithi Ghosh Halder
- Applied Cancer Research and Drug Discovery, Translational Genomics Research Institute (TGen), Phoenix, Arizona (R.S., T.G.H., S.S., A.W., T.T., R.R.d.V., K.D., M.R.K., S.S.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.V.); MD Anderson Cancer Center, University of Texas, Department of Leukemia, Division of Cancer Medicine, Houston, Texas (K.N.B.); Iterion Therapeutics, Inc., Houston, Texas (S.K.H.); College of Medicine, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska (S.K.B.); City of Hope Comprehensive Cancer Center, Duarte, California (R.S.)
| | - Samuel Sampson
- Applied Cancer Research and Drug Discovery, Translational Genomics Research Institute (TGen), Phoenix, Arizona (R.S., T.G.H., S.S., A.W., T.T., R.R.d.V., K.D., M.R.K., S.S.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.V.); MD Anderson Cancer Center, University of Texas, Department of Leukemia, Division of Cancer Medicine, Houston, Texas (K.N.B.); Iterion Therapeutics, Inc., Houston, Texas (S.K.H.); College of Medicine, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska (S.K.B.); City of Hope Comprehensive Cancer Center, Duarte, California (R.S.)
| | - Hariprasad Vankayalapati
- Applied Cancer Research and Drug Discovery, Translational Genomics Research Institute (TGen), Phoenix, Arizona (R.S., T.G.H., S.S., A.W., T.T., R.R.d.V., K.D., M.R.K., S.S.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.V.); MD Anderson Cancer Center, University of Texas, Department of Leukemia, Division of Cancer Medicine, Houston, Texas (K.N.B.); Iterion Therapeutics, Inc., Houston, Texas (S.K.H.); College of Medicine, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska (S.K.B.); City of Hope Comprehensive Cancer Center, Duarte, California (R.S.)
| | - Alexis Weston
- Applied Cancer Research and Drug Discovery, Translational Genomics Research Institute (TGen), Phoenix, Arizona (R.S., T.G.H., S.S., A.W., T.T., R.R.d.V., K.D., M.R.K., S.S.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.V.); MD Anderson Cancer Center, University of Texas, Department of Leukemia, Division of Cancer Medicine, Houston, Texas (K.N.B.); Iterion Therapeutics, Inc., Houston, Texas (S.K.H.); College of Medicine, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska (S.K.B.); City of Hope Comprehensive Cancer Center, Duarte, California (R.S.)
| | - Trason Thode
- Applied Cancer Research and Drug Discovery, Translational Genomics Research Institute (TGen), Phoenix, Arizona (R.S., T.G.H., S.S., A.W., T.T., R.R.d.V., K.D., M.R.K., S.S.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.V.); MD Anderson Cancer Center, University of Texas, Department of Leukemia, Division of Cancer Medicine, Houston, Texas (K.N.B.); Iterion Therapeutics, Inc., Houston, Texas (S.K.H.); College of Medicine, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska (S.K.B.); City of Hope Comprehensive Cancer Center, Duarte, California (R.S.)
| | - Kapil N Bhalla
- Applied Cancer Research and Drug Discovery, Translational Genomics Research Institute (TGen), Phoenix, Arizona (R.S., T.G.H., S.S., A.W., T.T., R.R.d.V., K.D., M.R.K., S.S.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.V.); MD Anderson Cancer Center, University of Texas, Department of Leukemia, Division of Cancer Medicine, Houston, Texas (K.N.B.); Iterion Therapeutics, Inc., Houston, Texas (S.K.H.); College of Medicine, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska (S.K.B.); City of Hope Comprehensive Cancer Center, Duarte, California (R.S.)
| | - Serina Ng
- Applied Cancer Research and Drug Discovery, Translational Genomics Research Institute (TGen), Phoenix, Arizona (R.S., T.G.H., S.S., A.W., T.T., R.R.d.V., K.D., M.R.K., S.S.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.V.); MD Anderson Cancer Center, University of Texas, Department of Leukemia, Division of Cancer Medicine, Houston, Texas (K.N.B.); Iterion Therapeutics, Inc., Houston, Texas (S.K.H.); College of Medicine, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska (S.K.B.); City of Hope Comprehensive Cancer Center, Duarte, California (R.S.)
| | - Ryan Rodriguez Del Villar
- Applied Cancer Research and Drug Discovery, Translational Genomics Research Institute (TGen), Phoenix, Arizona (R.S., T.G.H., S.S., A.W., T.T., R.R.d.V., K.D., M.R.K., S.S.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.V.); MD Anderson Cancer Center, University of Texas, Department of Leukemia, Division of Cancer Medicine, Houston, Texas (K.N.B.); Iterion Therapeutics, Inc., Houston, Texas (S.K.H.); College of Medicine, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska (S.K.B.); City of Hope Comprehensive Cancer Center, Duarte, California (R.S.)
| | - Kevin Drenner
- Applied Cancer Research and Drug Discovery, Translational Genomics Research Institute (TGen), Phoenix, Arizona (R.S., T.G.H., S.S., A.W., T.T., R.R.d.V., K.D., M.R.K., S.S.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.V.); MD Anderson Cancer Center, University of Texas, Department of Leukemia, Division of Cancer Medicine, Houston, Texas (K.N.B.); Iterion Therapeutics, Inc., Houston, Texas (S.K.H.); College of Medicine, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska (S.K.B.); City of Hope Comprehensive Cancer Center, Duarte, California (R.S.)
| | - Mohan R Kaadige
- Applied Cancer Research and Drug Discovery, Translational Genomics Research Institute (TGen), Phoenix, Arizona (R.S., T.G.H., S.S., A.W., T.T., R.R.d.V., K.D., M.R.K., S.S.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.V.); MD Anderson Cancer Center, University of Texas, Department of Leukemia, Division of Cancer Medicine, Houston, Texas (K.N.B.); Iterion Therapeutics, Inc., Houston, Texas (S.K.H.); College of Medicine, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska (S.K.B.); City of Hope Comprehensive Cancer Center, Duarte, California (R.S.)
| | - Stephen K Horrigan
- Applied Cancer Research and Drug Discovery, Translational Genomics Research Institute (TGen), Phoenix, Arizona (R.S., T.G.H., S.S., A.W., T.T., R.R.d.V., K.D., M.R.K., S.S.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.V.); MD Anderson Cancer Center, University of Texas, Department of Leukemia, Division of Cancer Medicine, Houston, Texas (K.N.B.); Iterion Therapeutics, Inc., Houston, Texas (S.K.H.); College of Medicine, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska (S.K.B.); City of Hope Comprehensive Cancer Center, Duarte, California (R.S.)
| | - Surinder K Batra
- Applied Cancer Research and Drug Discovery, Translational Genomics Research Institute (TGen), Phoenix, Arizona (R.S., T.G.H., S.S., A.W., T.T., R.R.d.V., K.D., M.R.K., S.S.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.V.); MD Anderson Cancer Center, University of Texas, Department of Leukemia, Division of Cancer Medicine, Houston, Texas (K.N.B.); Iterion Therapeutics, Inc., Houston, Texas (S.K.H.); College of Medicine, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska (S.K.B.); City of Hope Comprehensive Cancer Center, Duarte, California (R.S.)
| | - Ravi Salgia
- Applied Cancer Research and Drug Discovery, Translational Genomics Research Institute (TGen), Phoenix, Arizona (R.S., T.G.H., S.S., A.W., T.T., R.R.d.V., K.D., M.R.K., S.S.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.V.); MD Anderson Cancer Center, University of Texas, Department of Leukemia, Division of Cancer Medicine, Houston, Texas (K.N.B.); Iterion Therapeutics, Inc., Houston, Texas (S.K.H.); College of Medicine, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska (S.K.B.); City of Hope Comprehensive Cancer Center, Duarte, California (R.S.)
| | - Sunil Sharma
- Applied Cancer Research and Drug Discovery, Translational Genomics Research Institute (TGen), Phoenix, Arizona (R.S., T.G.H., S.S., A.W., T.T., R.R.d.V., K.D., M.R.K., S.S.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.V.); MD Anderson Cancer Center, University of Texas, Department of Leukemia, Division of Cancer Medicine, Houston, Texas (K.N.B.); Iterion Therapeutics, Inc., Houston, Texas (S.K.H.); College of Medicine, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska (S.K.B.); City of Hope Comprehensive Cancer Center, Duarte, California (R.S.)
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25
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Abstract
Mucins are high molecular-weight epithelial glycoproteins and are implicated in many physiological processes, including epithelial cell protection, signaling transduction, and tissue homeostasis. Abnormality of mucus expression and structure contributes to biological properties related to human cancer progression. Tumor growth sites induce inhospitable conditions. Many kinds of research suggest that mucins provide a microenvironment to avoid hypoxia, acidic, and other biological conditions that promote cancer progression. Given that the mucus layer captures growth factors or cytokines, we propose that mucin helps to ameliorate inhospitable conditions in tumor-growing sites. Additionally, the composition and structure of mucins enable them to mimic the surface of normal epithelial cells, allowing tumor cells to escape from immune surveillance. Indeed, human cancers such as mucinous carcinoma, show a higher incidence of invasion to adjacent organs and lymph node metastasis than do non-mucinous carcinoma. In this mini-review, we discuss how mucin provides a tumor-friendly environment and contributes to increased cancer malignancy in mucinous carcinoma.
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Affiliation(s)
- Dong-Han Wi
- Department of Life Science, Chung-Ang University, Seoul, 06974, Korea
| | - Jong-Ho Cha
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 22212, Korea
- Department of Biomedical Science, Program in Biomedical Science and Engineering, Graduate school, Inha University, Incheon 22212, Korea
| | - Youn-Sang Jung
- Department of Life Science, Chung-Ang University, Seoul, 06974, Korea
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26
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Miller SA, Policastro RA, Sriramkumar S, Lai T, Huntington TD, Ladaika CA, Kim D, Hao C, Zentner GE, O'Hagan HM. LSD1 and Aberrant DNA Methylation Mediate Persistence of Enteroendocrine Progenitors That Support BRAF-Mutant Colorectal Cancer. Cancer Res 2021; 81:3791-3805. [PMID: 34035083 DOI: 10.1158/0008-5472.can-20-3562] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 03/23/2021] [Accepted: 05/05/2021] [Indexed: 11/16/2022]
Abstract
Despite the connection of secretory cells, including goblet and enteroendocrine (EEC) cells, to distinct mucus-containing colorectal cancer histologic subtypes, their role in colorectal cancer progression has been underexplored. Here, our analysis of The Cancer Genome Atlas (TCGA) and single-cell RNA-sequencing data demonstrates that EEC progenitor cells are enriched in BRAF-mutant colorectal cancer patient tumors, cell lines, and patient-derived organoids. In BRAF-mutant colorectal cancer, EEC progenitors were blocked from differentiating further by DNA methylation and silencing of NEUROD1, a key gene required for differentiation of intermediate EECs. Mechanistically, secretory cells and the factors they secrete, such as trefoil factor 3, promoted colony formation and activation of cell survival pathways in the entire cell population. Lysine-specific demethylase 1 (LSD1) was identified as a critical regulator of secretory cell specification in vitro and in a colon orthotopic xenograft model, where LSD1 loss blocks formation of EEC progenitors and reduces tumor growth and metastasis. These findings reveal an important role for EEC progenitors in supporting colorectal cancer. SIGNIFICANCE: This study establishes enteroendocrine progenitors as a targetable population that promotes BRAF-mutant colorectal cancer and can be blocked by LSD1 inhibition to suppress tumor growth.
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Affiliation(s)
- Samuel A Miller
- Genome, Cell, and Developmental Biology, Department of Biology, Indiana University Bloomington, Bloomington, Indiana.,Medical Sciences Program, Indiana University School of Medicine, Bloomington, Indiana
| | - Robert A Policastro
- Genome, Cell, and Developmental Biology, Department of Biology, Indiana University Bloomington, Bloomington, Indiana
| | - Shruthi Sriramkumar
- Medical Sciences Program, Indiana University School of Medicine, Bloomington, Indiana.,Cell, Molecular and Cancer Biology Graduate Program, Indiana University School of Medicine, Bloomington, Indiana
| | - Tim Lai
- Medical Sciences Program, Indiana University School of Medicine, Bloomington, Indiana.,Luddy School of Informatics, Computing, and Engineering, Indiana University, Bloomington, Indiana.,Department of Mathematics, Indiana University, Bloomington, Indiana
| | - Thomas D Huntington
- Medical Sciences Program, Indiana University School of Medicine, Bloomington, Indiana
| | - Christopher A Ladaika
- Genome, Cell, and Developmental Biology, Department of Biology, Indiana University Bloomington, Bloomington, Indiana.,Medical Sciences Program, Indiana University School of Medicine, Bloomington, Indiana
| | - Daeho Kim
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Chunhai Hao
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana.,Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana
| | - Gabriel E Zentner
- Genome, Cell, and Developmental Biology, Department of Biology, Indiana University Bloomington, Bloomington, Indiana.,Cell, Molecular and Cancer Biology Graduate Program, Indiana University School of Medicine, Bloomington, Indiana.,Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana
| | - Heather M O'Hagan
- Medical Sciences Program, Indiana University School of Medicine, Bloomington, Indiana. .,Cell, Molecular and Cancer Biology Graduate Program, Indiana University School of Medicine, Bloomington, Indiana.,Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana.,Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
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27
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Condorelli AG, El Hachem M, Zambruno G, Nystrom A, Candi E, Castiglia D. Notch-ing up knowledge on molecular mechanisms of skin fibrosis: focus on the multifaceted Notch signalling pathway. J Biomed Sci 2021; 28:36. [PMID: 33966637 PMCID: PMC8106838 DOI: 10.1186/s12929-021-00732-8] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 05/04/2021] [Indexed: 12/15/2022] Open
Abstract
Fibrosis can be defined as an excessive and deregulated deposition of extracellular matrix proteins, causing loss of physiological architecture and dysfunction of different tissues and organs. In the skin, fibrosis represents the hallmark of several acquired (e.g. systemic sclerosis and hypertrophic scars) and inherited (i.e. dystrophic epidermolysis bullosa) diseases. A complex series of interactions among a variety of cellular types and a wide range of molecular players drive the fibrogenic process, often in a context-dependent manner. However, the pathogenetic mechanisms leading to skin fibrosis are not completely elucidated. In this scenario, an increasing body of evidence has recently disclosed the involvement of Notch signalling cascade in fibrosis of the skin and other organs. Despite its apparent simplicity, Notch represents one of the most multifaceted, strictly regulated and intricate pathways with still unknown features both in health and disease conditions. Starting from the most recent advances in Notch activation and regulation, this review focuses on the pro-fibrotic function of Notch pathway in fibroproliferative skin disorders describing molecular networks, interplay with other pro-fibrotic molecules and pathways, including the transforming growth factor-β1, and therapeutic strategies under development.
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Affiliation(s)
- Angelo Giuseppe Condorelli
- Genodermatosis Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Piazza Sant' Onofrio 4, 00165, Rome, Italy.
| | - May El Hachem
- Dermatology Unit and Genodermatosis Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Piazza Sant' Onofrio 4, 00165, Rome, Italy
| | - Giovanna Zambruno
- Genodermatosis Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Piazza Sant' Onofrio 4, 00165, Rome, Italy
| | - Alexander Nystrom
- Department of Dermatology, Medical Faculty, Medical Center, University of Freiburg, Freiburg, Germany
| | - Eleonora Candi
- Department of Experimental Medicine, University of Rome "Tor Vergata", via Montpellier, 1, 00133, Rome, Italy.,IDI-IRCCS, via Monti di Creta 104, 00167, Rome, Italy
| | - Daniele Castiglia
- Laboratory of Molecular and Cell Biology, IDI-IRCCS, via Monti di Creta 104, 00167, Rome, Italy
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28
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Zhu C, Ho YJ, Salomao MA, Dapito DH, Bartolome A, Schwabe RF, Lee JS, Lowe SW, Pajvani UB. Notch activity characterizes a common hepatocellular carcinoma subtype with unique molecular and clinicopathologic features. J Hepatol 2021; 74:613-626. [PMID: 33038431 PMCID: PMC7897246 DOI: 10.1016/j.jhep.2020.09.032] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 09/27/2020] [Accepted: 09/29/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS The hepatocyte Notch pathway is a pathogenic factor in non-alcoholic steatohepatitis (NASH)-associated fibrosis, but its role in hepatocellular carcinoma (HCC) is less well defined. Herein, we aimed to characterize the molecular and clinical features of Notch-active human HCC, and to investigate the mechanisms by which Notch affects NASH-driven HCC. METHODS Using a 14-gene Notch score, we stratified human HCCs from multiple comprehensively profiled datasets. We performed gene set enrichment analyses to compare Notch-active HCCs with published HCC subtype signatures. Next, we sorted Notch-active hepatocytes from Notch reporter mice for RNA sequencing and characterized Notch-active tumors in an HCC model combining a carcinogen and a NASH-inducing diet. We used genetic mouse models to manipulate hepatocyte Notch to investigate the sufficiency and necessity of Notch in NASH-driven tumorigenesis. RESULTS Notch-active signatures were found in ~30% of human HCCs that transcriptionally resemble cholangiocarcinoma-like HCC, exhibiting a lack of activating CTNNB1 (β-catenin) mutations and a generally poor prognosis. Endogenous Notch activation in hepatocytes is associated with repressed β-catenin signaling and hepatic metabolic functions, in lieu of increased interactions with the extracellular matrix in NASH. Constitutive hepatocyte Notch activation is sufficient to induce β-catenin-inactive HCC in mice with NASH. Notch and β-catenin show a pattern of mutual exclusivity in carcinogen-induced HCC; in this mouse model, chronic blockade of Notch led to β-catenin-dependent tumor development. CONCLUSIONS Notch activity characterizes a distinct HCC molecular subtype with unique histology and prognosis. Sustained Notch signaling in chronic liver diseases can drive tumor formation without acquiring specific genomic driver mutations. LAY SUMMARY The Notch signaling pathway is known to be involved in the pathogenesis of liver fibrosis. However, its role in liver cancer has not been well defined. Herein, we show that Notch activity is increased in a subset of liver cancers and is associated with poor outcomes. We also used a mouse model to show that aberrant Notch activity can drive cancer progression in obese mice.
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Affiliation(s)
- Changyu Zhu
- Department of Medicine, Columbia University, New York, NY, USA;,Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yu-Jui Ho
- Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Marcela A. Salomao
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ, USA
| | | | | | | | - Ju-Seog Lee
- Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Scott W. Lowe
- Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA;,Howard Hughes Medical Institute, Chevy Chase, MD, USA
| | - Utpal B. Pajvani
- Department of Medicine, Columbia University, New York, NY, USA;,Corresponding author: Utpal B. Pajvani, Department of Medicine, Columbia University, Russ Berrie Medical Science Pavilion, 1150 St Nicholas Ave, New York, NY, 10032. ; fax: (212) 851-5493
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29
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Zhu Y, Hryniuk A, Foley T, Hess B, Lohnes D. Cdx2 Regulates Intestinal EphrinB1 through the Notch Pathway. Genes (Basel) 2021; 12:genes12020188. [PMID: 33525395 PMCID: PMC7911442 DOI: 10.3390/genes12020188] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 01/23/2021] [Indexed: 01/07/2023] Open
Abstract
The majority of colorectal cancers harbor loss-of-function mutations in APC, a negative regulator of canonical Wnt signaling, leading to intestinal polyps that are predisposed to malignant progression. Comparable murine APC alleles also evoke intestinal polyps, which are typically confined to the small intestine and proximal colon, but do not progress to carcinoma in the absence of additional mutations. The Cdx transcription factors Cdx1 and Cdx2 are essential for homeostasis of the intestinal epithelium, and loss of Cdx2 has been associated with more aggressive subtypes of colorectal cancer in the human population. Consistent with this, concomitant loss of Cdx1 and Cdx2 in a murine APC mutant background leads to an increase in polyps throughout the intestinal tract. These polyps also exhibit a villous phenotype associated with the loss of EphrinB1. However, the basis for these outcomes is poorly understood. To further explore this, we modeled Cdx2 loss in SW480 colorectal cancer cells. We found that Cdx2 impacted Notch signaling in SW480 cells, and that EphrinB1 is a Notch target gene. As EphrinB1 loss also leads to a villus tumor phenotype, these findings evoke a mechanism by which Cdx2 impacts colorectal cancer via Notch-dependent EphrinB1 signaling.
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Affiliation(s)
- Yalun Zhu
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada; (Y.Z.); (A.H.); (T.F.); (B.H.)
| | - Alexa Hryniuk
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada; (Y.Z.); (A.H.); (T.F.); (B.H.)
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, MB R3E 0J9, Canada
| | - Tanya Foley
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada; (Y.Z.); (A.H.); (T.F.); (B.H.)
| | - Bradley Hess
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada; (Y.Z.); (A.H.); (T.F.); (B.H.)
| | - David Lohnes
- Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada; (Y.Z.); (A.H.); (T.F.); (B.H.)
- Correspondence: ; Tel.: +1-613-562-5800 (ext. 8684)
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30
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Costa R, Muccioli S, Brillo V, Bachmann M, Szabò I, Leanza L. Mitochondrial dysfunction interferes with neural crest specification through the FoxD3 transcription factor. Pharmacol Res 2020; 164:105385. [PMID: 33348025 DOI: 10.1016/j.phrs.2020.105385] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 12/10/2020] [Accepted: 12/11/2020] [Indexed: 11/28/2022]
Abstract
The neural crest is an important group of cells with pluripotency and migratory ability that is crucially involved in tissue and cell specification during development. Craniofacial shaping, sensory neurons, body asymmetry, and pigmentation are linked to neural crest functionality. Despite its prominent role in embryogenesis, neural crest specification as well as the possible part mitochondria play in such a process remains unclarified. Mitochondria are important organelles not only for respiration, but also for regulation of cell proliferation, differentiation and death. Modulation of mitochondrial fitness and depletion of mitochondrial ATP synthesis has been shown to down-regulate Wnt signaling, both in vitro and in vivo. Since Wnt signaling is one of the crucial players during neural crest induction/specification, we hypothesized a signaling cascade connecting mitochondria to embryonic development and neural crest migration and differentiation. Here, by using pharmacological and genetic modulators of mitochondrial function, we provide evidence that a crosstalk between mitochondrial energy homeostasis and Wnt signaling is important in the development of neural crest-derived tissues. Furthermore, our results highlight the possibility to modulate neural crest cell specification by tuning mitochondrial metabolism via FoxD3, an important transcription factor that is regulated by Wnt. FoxD3 ensures the correct embryonic development and contributes to the maintenance of cell stemness and to the induction of epithelial-to-mesenchymal transition. In summary, our work offers new insights into the molecular mechanism of action of FoxD3 and demonstrates that mitochondrial fitness is linked to the regulation of this important transcription factor via Wnt signaling in the context of neural crest specification.
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Affiliation(s)
- Roberto Costa
- Department of Biology, University of Padova, Padova, Italy
| | | | | | | | - Ildikò Szabò
- Department of Biology, University of Padova, Padova, Italy
| | - Luigi Leanza
- Department of Biology, University of Padova, Padova, Italy.
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31
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Frick A, Khare V, Jimenez K, Dammann K, Lang M, Krnjic A, Gmainer C, Baumgartner M, Mesteri I, Gasche C. A Novel PAK1-Notch1 Axis Regulates Crypt Homeostasis in Intestinal Inflammation. Cell Mol Gastroenterol Hepatol 2020; 11:892-907.e1. [PMID: 33189893 PMCID: PMC7900837 DOI: 10.1016/j.jcmgh.2020.11.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Revised: 10/30/2020] [Accepted: 11/02/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS p21-activated kinase-1 (PAK1) belongs to a family of serine-threonine kinases and contributes to cellular pathways such as nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), and Wingless-related integration site(Wnt)/β-catenin, all of which are involved in intestinal homeostasis. Overexpression of PAK1 is linked to inflammatory bowel disease as well as colitis-associated cancer (CAC), and similarly was observed in interleukin (IL)10 knockout (KO) mice, a model of colitis and CAC. Here, we tested the effects of PAK1 deletion on intestinal inflammation and carcinogenesis in IL10 KO mice. METHODS IL10/PAK1 double-knockout (DKO) mice were generated and development of colitis and CAC was analyzed. Large intestines were measured and prepared for histology or RNA isolation. Swiss rolls were stained with H&E and periodic acid-Schiff. Co-immunoprecipitation and immunofluorescence were performed using intestinal organoids, SW480, and normal human colon epithelial cells 1CT. RESULTS When compared with IL10 KO mice, DKOs showed longer colons and prolonged crypts, despite having higher inflammation and numbers of dysplasia. Crypt hyperproliferation was associated with Notch1 activation and diminished crypt differentiation, indicated by a reduction of goblet cells. Gene expression analysis indicated up-regulation of the Notch1 target hairy and enhancer of split-1 and the stem cell receptor leucin-rich repeat-containing G-protein-coupled receptor 5 in DKO mice. Interestingly, the stem cell marker olfactomedin-4 was present in colonic tissue. Increased β-catenin messenger RNA and cytoplasmic accumulation indicated aberrant Wnt signaling. Co-localization and direct interaction of Notch1 and PAK1 was found in colon epithelial cells. Notch1 activation abrogated this effect whereas silencing of PAK1 led to Notch1 activation. CONCLUSIONS PAK1 contributes to the regulation of crypt homeostasis under inflammatory conditions by controlling Notch1. This identifies a novel PAK1-Notch1 axis in intestinal pathophysiology of inflammatory bowel disease and CAC.
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Affiliation(s)
- Adrian Frick
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Vineeta Khare
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Kristine Jimenez
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Kyle Dammann
- Department of Surgery, Saint Luke's University Hospital Bethlehem, Bethlehem, Pennsylvania
| | - Michaela Lang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Anita Krnjic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Christina Gmainer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Maximilian Baumgartner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | | | - Christoph Gasche
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
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Abstract
Head and neck cancer is a group of neoplastic diseases affecting the facial, oral, and neck region. It is one of the most common cancers worldwide with an aggressive, invasive evolution. Due to the heterogeneity of the tissues affected, it is particularly challenging to study the molecular mechanisms at the basis of these tumors, and to date we are still lacking accurate targets for prevention and therapy. The Notch signaling is involved in a variety of tumorigenic mechanisms, such as regulation of the tumor microenvironment, aberrant intercellular communication, and altered metabolism. Here, we provide an up-to-date review of the role of Notch in head and neck cancer and draw parallels with other types of solid tumors where the Notch pathway plays a crucial role in emergence, maintenance, and progression of the disease. We therefore give a perspective view on the importance of the pathway in neoplastic development in order to define future lines of research and novel therapeutic approaches.
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33
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The effects of a mixture of Lactobacillus species on colorectal tumor cells activity through modulation of Hes1 pathway. PHARMANUTRITION 2020. [DOI: 10.1016/j.phanu.2020.100207] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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34
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Fu Y, Yuan SS, Zhang LJ, Ji ZL, Quan XJ. Atonal bHLH transcription factor 1 is an important factor for maintaining the balance of cell proliferation and differentiation in tumorigenesis. Oncol Lett 2020; 20:2595-2605. [PMID: 32782577 PMCID: PMC7400680 DOI: 10.3892/ol.2020.11833] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 09/06/2019] [Indexed: 12/15/2022] Open
Abstract
Establishing the link between cellular processes and oncogenesis may aid the elucidation of targeted and effective therapies against tumor cell proliferation and metastasis. Previous studies have investigated the mechanisms involved in maintaining the balance between cell proliferation, differentiation and migration. There is increased interest in determining the conditions that allow cancer stem cells to differentiate as well as the identification of molecules that may serve as novel drug targets. Furthermore, the study of various genes, including transcription factors, which serve a crucial role in cellular processes, may present a promising direction for future therapy. The present review described the role of the transcription factor atonal bHLH transcription factor 1 (ATOH1) in signaling pathways in tumorigenesis, particularly in cerebellar tumor medulloblastoma and colorectal cancer, where ATOH1 serves as an oncogene or tumor suppressor, respectively. Additionally, the present review summarized the associated therapeutic interventions for these two types of tumors and discussed novel clinical targets and approaches.
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Affiliation(s)
- Ying Fu
- Key Laboratory of Diabetes Prevention and Research, Endocrinology Center, Lu He Hospital, Capital Medical University, Beijing 101149, P.R. China
| | - Sha-Sha Yuan
- Key Laboratory of Diabetes Prevention and Research, Endocrinology Center, Lu He Hospital, Capital Medical University, Beijing 101149, P.R. China
| | - Li-Jie Zhang
- Key Laboratory of Diabetes Prevention and Research, Endocrinology Center, Lu He Hospital, Capital Medical University, Beijing 101149, P.R. China
| | - Zhi-Li Ji
- Key Laboratory of Diabetes Prevention and Research, Endocrinology Center, Lu He Hospital, Capital Medical University, Beijing 101149, P.R. China
| | - Xiao-Jiang Quan
- Key Laboratory of Diabetes Prevention and Research, Endocrinology Center, Lu He Hospital, Capital Medical University, Beijing 101149, P.R. China.,Laboratory of Brain Development, Institut du Cerveau et de la Moelle Épinière, Hôpital Pitié-Salpêtrière, 75013 Paris, France
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35
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Kostouros A, Koliarakis I, Natsis K, Spandidos DA, Tsatsakis A, Tsiaoussis J. Large intestine embryogenesis: Molecular pathways and related disorders (Review). Int J Mol Med 2020; 46:27-57. [PMID: 32319546 PMCID: PMC7255481 DOI: 10.3892/ijmm.2020.4583] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 04/08/2020] [Indexed: 02/07/2023] Open
Abstract
The large intestine, part of the gastrointestinal tract (GI), is composed of all three germ layers, namely the endoderm, the mesoderm and the ectoderm, forming the epithelium, the smooth muscle layers and the enteric nervous system, respectively. Since gastrulation, these layers develop simultaneously during embryogenesis, signaling to each other continuously until adult age. Two invaginations, the anterior intestinal portal (AIP) and the caudal/posterior intestinal portal (CIP), elongate and fuse, creating the primitive gut tube, which is then patterned along the antero‑posterior (AP) axis and the radial (RAD) axis in the context of left‑right (LR) asymmetry. These events lead to the formation of three distinct regions, the foregut, midgut and hindgut. All the above‑mentioned phenomena are under strict control from various molecular pathways, which are critical for the normal intestinal development and function. Specifically, the intestinal epithelium constitutes a constantly developing tissue, deriving from the progenitor stem cells at the bottom of the intestinal crypt. Epithelial differentiation strongly depends on the crosstalk with the adjacent mesoderm. Major molecular pathways that are implicated in the embryogenesis of the large intestine include the canonical and non‑canonical wingless‑related integration site (Wnt), bone morphogenetic protein (BMP), Notch and hedgehog systems. The aberrant regulation of these pathways inevitably leads to several intestinal malformation syndromes, such as atresia, stenosis, or agangliosis. Novel theories, involving the regulation and homeostasis of intestinal stem cells, suggest an embryological basis for the pathogenesis of colorectal cancer (CRC). Thus, the present review article summarizes the diverse roles of these molecular factors in intestinal embryogenesis and related disorders.
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Affiliation(s)
- Antonios Kostouros
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Crete, 71110 Heraklion
| | - Ioannis Koliarakis
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Crete, 71110 Heraklion
| | - Konstantinos Natsis
- Department of Anatomy and Surgical Anatomy, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki
| | | | - Aristidis Tsatsakis
- Laboratory of Toxicology, Medical School, University of Crete, 71409 Heraklion, Greece
| | - John Tsiaoussis
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Crete, 71110 Heraklion
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36
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Exploitation of fibrin-based signaling niche for deriving progenitors from human adipose-derived mesenchymal stem cells towards potential neural engineering applications. Sci Rep 2020; 10:7116. [PMID: 32346006 PMCID: PMC7188903 DOI: 10.1038/s41598-020-63445-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Accepted: 03/19/2020] [Indexed: 02/06/2023] Open
Abstract
Adipose-derived mesenchymal stem cells (hADMSC) retaining proliferation and multi-differentiation potential may support the central nervous system (CNS) regeneration. Multipotency of MSC may result in both desirable and undesirable cells, post-transplantation. A better strategy to attain desired cells may be in vitro commitment of hADMSCs to uni-/bi- potent neural progenitor cells (NPCs), prior to transplantation. Derivation of stable NPCs may require a suitable niche eliciting proliferation and differentiation signals. The present study designed a biomimetic niche comprising insoluble fibrin supported adhesion matrix and exogenously added growth factors (GFs) for deriving different neural cells and established the role of Notch and Wnt signals for proliferation and differentiation of hADMSCs, respectively. The stable transformation of hADMSCs into neurospheres (NS) comprising Nestin+ve NPCs was achieved consistently. Slight modifications of niche enable differentiation of NS to NPCs; NPCs to neurons; NPCs to oligodendrocyte progenitor cells (OPCs); and OPCs to oligodendrocytes (OLG). Fibrin plays a crucial role in the conversion of hADMSC to NS and NPCs to OPCs; but, not essential for OPC to OLG maturation. Co-survival and cell-cell interaction of NPC derived neurons and OPCs promoting OLG maturation is illustrated. The designed biomimetic niche shows the potential for directing autologous ADMSCs to neural cells for applications in regenerative medicine.
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Gao Y, Yan Y, Tripathi S, Pentinmikko N, Amaral A, Päivinen P, Domènech-Moreno E, Andersson S, Wong IPL, Clevers H, Katajisto P, Mäkelä TP. LKB1 Represses ATOH1 via PDK4 and Energy Metabolism and Regulates Intestinal Stem Cell Fate. Gastroenterology 2020; 158:1389-1401.e10. [PMID: 31930988 DOI: 10.1053/j.gastro.2019.12.033] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 12/02/2019] [Accepted: 12/30/2019] [Indexed: 01/16/2023]
Abstract
BACKGROUND & AIMS In addition to the Notch and Wnt signaling pathways, energy metabolism also regulates intestinal stem cell (ISC) function. Tumor suppressor and kinase STK11 (also called LKB1) regulates stem cells and cell metabolism. We investigated whether loss of LKB1 alters ISC homeostasis in mice. METHODS We deleted LKB1 from ISCs in mice using Lgr5-regulated CRE-ERT2 (Lkb1Lgr5-KO mice) and the traced lineages by using a CRE-dependent TdTomato reporter. Intestinal tissues were collected and analyzed by immunohistochemical and immunofluorescence analyses. We purified ISCs and intestinal progenitors using flow cytometry and performed RNA-sequencing analysis. We measured organoid-forming capacity and ISC percentages using intestinal tissues from Lkb1Lgr5-KO mice. We analyzed human Ls174t cells with knockdown of LKB1 or other proteins by immunoblotting, real-time quantitative polymerase chain reaction, and the Seahorse live-cell metabolic assay. RESULTS Some intestinal crypts from Lkb1Lgr5-KO mice lost ISCs compared with crypts from control mice. However, most crypts from Lkb1Lgr5-KO mice contained functional ISCs that expressed increased levels of Atoh1 messenger RNA (mRNA), acquired a gene expression signature associated with secretory cells, and generated more cells in the secretory lineage compared with control mice. Knockdown of LKB1 in Ls174t cells induced expression of Atoh1 mRNA and a phenotype of increased mucin production; knockdown of ATOH1 prevented induction of this phenotype. The increased expression of Atoh1 mRNA after LKB1 loss from ISCs or Ls174t cells did not involve Notch or Wnt signaling. Knockdown of pyruvate dehydrogenase kinase 4 (PDK4) or inhibition with dichloroacetate reduced the up-regulation of Atoh1 mRNA after LKB1 knockdown in Ls174t cells. Cells with LKB1 knockdown had a reduced rate of oxygen consumption, which was partially restored by PDK4 inhibition with dichloroacetate. ISCs with knockout of LKB1 increased the expression of PDK4 and had an altered metabolic profile. CONCLUSIONS LKB1 represses transcription of ATOH1, via PDK4, in ISCs, restricting their differentiation into secretory lineages. These findings provide a connection between metabolism and the fate determination of ISCs.
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Affiliation(s)
- Yajing Gao
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Finland; HiLIFE-Helsinki Institute of Life Science, University of Helsinki, Finland
| | - Yan Yan
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Finland; HiLIFE-Helsinki Institute of Life Science, University of Helsinki, Finland.
| | - Sushil Tripathi
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Finland; HiLIFE-Helsinki Institute of Life Science, University of Helsinki, Finland
| | - Nalle Pentinmikko
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Finland; HiLIFE-Helsinki Institute of Life Science, University of Helsinki, Finland; Institute of Biotechnology, HiLIFE, University of Helsinki, Finland
| | - Ana Amaral
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
| | - Pekka Päivinen
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Finland; HiLIFE-Helsinki Institute of Life Science, University of Helsinki, Finland
| | - Eva Domènech-Moreno
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Finland; HiLIFE-Helsinki Institute of Life Science, University of Helsinki, Finland
| | - Simon Andersson
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Finland; HiLIFE-Helsinki Institute of Life Science, University of Helsinki, Finland; Institute of Biotechnology, HiLIFE, University of Helsinki, Finland
| | - Iris P L Wong
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Finland
| | - Hans Clevers
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and Cancer Genomics Netherlands, University Medical Center Utrecht and Princess Máxima Centre, Utrecht, The Netherlands
| | - Pekka Katajisto
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Finland; HiLIFE-Helsinki Institute of Life Science, University of Helsinki, Finland; Institute of Biotechnology, HiLIFE, University of Helsinki, Finland; Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
| | - Tomi P Mäkelä
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Finland; HiLIFE-Helsinki Institute of Life Science, University of Helsinki, Finland.
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Neural Differentiation Dynamics Controlled by Multiple Feedback Loops in a Comprehensive Molecular Interaction Network. Processes (Basel) 2020. [DOI: 10.3390/pr8020166] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Mathematical model simulation is a useful method for understanding the complex behavior of a living system. The construction of mathematical models using comprehensive information is one of the techniques of model construction. Such a comprehensive knowledge-based network tends to become a large-scale network. As a result, the variation of analyses is limited to a particular kind of analysis because of the size and complexity of the model. To analyze a large-scale regulatory network of neural differentiation, we propose a contractive method that preserves the dynamic behavior of a large network. The method consists of the following two steps: comprehensive network building and network reduction. The reduction phase can extract network loop structures from a large-scale regulatory network, and the subnetworks were combined to preserve the dynamics of the original large-scale network. We confirmed that the extracted loop combination reproduced the known dynamics of HES1 and ASCL1 before and after differentiation, including oscillation and equilibrium of their concentrations. The model also reproduced the effects of the overexpression and knockdown of the Id2 gene. Our model suggests that the characteristic change in HES1 and ASCL1 expression in the large-scale regulatory network is controlled by a combination of four feedback loops, including a large loop, which has not been focused on. The model extracted by our method has the potential to reveal the critical mechanisms of neural differentiation. The method is applicable to other biological events.
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Luu L, Johnston LJ, Derricott H, Armstrong SD, Randle N, Hartley CS, Duckworth CA, Campbell BJ, Wastling JM, Coombes JL. An Open-Format Enteroid Culture System for Interrogation of Interactions Between Toxoplasma gondii and the Intestinal Epithelium. Front Cell Infect Microbiol 2019; 9:300. [PMID: 31555604 PMCID: PMC6723115 DOI: 10.3389/fcimb.2019.00300] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 08/05/2019] [Indexed: 12/13/2022] Open
Abstract
When transmitted through the oral route, Toxoplasma gondii first interacts with its host at the small intestinal epithelium. This interaction is crucial to controlling initial invasion and replication, as well as shaping the quality of the systemic immune response. It is therefore an attractive target for the design of novel vaccines and adjuvants. However, due to a lack of tractable infection models, we understand surprisingly little about the molecular pathways that govern this interaction. The in vitro culture of small intestinal epithelium as 3D enteroids shows great promise for modeling the epithelial response to infection. However, the enclosed luminal space makes the application of infectious agents to the apical epithelial surface challenging. Here, we have developed three novel enteroid-based techniques for modeling T. gondii infection. In particular, we have adapted enteroid culture protocols to generate collagen-supported epithelial sheets with an exposed apical surface. These cultures retain epithelial polarization, and the presence of fully differentiated epithelial cell populations. They are susceptible to infection with, and support replication of, T. gondii. Using quantitative label-free mass spectrometry, we show that T. gondii infection of the enteroid epithelium is associated with up-regulation of proteins associated with cholesterol metabolism, extracellular exosomes, intermicrovillar adhesion, and cell junctions. Inhibition of host cholesterol and isoprenoid biosynthesis with Atorvastatin resulted in a reduction in parasite load only at higher doses, indicating that de novo synthesis may support, but is not required for, parasite replication. These novel models therefore offer tractable tools for investigating how interactions between T. gondii and the host intestinal epithelium influence the course of infection.
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Affiliation(s)
- Lisa Luu
- Department of Infection Biology, Faculty of Health and Life Sciences, School of Veterinary Science, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom
| | - Luke J. Johnston
- Department of Infection Biology, Faculty of Health and Life Sciences, School of Veterinary Science, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom
| | - Hayley Derricott
- Department of Infection Biology, Faculty of Health and Life Sciences, School of Veterinary Science, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom
| | - Stuart D. Armstrong
- Department of Infection Biology, Faculty of Health and Life Sciences, School of Veterinary Science, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom
| | - Nadine Randle
- Department of Infection Biology, Faculty of Health and Life Sciences, School of Veterinary Science, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom
| | - Catherine S. Hartley
- Department of Infection Biology, Faculty of Health and Life Sciences, School of Veterinary Science, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom
| | - Carrie A. Duckworth
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Barry J. Campbell
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Jonathan M. Wastling
- Department of Infection Biology, Faculty of Health and Life Sciences, School of Veterinary Science, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom
| | - Janine L. Coombes
- Department of Infection Biology, Faculty of Health and Life Sciences, School of Veterinary Science, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom
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Iyer DN, Sin WY, Ng L. Linking stemness with colorectal cancer initiation, progression, and therapy. World J Stem Cells 2019; 11:519-534. [PMID: 31523371 PMCID: PMC6716088 DOI: 10.4252/wjsc.v11.i8.519] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 06/12/2019] [Accepted: 06/20/2019] [Indexed: 02/06/2023] Open
Abstract
The discovery of cancer stem cells caused a paradigm shift in the concepts of origin and development of colorectal cancer. Several unresolved questions remain in this field though. Are colorectal cancer stem cells the cause or an effect of the disease? How do cancer stem cells assist in colorectal tumor dissemination to distant organs? What are the molecular or environmental factors affecting the roles of these cells in colorectal cancer? Through this review, we investigate the key findings until now and attempt to elucidate the origins, physical properties, microenvironmental niches, as well as the molecular signaling network that support the existence, self-renewal, plasticity, quiescence, and the overall maintenance of cancer stem cells in colorectal cancer. Increasing data show that the cancer stem cells play a crucial role not only in the establishment of the primary colorectal tumor but also in the distant spread of the disease. Hence, we will also look at the mechanisms adopted by cancer stem cells to influence the development of metastasis and evade therapeutic targeting and its role in the overall disease prognosis. Finally, we will illustrate the importance of understanding the biology of these cells to develop improved clinical strategies to tackle colorectal cancer.
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Affiliation(s)
- Deepak Narayanan Iyer
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Wai-Yan Sin
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Lui Ng
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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Li S, Peppelenbosch MP, Smits R. Bacterial biofilms as a potential contributor to mucinous colorectal cancer formation. Biochim Biophys Acta Rev Cancer 2019; 1872:74-79. [DOI: 10.1016/j.bbcan.2019.05.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Revised: 05/31/2019] [Accepted: 05/31/2019] [Indexed: 02/07/2023]
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Dougherty U, Mustafi R, Haider HI, Khalil A, Souris JS, Joseph L, Hart J, Konda VJ, Zhang W, Pekow J, Li YC, Bissonnette M. Losartan and Vitamin D Inhibit Colonic Tumor Development in a Conditional Apc-Deleted Mouse Model of Sporadic Colon Cancer. Cancer Prev Res (Phila) 2019; 12:433-448. [PMID: 31088824 DOI: 10.1158/1940-6207.capr-18-0380] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 04/02/2019] [Accepted: 05/06/2019] [Indexed: 12/20/2022]
Abstract
Colorectal cancer is a leading cause of cancer deaths. The renin-angiotensin system (RAS) is upregulated in colorectal cancer, and epidemiologic studies suggest RAS inhibitors reduce cancer risk. Because vitamin D (VD) receptor negatively regulates renin, we examined anticancer efficacy of VD and losartan (L), an angiotensin receptor blocker. Control Apc+/LoxP mice and tumor-forming Apc+/LoxP Cdx2P-Cre mice were randomized to unsupplemented Western diet (UN), or diets supplemented with VD, L, or VD+L, the latter to assess additive or synergistic effects. At 6 months, mice were killed. Plasma Ca2+, 25(OH)D3, 1α, 25(OH)2D3, renin, and angiotensin II (Ang II) were quantified. Colonic transcripts were assessed by qPCR and proteins by immunostaining and blotting. Cancer incidence and tumor burden were significantly lower in Cre+ VD and Cre+ L, but not in the Cre+ VD+L group. In Apc+/LoxP mice, VD increased plasma 1,25(OH)2D3 and colonic VDR. In Apc+/LoxP-Cdx2P-Cre mice, plasma renin and Ang II, and colonic tumor AT1, AT2, and Cyp27B1 were increased and VDR downregulated. L increased, whereas VD decreased plasma renin and Ang II in Cre+ mice. VD or L inhibited tumor development, while exerting differential effects on plasma VD metabolites and RAS components. We speculate that AT1 is critical for tumor development, whereas RAS suppression plays a key role in VD chemoprevention. When combined with L, VD no longer increases active VD and colonic VDR in Cre- mice nor suppresses renin and Ang II in Cre+ mice, likely contributing to lack of chemopreventive efficacy of the combination.
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Affiliation(s)
| | - Reba Mustafi
- Department of Medicine, University of Chicago, Chicago, Illinois
| | - Haider I Haider
- Department of Medicine, University of Chicago, Chicago, Illinois
| | | | - Jeffrey S Souris
- Department of Radiology, University of Chicago, Chicago, Illinois
| | - Loren Joseph
- Department of Pathology, Beth Israel, Harvard Medical School, Boston, Massachusetts
| | - John Hart
- Department of Pathology, University of Chicago, Chicago, Illinois
| | - Vani J Konda
- Department of Medicine, University of Chicago, Chicago, Illinois
| | - Wei Zhang
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Joel Pekow
- Department of Medicine, University of Chicago, Chicago, Illinois
| | - Yan Chun Li
- Department of Medicine, University of Chicago, Chicago, Illinois
| | - Marc Bissonnette
- Department of Medicine, University of Chicago, Chicago, Illinois.
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Bhat R, Glimm T, Linde-Medina M, Cui C, Newman SA. Synchronization of Hes1 oscillations coordinates and refines condensation formation and patterning of the avian limb skeleton. Mech Dev 2019; 156:41-54. [DOI: 10.1016/j.mod.2019.03.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 03/08/2019] [Accepted: 03/08/2019] [Indexed: 10/27/2022]
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Lu JW, Raghuram D, Fong PSA, Gong Z. Inducible Intestine-Specific Expression of kras V12 Triggers Intestinal Tumorigenesis In Transgenic Zebrafish. Neoplasia 2018; 20:1187-1197. [PMID: 30390498 PMCID: PMC6215966 DOI: 10.1016/j.neo.2018.10.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Revised: 10/10/2018] [Accepted: 10/11/2018] [Indexed: 02/06/2023] Open
Abstract
KRAS mutations are a major risk factor in colorectal cancers. In particular, a point mutation of KRAS of amino acid 12, such as KRASV12, renders it stable activity in oncogenesis. We found that krasV12 promotes intestinal carcinogenesis by generating a transgenic zebrafish line with inducible krasV12 expression in the intestine, Tg(ifabp:EGFP-krasV12). The transgenic fish generated exhibited significant increases in the rates of intestinal epithelial outgrowth, proliferation, and cross talk in the active Ras signaling pathway involving in epithelial-mesenchymal transition (EMT). These results provide in vivo evidence of Ras pathway activation via krasV12 overexpression. Long-term transgenic expression of krasV12 resulted in enteritis, epithelial hyperplasia, and tubular adenoma in adult fish. This was accompanied by increased levels of the signaling proteins p-Erk and p-Akt and by downregulation of the EMT marker E-cadherin. Furthermore, we also observed a synergistic effect of krasV12 expression and dextran sodium sulfate treatment to enhance intestinal tumor in zebrafish. Our results demonstrate that krasV12 overexpression induces intestinal tumorigenesis in zebrafish, which mimics intestinal tumor formation in humans. Thus, our transgenic zebrafish may provide a valuable in vivo platform that can be used to investigate tumor initiation and anticancer drugs for gastrointestinal cancers.
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Affiliation(s)
- Jeng-Wei Lu
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Divya Raghuram
- Department of Biological Sciences, National University of Singapore, Singapore
| | | | - Zhiyuan Gong
- Department of Biological Sciences, National University of Singapore, Singapore.
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Högström J, Heino S, Kallio P, Lähde M, Leppänen VM, Balboa D, Wiener Z, Alitalo K. Transcription Factor PROX1 Suppresses Notch Pathway Activation via the Nucleosome Remodeling and Deacetylase Complex in Colorectal Cancer Stem-like Cells. Cancer Res 2018; 78:5820-5832. [PMID: 30154153 DOI: 10.1158/0008-5472.can-18-0451] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 06/25/2018] [Accepted: 08/20/2018] [Indexed: 11/16/2022]
Abstract
The homeobox transcription factor PROX1 is induced by high Wnt/β-catenin activity in intestinal adenomas and colorectal cancer, where it promotes tumor progression. Here we report that in LGR5+ colorectal cancer cells, PROX1 suppresses the Notch pathway, which is essential for cell fate in intestinal stem cells. Pharmacologic inhibition of Notch in ex vivo 3D organoid cultures from transgenic mouse intestinal adenoma models increased Prox1 expression and the number of PROX1-positive cells. Notch inhibition led to increased proliferation of the PROX1-positive colorectal cancer cells, but did not affect their ability to give rise to PROX1-negative secretory cells. Conversely, PROX1 deletion increased Notch target gene expression and NOTCH1 promoter activity, indicating reciprocal regulation between PROX1 and the Notch pathway in colorectal cancer. PROX1 interacted with the nucleosome remodeling and deacetylase (NuRD) complex to suppress the Notch pathway. Thus, our data suggests that PROX1 and Notch suppress each other and that PROX1-mediated suppression of Notch mediates its stem cell function in colorectal cancer.Significance: These findings address the role of the PROX1 homeobox factor as a downstream effector of Wnt/β-catenin singling in colorectal cancer stem cells and show that PROX1 inhibits the Notch pathway and helps to enforce the stem cell phenotype and inhibit differentiation. Cancer Res; 78(20); 5820-32. ©2018 AACR.
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Affiliation(s)
- Jenny Högström
- Translational Cancer Biology Research Program, University of Helsinki, Helsinki, Finland
| | - Sarika Heino
- Translational Cancer Biology Research Program, University of Helsinki, Helsinki, Finland
| | - Pauliina Kallio
- Translational Cancer Biology Research Program, University of Helsinki, Helsinki, Finland
| | - Marianne Lähde
- Translational Cancer Biology Research Program, University of Helsinki, Helsinki, Finland
| | - Veli-Matti Leppänen
- Translational Cancer Biology Research Program, University of Helsinki, Helsinki, Finland
| | - Diego Balboa
- Molecular Neurology Program and Biomedicum Stem Cell Center, University of Helsinki, Helsinki, Finland
| | - Zoltán Wiener
- Translational Cancer Biology Research Program, University of Helsinki, Helsinki, Finland
| | - Kari Alitalo
- Translational Cancer Biology Research Program, University of Helsinki, Helsinki, Finland.
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Knoop KA, Gustafsson JK, McDonald KG, Kulkarni DH, Coughlin PE, McCrate S, Kim D, Hsieh CS, Hogan SP, Elson CO, Tarr PI, Newberry RD. Microbial antigen encounter during a preweaning interval is critical for tolerance to gut bacteria. Sci Immunol 2017; 2:eaao1314. [PMID: 29246946 PMCID: PMC5759965 DOI: 10.1126/sciimmunol.aao1314] [Citation(s) in RCA: 172] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 10/06/2017] [Indexed: 12/28/2022]
Abstract
We have a mutually beneficial relationship with the trillions of microorganisms inhabiting our gastrointestinal tract. However, maintaining this relationship requires recognizing these organisms as affable and restraining inflammatory responses to these organisms when encountered in hostile settings. How and when the immune system develops tolerance to our gut microbial members is not well understood. We identify a specific preweaning interval in which gut microbial antigens are encountered by the immune system to induce antigen-specific tolerance to gut bacteria. For some bacterial taxa, physiologic encounters with the immune system are restricted to this interval, despite abundance of these taxa in the gut lumen at later times outside this interval. Antigen-specific tolerance to gut bacteria induced during this preweaning interval is stable and maintained even if these taxa are encountered later in life in an inflammatory setting. However, inhibiting microbial antigen encounter during this interval or extending these encounters beyond the normal interval results in a failure to induce tolerance and robust antigen-specific effector responses to gut bacteria upon reencounter in an inflammatory setting. Thus, we have identified a defined preweaning interval critical for developing tolerance to gut bacteria and maintaining the mutually beneficial relationship with our gut microbiota.
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Affiliation(s)
- Kathryn A Knoop
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Jenny K Gustafsson
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Keely G McDonald
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Devesha H Kulkarni
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Paige E Coughlin
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Stephanie McCrate
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Dongyeon Kim
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Chyi-Song Hsieh
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Simon P Hogan
- Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Charles O Elson
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Phillip I Tarr
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Rodney D Newberry
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
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Dempsey PJ. Role of ADAM10 in intestinal crypt homeostasis and tumorigenesis. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2017; 1864:2228-2239. [PMID: 28739265 PMCID: PMC5632589 DOI: 10.1016/j.bbamcr.2017.07.011] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2017] [Revised: 07/19/2017] [Accepted: 07/20/2017] [Indexed: 12/17/2022]
Abstract
A disintegrin and metalloproteinases (ADAMs) are a family of mSultidomain, membrane-anchored proteases that regulate diverse cellular functions, including cell adhesion, migration, proteolysis and other cell signaling events. Catalytically-active ADAMs act as ectodomain sheddases that proteolytically cleave type I and type II transmembrane proteins and some GPI-anchored proteins from the cellular surface. ADAMs can also modulate other cellular signaling events through a process known as regulated intramembrane proteolysis (RIP). Through their proteolytic activity, ADAMs can rapidly modulate key cell signaling pathways in response to changes in the extracellular environment (e.g. inflammation) and play a central role in coordinating intercellular communication. Dysregulation of these processes through aberrant expression, or sustained ADAM activity, is linked to chronic inflammation, inflammation-associated cancer and tumorigenesis. ADAM10 was the first disintegrin-metalloproteinase demonstrated to have proteolytic activity and is the prototypic ADAM associated with RIP activity (e.g. sequential Notch receptor processing). ADAM10 is abundantly expressed throughout the gastrointestinal tract and during normal intestinal homeostasis ADAM10 regulates many cellular processes associated with intestinal development, cell fate specification and maintenance of intestinal stem cell/progenitor populations. In addition, several signaling pathways that undergo ectodomain shedding by ADAM10 (e.g. Notch, EGFR/ErbB, IL-6/sIL-6R) help control intestinal injury/regenerative responses and may drive intestinal inflammation and colon cancer initiation and progression. Here, I review some of the proposed functions of ADAM10 associated with intestinal crypt homeostasis and tumorigenesis within the gastrointestinal tract in vivo. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John.
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Affiliation(s)
- Peter J Dempsey
- Graduate Program in Cell Biology, Stem Cells, and Development Program, University of Colorado Medical School, Aurora, CO 80045, United States; Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado Medical School, Aurora, CO 80045, United States.
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Constitutive Immune Activity Promotes Tumorigenesis in Drosophila Intestinal Progenitor Cells. Cell Rep 2017; 20:1784-1793. [DOI: 10.1016/j.celrep.2017.07.078] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 06/05/2017] [Accepted: 07/27/2017] [Indexed: 02/02/2023] Open
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Triki M, Lapierre M, Cavailles V, Mokdad-Gargouri R. Expression and role of nuclear receptor coregulators in colorectal cancer. World J Gastroenterol 2017; 23:4480-4490. [PMID: 28740336 PMCID: PMC5504363 DOI: 10.3748/wjg.v23.i25.4480] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 09/30/2016] [Accepted: 10/31/2016] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common human cancers and the cause of about 700000 deaths per year worldwide. Deregulation of the WNT/β-catenin pathway is a key event in CRC initiation. This pathway interacts with other nuclear signaling pathways, including members of the nuclear receptor superfamily and their transcription coregulators. In this review, we provide an overview of the literature dealing with the main coactivators (NCoA-1 to 3, NCoA-6, PGC1-α, p300, CREBBP and MED1) and corepressors (N-CoR1 and 2, NRIP1 and MTA1) of nuclear receptors and summarize their links with the WNT/β-catenin signaling cascade, their expression in CRC and their role in intestinal physiopathology.
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Gao Q, Wang K, Chen K, Liang L, Zheng Y, Zhang Y, Xiang J, Tang N. HBx protein-mediated ATOH1 downregulation suppresses ARID2 expression and promotes hepatocellular carcinoma. Cancer Sci 2017; 108:1328-1337. [PMID: 28498550 PMCID: PMC5497798 DOI: 10.1111/cas.13277] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 04/10/2017] [Accepted: 05/01/2017] [Indexed: 12/11/2022] Open
Abstract
Hepatitis B virus X protein plays a crucial role in the pathogenesis of hepatocellular carcinoma. We previously showed that the tumor suppressor ARID2 inhibits hepatoma cell cycle progression and tumor growth. Here, we evaluated whether hepatitis B virus X protein was involved in the modulation of ARID2 expression and hepatocarcinogenesis associated with hepatitis B virus infection. ARID2 expression was downregulated in HBV‐replicative hepatoma cells, HBV transgenic mice, and HBV‐related clinical HCC tissues. The expression levels of HBx were negatively associated with those of ARID2 in hepatocellular carcinoma tissues. Furthermore, HBx suppressed ARID2 at transcriptional level. Mechanistically, the promoter region of ARID2 gene inhibited by HBx was located at nt‐1040/nt‐601 and contained potential ATOH1 binding elements. In addition, ectopic expression of ATOH1 or mutation of ATOH1 binding sites within ARID2 promoter partially abolished HBx‐triggered ARID2 transcriptional repression. Functionally, ARID2 abrogated HBx‐enhanced migration and proliferation of hepatoma cells, whereas depletion of ATOH1 enhanced tumorigenecity of HCC cells. Therefore, our findings suggested that deregulation of ARID2 by HBx through ATOH1 may be involved in HBV‐related hepatocellular carcinoma development.
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Affiliation(s)
- Qingzhu Gao
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Kai Wang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Ke Chen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Li Liang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Yaqiu Zheng
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Yunzhi Zhang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Jin Xiang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Ni Tang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.,The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (CCID), Zhejiang University, Hangzhou, China
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