1
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Padron F, Adlam T, Chaffins M, Zarbo A. Pigmented Plaque on the Hip of a 6-Year-Old Girl. Pediatr Dermatol 2025. [PMID: 40276868 DOI: 10.1111/pde.15919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 02/05/2025] [Accepted: 02/23/2025] [Indexed: 04/26/2025]
Affiliation(s)
- Francisco Padron
- Department of Dermatology, University of Illinois-Chicago, Chicago, Illinois, USA
| | - Taylor Adlam
- Department of Dermatology, Wayne State University, Detroit, Michigan, USA
| | - Marsha Chaffins
- Dermatopathology, Henry Ford Hospital Dermatology, Detroit, Michigan, USA
| | - Allison Zarbo
- Pediatric Dermatology, Henry Ford Hospital Dermatology, Detroit, Michigan, USA
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2
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Yoshida Y. Neurofibromatosis 1 (von Recklinghausen Disease). Keio J Med 2025; 74:37-41. [PMID: 37635082 DOI: 10.2302/kjm.2023-0013-ir] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/29/2023]
Abstract
Neurofibromatosis 1 (NF1), also known as von Recklinghausen disease, is one of the most common neurocutaneous genetic disorders. Loss of function of the NF1 gene results in overactivation of the RAS/MAPK pathway, leading to neurocutaneous manifestations and osseous abnormalities. Because of medical progress, molecular testing for NF1 after genetic counseling is now available in Japan. In addition, revised diagnostic criteria for NF1 were proposed by NF1 experts of an international panel in 2021. Because the overall degree of severity and manifestations in each patient are not predictable, age-specific annual monitoring and patient education by a multidisciplinary team are important for the management of NF1. Although treatment of plexiform neurofibroma has been challenging, selumetinib (an oral selective MEK1/2 inhibitor), which targets a pathway downstream of RAS, was approved in 2022 for use in children with inoperable, symptomatic plexiform neurofibromas in Japan. This article summarizes recent progress in diagnosis, clinical characteristics, and treatment of various manifestations of NF1 and proposes the future direction required to resolve unmet needs in patients with NF1 in Japan.
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Affiliation(s)
- Yuichi Yoshida
- Division of Dermatology, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, Tottori University, Yonago, Japan
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3
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Zhang L, Xie J, Dai W, Lu B, Yi S. Schwann cells in regeneration and cancer. Front Pharmacol 2025; 16:1506552. [PMID: 39981185 PMCID: PMC11840318 DOI: 10.3389/fphar.2025.1506552] [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: 10/05/2024] [Accepted: 01/09/2025] [Indexed: 02/22/2025] Open
Abstract
Schwann cells are specific peripheral glial cells with remarkable plasticity following peripheral nerve injury. Injury responses stimulate c-Jun activation in Schwann cells, drive epithelial-mesenchymal transition and cellular phenotypic changes, and induce the generation of reprogrammed repair Schwann cells to orchestrate peripheral nerve regeneration process. Schwann cells and/or Schwann cell-derived molecules are commonly used as supporting cells and/or neurotrophic factors to construct Schwann cell-based tissue-engineered nerve grafts for repairing severe peripheral nerve injury with long defects. Transplantation of Schwann cells and/or Schwann cell-derived molecules also serves as a helpful approach for the treatment of other injured tissues, such as the spinal cord, skin, digit tip, and bone. Schwann cells are not only associated with tissue regeneration but also involved in tumorigenesis and tumor progression. Schwann cells are the major cellular component of neurofibromatosis type 1 and the sole cell type in neurofibromatosis type 2 and schwannomatosis. In addition, Schwann cells also function as an important player in the tumor microenvironment and aid in the growth and invasiveness of many other solid cancers. In the present review, we outline the physiological and pathological activities of Schwann cells and discuss the functional roles of Schwann cells in homeostasis, regeneration, and cancer.
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Affiliation(s)
- Lan Zhang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu, China
| | - Jiale Xie
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu, China
| | - Wenyu Dai
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu, China
| | - Bing Lu
- Department of Clinical Biobank and Institute of Oncology, Affiliated Hospital of Nantong University, Nantong University, Nantong, Jiangsu, China
| | - Sheng Yi
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu, China
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4
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Sarkar H, Lee E, Lopez-Darwin SL, Kang Y. Deciphering normal and cancer stem cell niches by spatial transcriptomics: opportunities and challenges. Genes Dev 2025; 39:64-85. [PMID: 39496456 PMCID: PMC11789490 DOI: 10.1101/gad.351956.124] [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] [Indexed: 11/06/2024]
Abstract
Cancer stem cells (CSCs) often exhibit stem-like attributes that depend on an intricate stemness-promoting cellular ecosystem within their niche. The interplay between CSCs and their niche has been implicated in tumor heterogeneity and therapeutic resistance. Normal stem cells (NSCs) and CSCs share stemness features and common microenvironmental components, displaying significant phenotypic and functional plasticity. Investigating these properties across diverse organs during normal development and tumorigenesis is of paramount research interest and translational potential. Advancements in next-generation sequencing (NGS), single-cell transcriptomics, and spatial transcriptomics have ushered in a new era in cancer research, providing high-resolution and comprehensive molecular maps of diseased tissues. Various spatial technologies, with their unique ability to measure the location and molecular profile of a cell within tissue, have enabled studies on intratumoral architecture and cellular cross-talk within the specific niches. Moreover, delineation of spatial patterns for niche-specific properties such as hypoxia, glucose deprivation, and other microenvironmental remodeling are revealed through multilevel spatial sequencing. This tremendous progress in technology has also been paired with the advent of computational tools to mitigate technology-specific bottlenecks. Here we discuss how different spatial technologies are used to identify NSCs and CSCs, as well as their associated niches. Additionally, by exploring related public data sets, we review the current challenges in characterizing such niches, which are often hindered by technological limitations, and the computational solutions used to address them.
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Affiliation(s)
- Hirak Sarkar
- Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA
- Ludwig Institute for Cancer Research Princeton Branch, Princeton, New Jersey 08544, USA
- Department of Computer Science, Princeton, New Jersey 08544, USA
| | - Eunmi Lee
- Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA
| | - Sereno L Lopez-Darwin
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08544, USA
| | - Yibin Kang
- Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA;
- Ludwig Institute for Cancer Research Princeton Branch, Princeton, New Jersey 08544, USA
- Cancer Metabolism and Growth Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA
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5
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Cole JJ, Ferner RE, Gutmann DH. Neurofibromatosis type 1. ROSENBERG'S MOLECULAR AND GENETIC BASIS OF NEUROLOGICAL AND PSYCHIATRIC DISEASE 2025:231-249. [DOI: 10.1016/b978-0-443-19176-3.00017-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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6
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Yu X, Gu Y, Liu J, Huang J, Li Q, Wang Z. Emerging mechanism and therapeutic potential of neurofibromatosis type 1-related nerve system tumor: Advancing insights into tumor development. Neurooncol Adv 2025; 7:vdaf040. [PMID: 40134850 PMCID: PMC11934560 DOI: 10.1093/noajnl/vdaf040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/27/2025] Open
Abstract
Neurofibromatosis Type 1 (NF1) is a genetic disorder resulting from mutations in the NF1 gene, which increases susceptibility to various nervous system tumors, including plexiform neurofibromas, malignant peripheral nerve sheath tumors, and optic pathway gliomas. Recent research has shown that these tumors are intricately connected to the complex, dynamic interactions within neurons, culminating in neuronal signaling that fosters tumor growth. These interactions offer crucial insights into the molecular mechanisms underpinning tumor development, as well as broader implications for therapeutic strategies. This review summarizes the mechanisms through which mutations in the NF1 gene within neural tissues trigger tumorigenesis, while examining the role of the neuron-via factors such as visual experience, neurotransmitter, tumor microenvironment, and psychological influences-in both promoting tumor progression and being affected by the tumors themselves. By investigating the dynamic relationship between NF1-associated nervous system tumor cells and neurons, we aim to shed light on novel biological pathways and disease processes, emphasizing the potential of interdisciplinary approaches that combine neurobiology, oncology, and pharmacology to enhance treatment strategies and even inhibit the tumorigenesis.
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Affiliation(s)
- Xuan Yu
- Neurofibromatosis Type 1 Center and Laboratory for Neurofibromatosis Type 1 Research, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yihui Gu
- Neurofibromatosis Type 1 Center and Laboratory for Neurofibromatosis Type 1 Research, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Liu
- Neurofibromatosis Type 1 Center and Laboratory for Neurofibromatosis Type 1 Research, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jingxuan Huang
- Neurofibromatosis Type 1 Center and Laboratory for Neurofibromatosis Type 1 Research, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qingfeng Li
- Neurofibromatosis Type 1 Center and Laboratory for Neurofibromatosis Type 1 Research, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhichao Wang
- Neurofibromatosis Type 1 Center and Laboratory for Neurofibromatosis Type 1 Research, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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7
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Zhang L, Maalouf A, Makri SC, Banerjee J, Suru A, Tam AJ, Calizo A, Pollard K, Wang J, Danilova L, Ioannou M, Levin AS, Morris CD, Rhee DS, Belzberg AJ, Blakeley JO, Ladle BH, Pardoll DM, Lucas CHG, Rodriguez FJ, Gross JM, Anders RA, Pratilas CA, Llosa NJ. Multidimensional Immunotyping of Human NF1-Associated Peripheral Nerve Sheath Tumors Uncovers Tumor-Associated Macrophages as Key Drivers of Immune Evasion in the Tumor Microenvironment. Clin Cancer Res 2024; 30:5459-5472. [PMID: 39321200 PMCID: PMC11866061 DOI: 10.1158/1078-0432.ccr-24-1454] [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: 05/10/2024] [Revised: 06/15/2024] [Accepted: 09/17/2024] [Indexed: 09/27/2024]
Abstract
PURPOSE Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft-tissue sarcomas and the leading cause of mortality in individuals with neurofibromatosis type 1 (NF1). Despite many clinical trials, outcomes for patients with MPNST have remained stagnant, and most succumb to their disease; thus, novel therapeutic approaches are needed. A better understanding of the MPNST immune ecosystem will aid in the development of strategies to activate the immune system against the tumor. In this study, we profile the tumor immune microenvironment (TIME) in NF1-associated peripheral nerve sheath tumors (PNST) to discover insights on the role played by tumor-infiltrating immune cells in malignant transformation. EXPERIMENTAL DESIGN Using fresh and formalin-fixed paraffin-embedded tissue from patients diagnosed with NF1-PNST, we dissected the TIME through IHC, multiparameter flow cytometry, and comparative transcriptomic studies. RESULTS Immunophenotyping confirmed increased immune cell infiltration during malignant progression, with a predominance of infiltrating myeloid cells, particularly CD163+ tumor-associated macrophages (TAM). The T cells within MPNST exhibited signs of tumor activation, characterized by high programmed cell death 1 expression. Additionally, MPNST specimens demonstrated elevated levels of immunosuppressive TAM, with heightened PD-L1 expression. The proportion of CD163+ myeloid cells within the TIME correlated with poorer progression-free survival. Notably, loss of H3K27 trimethylation correlated with low immune cell infiltration in MPNST. CONCLUSIONS Malignant transformation of NF1-PNST is characterized by an immunosuppressive microenvironment comprising TAM with high expression of PD-L1, which is associated with inferior outcomes. These findings suggest the clinical potential of immune-modulating therapeutics that can unleash an antitumor immune response.
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MESH Headings
- Humans
- Tumor Microenvironment/immunology
- Tumor-Associated Macrophages/immunology
- Tumor-Associated Macrophages/metabolism
- Tumor-Associated Macrophages/pathology
- Neurofibromatosis 1/immunology
- Neurofibromatosis 1/pathology
- Neurofibromatosis 1/genetics
- Neurofibromatosis 1/complications
- Immunophenotyping
- Nerve Sheath Neoplasms/pathology
- Nerve Sheath Neoplasms/immunology
- Nerve Sheath Neoplasms/genetics
- Antigens, Differentiation, Myelomonocytic/metabolism
- Antigens, Differentiation, Myelomonocytic/genetics
- B7-H1 Antigen/genetics
- B7-H1 Antigen/metabolism
- Tumor Escape
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Neurofibrosarcoma/pathology
- Neurofibrosarcoma/genetics
- Neurofibrosarcoma/immunology
- Female
- Receptors, Cell Surface/genetics
- Receptors, Cell Surface/metabolism
- Male
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/metabolism
- CD163 Antigen
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Affiliation(s)
- Lindy Zhang
- Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
- Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
| | - Alexandre Maalouf
- Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
| | - Stavriani C. Makri
- Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
| | | | - Aditya Suru
- Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
| | - Ada J. Tam
- Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
| | - Ana Calizo
- Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
- Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Kai Pollard
- Laboratory Corporation of America (Labcorp), Burlington, NC
| | - Jiawan Wang
- Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ludmila Danilova
- Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
| | - Maria Ioannou
- Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Adam S. Levin
- Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Carol D. Morris
- Orthopedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Daniel S. Rhee
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Allan J. Belzberg
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Jaishri O. Blakeley
- Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Brian H. Ladle
- Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
- Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
| | - Drew M. Pardoll
- Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
| | | | - Fausto J. Rodriguez
- Department of Pathology, University of California Los Angeles, Los Angeles, CA
| | - John M. Gross
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Robert A. Anders
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Christine A. Pratilas
- Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
- Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Nicolas J. Llosa
- Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
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8
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Carneiro AD, Schaffer DV. Engineering novel adeno-associated viruses (AAVs) for improved delivery in the nervous system. Curr Opin Chem Biol 2024; 83:102532. [PMID: 39342684 DOI: 10.1016/j.cbpa.2024.102532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 08/27/2024] [Accepted: 09/03/2024] [Indexed: 10/01/2024]
Abstract
Harnessing adeno-associated virus (AAV) vectors for therapeutic gene delivery has emerged as a progressively promising strategy to treat disorders of both the central nervous system (CNS) and peripheral nervous system (PNS), and there are many ongoing clinical trials. However, unique physiological and molecular characteristics of the CNS and PNS pose obstacles to efficient vector delivery, ranging from the blood-brain barrier to the diverse nature of nervous system disorders. Engineering novel AAV capsids may help overcome these ongoing challenges and maximize therapeutic transgene delivery. This article discusses strategies for innovative AAV capsid development, highlighting recent advances. Notably, advances in next generation sequencing and machine learning have sparked new approaches for capsid investigation and engineering. Furthermore, we outline future directions and additional challenges in AAV-mediated gene therapy in the CNS and PNS.
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Affiliation(s)
- Ana D Carneiro
- Department of Chemical and Biomolecular Engineering, University of California, Berkeley, CA 94720, USA
| | - David V Schaffer
- Department of Chemical and Biomolecular Engineering, University of California, Berkeley, CA 94720, USA; Department of Bioengineering, University of California, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA; California Institute for Quantitative Biosciences, University of California, Berkeley, CA 94720, USA; Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720, USA.
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9
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Li CMC, Cordes A, Oliphant MUJ, Quinn SA, Thomas M, Selfors LM, Silvestri F, Girnius N, Rinaldi G, Zoeller JJ, Shapiro H, Tsiobikas C, Gupta KP, Pathania S, Regev A, Kadoch C, Muthuswamy SK, Brugge JS. Brca1 haploinsufficiency promotes early tumor onset and epigenetic alterations in a mouse model of hereditary breast cancer. Nat Genet 2024; 56:2763-2775. [PMID: 39528827 DOI: 10.1038/s41588-024-01958-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 09/23/2024] [Indexed: 11/16/2024]
Abstract
Germline BRCA1 mutation carriers face a high breast cancer risk; however, the underlying mechanisms for this risk are not completely understood. Using a new genetically engineered mouse model of germline Brca1 heterozygosity, we demonstrate that early tumor onset in a Brca1 heterozygous background cannot be fully explained by the conventional 'two-hit' hypothesis, suggesting the existence of inherent tumor-promoting alterations in the Brca1 heterozygous state. Single-cell RNA sequencing and assay for transposase-accessible chromatin with sequencing analyses uncover a unique set of differentially accessible chromatin regions in ostensibly normal Brca1 heterozygous mammary epithelial cells, distinct from wild-type cells and partially mimicking the chromatin and RNA-level changes in tumor cells. Transcription factor analyses identify loss of ELF5 and gain of AP-1 sites in these epigenetically primed regions; in vivo experiments further implicate AP-1 and Wnt10a as strong promoters of Brca1-related breast cancer. These findings reveal a previously unappreciated epigenetic effect of Brca1 haploinsufficiency in accelerating tumorigenesis, advancing our mechanistic understanding and informing potential therapeutic strategies.
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Affiliation(s)
| | - Alyssa Cordes
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | | | - S Aidan Quinn
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Mayura Thomas
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Laura M Selfors
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | | | - Nomeda Girnius
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | | | - Jason J Zoeller
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Hana Shapiro
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | | | - Kushali P Gupta
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Shailja Pathania
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Biology, University of Massachusetts Boston, Boston, MA, USA
| | - Aviv Regev
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Genentech, South San Francisco, CA, USA
| | - Cigall Kadoch
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Senthil K Muthuswamy
- Cancer Research Institute, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Joan S Brugge
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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10
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Khan S, Alson D, Sun L, Maloney C, Sun D. Leveraging Neural Crest-Derived Tumors to Identify NF1 Cancer Stem Cell Signatures. Cancers (Basel) 2024; 16:3639. [PMID: 39518076 PMCID: PMC11545784 DOI: 10.3390/cancers16213639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 10/23/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024] Open
Abstract
Neurofibromatosis type 1 (NF1) is a genetic disorder that predisposes individuals to develop benign and malignant tumors of the nerve sheath. Understanding the signatures of cancer stem cells (CSCs) for NF1-associated tumors may facilitate the early detection of tumor progression. Background: Neural crest cells, the cell of origin of NF1-associated tumors, can initiate multiple tumor types, including melanoma, neuroblastoma, and schwannoma. CSCs within these tumors have been reported; however, identifying and targeting CSC populations remains a challenge. Results: This study aims to leverage existing studies on neural crest-derived CSCs to explore markers pertinent to NF1 tumorigenesis. By focusing on the molecular and cellular dynamics within these tumors, we summarize CSC signatures in tumor maintenance, progression, and treatment resistance. Conclusion: A review of these signatures in the context of NF1 will provide insights into NF1 tumor biology and pave the way for developing targeted therapies and improving treatment outcomes for NF1 patients.
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Affiliation(s)
- Sajjad Khan
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Donia Alson
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Li Sun
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Caroline Maloney
- Department of Pediatric Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Daochun Sun
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Department of Pediatric, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Children Research Institute, Milwaukee, WI 53226, USA
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11
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Park GH, Park E, Lee SJ, Lim K, Kim J, Park JE, Jeong SY. Interferon-Induced Transmembrane Protein 1 (IFITM1) Is Downregulated in Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors. Int J Mol Sci 2024; 25:9265. [PMID: 39273214 PMCID: PMC11395022 DOI: 10.3390/ijms25179265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 08/12/2024] [Accepted: 08/14/2024] [Indexed: 09/15/2024] Open
Abstract
Neurofibromatosis type 1 (NF1), an autosomal dominant genetic disorder, is caused by mutations in the NF1 gene, which encodes the GTPase-activating protein neurofibromin. The pathogenesis of the tumor progression of benign plexiform neurofibromas (PNs) and malignant peripheral nerve sheath tumors (MPNSTs) remain unclear. Here, we found that interferon-induced transmembrane protein 1 (IFITM1) was downregulated in MPNST tissues compared to those in PN tissues from patients with NF1. Overexpression of IFITM1 in NF1-associated MPNST cells resulted in a significant decrease in Ras activation (GTP-Ras) and downstream extracellular regulatory kinase 1/2 (ERK1/2) phosphorylation, whereas downregulation of IFITM1 via treatment with small interfering RNA in normal Schwann cells had the opposite result, indicating that expression levels of IFITM1 are closely associated with tumor progression in NF1. Treatment of MPNST cells with interferon-gamma (IFN-γ) significantly augmented the expression of IFITM1, thereby leading to a decrease in Ras and ERK1/2 activation. Despite the small number of patient samples, these findings may potentially provide a new target for chemotherapy in patients with NF1-associated MPNSTs. In xenograft mice injected with MPNST cells, IFN-γ treatment successfully suppressed tumor progression with increased IFITM1 expression and decreased Ras and ERK1/2 activation in tumor tissues. Collectively, these results suggest that IFITM1 is closely involved in MPNST pathogenesis and that IFN-γ is a good candidate for the therapeutic treatment of MPNSTs in NF1.
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Affiliation(s)
- Gun-Hoo Park
- Department of Medical Genetics, Ajou University School of Medicine, Suwon 16499, Republic of Korea
- Jeju Bio Research Center, Jeju Research Institute, Korea Institute of Ocean Science & Technology (KIOST), Jeju-si 63349, Republic of Korea
| | - Eunkuk Park
- Department of Medical Genetics, Ajou University School of Medicine, Suwon 16499, Republic of Korea
- Jeonbuk Institute for Food-Bioindustry, Jeonju 54810, Republic of Korea
| | - Su-Jin Lee
- Department of Medical Genetics, Ajou University School of Medicine, Suwon 16499, Republic of Korea
- Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon 16499, Republic of Korea
| | - Kyubin Lim
- Department of Medical Genetics, Ajou University School of Medicine, Suwon 16499, Republic of Korea
- Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon 16499, Republic of Korea
| | - Jeonghyun Kim
- Department of Medical Genetics, Ajou University School of Medicine, Suwon 16499, Republic of Korea
- Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon 16499, Republic of Korea
| | - Jun Eun Park
- Department of Pediatrics, Anam Hospital, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Seon-Yong Jeong
- Department of Medical Genetics, Ajou University School of Medicine, Suwon 16499, Republic of Korea
- Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon 16499, Republic of Korea
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12
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Bhandarkar AR, Bhandarkar S, Babovic-Vuksanovic D, Raghunathan A, Schwartz J, Spinner RJ. Precision oncology in neurofibromatosis type 1: quantification of differential sensitivity to selumetinib in plexiform neurofibromas using single-cell RNA sequencing. J Neurooncol 2024; 169:147-153. [PMID: 38739187 DOI: 10.1007/s11060-024-04711-5] [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: 03/31/2024] [Accepted: 05/04/2024] [Indexed: 05/14/2024]
Abstract
PURPOSE Selumetinib is an FDA-approved targeted therapy for plexiform neurofibromas in neurofibromatosis type 1(NF1) with durable response rates seen in most, but not all patients. In this proof-of-concept study, we demonstrate single-cell RNA sequencing(scRNAseq) as a technique for quantifying drug response to selumetinib at the single cell level. METHODS scRNAseq data from neurofibroma biopsies was obtained from a public genomics repository. Schwann cell populations were identified through standard clustering techniques and single-cell selumetinib sensitivity was quantified on a scale of 0(resistant) to 1(sensitive) based on the expression pattern of a 500 gene selumetinib sensitivity signature from the BeyondCell sensitivity library. RESULTS A total of seven plexiform neurofibromas were included in our final analysis. The median absolute number of Schwann cells across samples was 658 cells (IQR: 1,029 cells, Q1-Q3: 135 cells to 1,163 cells). There was a statistically significant difference in selumetinib sensitivity profiles across samples (p < 0.001). The tumor with the highest median selumetinib sensitivity score had a median selumetinib sensitivity score of 0.64(IQR: 0.14, Q1-Q3: 0.59-0.70, n = 112 cells) and the tumor with the lowest median selumetinib sensitivity score had a median score of 0.37 (IQR: 0.21, Q1-Q3: 0.27-0.48, n = 1,034 cells). CONCLUSIONS scRNAseq of plexiform neurofibroma biopsies reveals differential susceptibilities to selumetinib on a single cell level. These findings may explain the partial responses seen in clinical trials of selumetinib for NF1 and demonstrate the value of collecting scRNAseq data for future NF1 trials.
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Affiliation(s)
| | - Shaan Bhandarkar
- Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Dusica Babovic-Vuksanovic
- Division of Pediatric Genetics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA
- Division of Laboratory Genetics and Genomics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Aditya Raghunathan
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Jonathan Schwartz
- Department of Pediatric Hematology/Oncology, Section of Neuro-Oncology, Mayo Clinic, Rochester, MN, USA
| | - Robert J Spinner
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA.
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13
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Perrin S, Protic S, Bretegnier V, Laurendeau I, de Lageneste OD, Panara N, Ruckebusch O, Luka M, Masson C, Maillard T, Coulpier F, Pannier S, Wicart P, Hadj-Rabia S, Radomska KJ, Zarhrate M, Ménager M, Vidaud D, Topilko P, Parfait B, Colnot C. MEK-SHP2 inhibition prevents tibial pseudarthrosis caused by NF1 loss in Schwann cells and skeletal stem/progenitor cells. Sci Transl Med 2024; 16:eadj1597. [PMID: 38924432 DOI: 10.1126/scitranslmed.adj1597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 01/15/2024] [Accepted: 05/24/2024] [Indexed: 06/28/2024]
Abstract
Congenital pseudarthrosis of the tibia (CPT) is a severe pathology marked by spontaneous bone fractures that fail to heal, leading to fibrous nonunion. Half of patients with CPT are affected by the multisystemic genetic disorder neurofibromatosis type 1 (NF1) caused by mutations in the NF1 tumor suppressor gene, a negative regulator of RAS-mitogen-activated protein kinase (MAPK) signaling pathway. Here, we analyzed patients with CPT and Prss56-Nf1 knockout mice to elucidate the pathogenic mechanisms of CPT-related fibrous nonunion and explored a pharmacological approach to treat CPT. We identified NF1-deficient Schwann cells and skeletal stem/progenitor cells (SSPCs) in pathological periosteum as affected cell types driving fibrosis. Whereas NF1-deficient SSPCs adopted a fibrotic fate, NF1-deficient Schwann cells produced critical paracrine factors including transforming growth factor-β and induced fibrotic differentiation of wild-type SSPCs. To counteract the elevated RAS-MAPK signaling in both NF1-deficient Schwann cells and SSPCs, we used MAPK kinase (MEK) and Src homology 2 containing protein tyrosine phosphatase 2 (SHP2) inhibitors. Combined MEK-SHP2 inhibition in vivo prevented fibrous nonunion in the Prss56-Nf1 knockout mouse model, providing a promising therapeutic strategy for the treatment of fibrous nonunion in CPT.
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Affiliation(s)
- Simon Perrin
- Université Paris Est Creteil, INSERM, IMRB, 94000 Creteil, France
| | - Sanela Protic
- Université Paris Est Creteil, INSERM, IMRB, 94000 Creteil, France
| | | | - Ingrid Laurendeau
- INSERM UMR S1016, Institut Cochin, Université Paris Cité, 75014 Paris, France
| | | | - Nicolas Panara
- INSERM UMR S1016, Institut Cochin, Université Paris Cité, 75014 Paris, France
| | - Odile Ruckebusch
- Université Paris Est Creteil, INSERM, IMRB, Plateforme de Cytométrie en flux, 94000 Creteil, France
| | - Marine Luka
- Paris Cité University, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163, 75015 Paris, France
- Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163, 75015 Paris, France
| | - Cécile Masson
- Bioinformatics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163, 75015 Paris, France
- INSERM US24/CNRS UAR3633, Paris Cité University, 75015 Paris, France
| | - Théodora Maillard
- Service de Médecine Génomique des Maladies de Système et d'Organe, Hôpital Cochin, DMU BioPhyGen, Assistance Publique-Hôpitaux de Paris, AP-HP, Centre-Université Paris Cité, F-75014 Paris, France
| | - Fanny Coulpier
- Université Paris Est Creteil, INSERM, IMRB, 94000 Creteil, France
| | - Stéphanie Pannier
- Department of Pediatric Orthopedic Surgery and Traumatology, Necker-Enfants Malades Hospital, AP-HP, Paris Cité University, 75015 Paris, France
| | - Philippe Wicart
- Department of Pediatric Orthopedic Surgery and Traumatology, Necker-Enfants Malades Hospital, AP-HP, Paris Cité University, 75015 Paris, France
| | - Smail Hadj-Rabia
- Department of Dermatology, Reference Center for Rare Skin Diseases (MAGEC), Imagine Institute, Necker-Enfants Malades Hospital, AP-HP, Paris Cité University, 75015 Paris, France
| | | | - Mohammed Zarhrate
- INSERM US24/CNRS UAR3633, Paris Cité University, 75015 Paris, France
- Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163, 75015 Paris, France
| | - Mickael Ménager
- Paris Cité University, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163, 75015 Paris, France
- Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163, 75015 Paris, France
| | - Dominique Vidaud
- INSERM UMR S1016, Institut Cochin, Université Paris Cité, 75014 Paris, France
- Service de Médecine Génomique des Maladies de Système et d'Organe, Hôpital Cochin, DMU BioPhyGen, Assistance Publique-Hôpitaux de Paris, AP-HP, Centre-Université Paris Cité, F-75014 Paris, France
| | - Piotr Topilko
- Université Paris Est Creteil, INSERM, IMRB, 94000 Creteil, France
| | - Béatrice Parfait
- INSERM UMR S1016, Institut Cochin, Université Paris Cité, 75014 Paris, France
- Service de Médecine Génomique des Maladies de Système et d'Organe, Hôpital Cochin, DMU BioPhyGen, Assistance Publique-Hôpitaux de Paris, AP-HP, Centre-Université Paris Cité, F-75014 Paris, France
| | - Céline Colnot
- Université Paris Est Creteil, INSERM, IMRB, 94000 Creteil, France
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14
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Plante C, Mohamad T, Hewa Bostanthirige D, Renaud M, Sidhu H, ElChoueiry M, Vatasescu JPS, Poirier M, Geha S, Brosseau JP. Revisiting the NPcis mouse model: A new tool to model plexiform neurofibroma. PLoS One 2024; 19:e0301040. [PMID: 38900740 PMCID: PMC11189233 DOI: 10.1371/journal.pone.0301040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 03/10/2024] [Indexed: 06/22/2024] Open
Abstract
Neurofibromatosis Type I (NF1) is a rare genetic disorder. NF1 patients frequently develop a benign tumor in peripheral nerve plexuses called plexiform neurofibroma. In the past two decades, tissue-specific Nf1 knockout mouse models were developed using commercially available tissue-specific Cre recombinase and the Nf1 flox mice to mimic neurofibroma development. However, these models develop para-spinal neurofibroma, recapitulating a rare type of neurofibroma found in NF1 patients. The NPcis mouse model developed a malignant version of neurofibroma called malignant peripheral nerve sheath tumor (MPNST) within 3 to 6 months but intriguingly without apparent benign precursor lesion. Here, we revisited the NPcis model and discovered that about 20% display clinical signs similar to Nf1 tissue-specific knockout mice models. However, a systematic histological analysis could not explain the clinical signs we observed although we noticed lesions reminiscent of a neurofibroma in a peripheral nerve, a cutaneous neurofibroma, and para-spinal neurofibroma on rare occasions in NPcis mice. We also observed that 10% of the mice developed a malignant peripheral nerve sheath tumor (MPNST) spontaneously, coinciding with their earring tag identification. Strikingly, half of the sciatic nerves from NPcis mice developed plexiform neurofibroma within 1-6 months when intentionally injured. Thus, we provided a procedure to turn the widely used NPcis sarcoma model into a model recapitulating plexiform neurofibroma.
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Affiliation(s)
- Camille Plante
- Department of Biochemistry and Functional Genomic, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Teddy Mohamad
- Department of Biochemistry and Functional Genomic, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | | | - Michel Renaud
- Department of Biochemistry and Functional Genomic, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Harsimran Sidhu
- Department of Biochemistry and Functional Genomic, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Michel ElChoueiry
- Department of Biochemistry and Functional Genomic, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Jean-Paul Sabo Vatasescu
- Department of Biochemistry and Functional Genomic, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Mikael Poirier
- Department of Biochemistry and Functional Genomic, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Sameh Geha
- Department of Pathology, Université de Sherbrooke, Sherbrooke, Quebec, Canada
- Centre de recherche du Centre Hospitalier de Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
- Institut de recherche sur le Cancer de l`Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Jean-Philippe Brosseau
- Department of Biochemistry and Functional Genomic, Université de Sherbrooke, Sherbrooke, Quebec, Canada
- Centre de recherche du Centre Hospitalier de Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
- Institut de recherche sur le Cancer de l`Université de Sherbrooke, Sherbrooke, Quebec, Canada
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15
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Drouyer M, Chu TH, Labit E, Haase F, Navarro RG, Nazareth D, Rosin N, Merjane J, Scott S, Cabanes-Creus M, Westhaus A, Zhu E, Midha R, Alexander IE, Biernaskie J, Ginn SL, Lisowski L. Novel AAV variants with improved tropism for human Schwann cells. Mol Ther Methods Clin Dev 2024; 32:101234. [PMID: 38558569 PMCID: PMC10978538 DOI: 10.1016/j.omtm.2024.101234] [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: 07/11/2023] [Accepted: 03/08/2024] [Indexed: 04/04/2024]
Abstract
Gene therapies and associated technologies are transforming biomedical research and enabling novel therapeutic options for patients living with debilitating and incurable genetic disorders. The vector system based on recombinant adeno-associated viral vectors (AAVs) has shown great promise in recent clinical trials for genetic diseases of multiple organs, such as the liver and the nervous system. Despite recent successes toward the development of novel bioengineered AAV variants for improved transduction of primary human tissues and cells, vectors that can efficiently transduce human Schwann cells (hSCs) have yet to be identified. Here, we report the application of the functional transduction-RNA selection method in primary hSCs for the development of AAV variants for specific and efficient transgene delivery to hSCs. The two identified capsid variants, Pep2hSC1 and Pep2hSC2, show conserved potency for delivery across various in vitro, in vivo, and ex vivo models of hSCs. These novel AAV capsids will serve as valuable research tools, forming the basis for therapeutic solutions for both SC-related disorders or peripheral nervous system injury.
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Affiliation(s)
- Matthieu Drouyer
- Translational Vectorology Research Unit, Children’s Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia
| | - Tak-Ho Chu
- Department of Clinical Neurosciences and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Elodie Labit
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Florencia Haase
- Translational Vectorology Research Unit, Children’s Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia
| | - Renina Gale Navarro
- Translational Vectorology Research Unit, Children’s Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia
| | - Deborah Nazareth
- Translational Vectorology Research Unit, Children’s Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia
| | - Nicole Rosin
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Jessica Merjane
- Translational Vectorology Research Unit, Children’s Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia
| | - Suzanne Scott
- Translational Vectorology Research Unit, Children’s Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia
| | - Marti Cabanes-Creus
- Translational Vectorology Research Unit, Children’s Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia
| | - Adrian Westhaus
- Translational Vectorology Research Unit, Children’s Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia
| | - Erhua Zhu
- Gene Therapy Research Unit, Children’s Medical Research Institute and Sydney Children’s Hospitals Network, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia
| | - Rajiv Midha
- Department of Clinical Neurosciences and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Ian E. Alexander
- Gene Therapy Research Unit, Children’s Medical Research Institute and Sydney Children’s Hospitals Network, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia
- Discipline of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Jeff Biernaskie
- Department of Clinical Neurosciences and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
- Department of Surgery, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Samantha L. Ginn
- Gene Therapy Research Unit, Children’s Medical Research Institute and Sydney Children’s Hospitals Network, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia
| | - Leszek Lisowski
- Translational Vectorology Research Unit, Children’s Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia
- Australian Genome Therapeutics Centre, Children’s Medical Research Institute and Sydney Children’s Hospitals Network, Westmead, NSW, Australia
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine - National Research Institute, Warsaw, Poland
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16
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Stassart RM, Gomez-Sanchez JA, Lloyd AC. Schwann Cells as Orchestrators of Nerve Repair: Implications for Tissue Regeneration and Pathologies. Cold Spring Harb Perspect Biol 2024; 16:a041363. [PMID: 38199866 PMCID: PMC11146315 DOI: 10.1101/cshperspect.a041363] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2024]
Abstract
Peripheral nerves exist in a stable state in adulthood providing a rapid bidirectional signaling system to control tissue structure and function. However, following injury, peripheral nerves can regenerate much more effectively than those of the central nervous system (CNS). This multicellular process is coordinated by peripheral glia, in particular Schwann cells, which have multiple roles in stimulating and nurturing the regrowth of damaged axons back to their targets. Aside from the repair of damaged nerves themselves, nerve regenerative processes have been linked to the repair of other tissues and de novo innervation appears important in establishing an environment conducive for the development and spread of tumors. In contrast, defects in these processes are linked to neuropathies, aging, and pain. In this review, we focus on the role of peripheral glia, especially Schwann cells, in multiple aspects of nerve regeneration and discuss how these findings may be relevant for pathologies associated with these processes.
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Affiliation(s)
- Ruth M Stassart
- Paul-Flechsig-Institute of Neuropathology, University Clinic Leipzig, Leipzig 04103, Germany
| | - Jose A Gomez-Sanchez
- Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante 03010, Spain
- Instituto de Neurociencias CSIC-UMH, Sant Joan de Alicante 03550, Spain
| | - Alison C Lloyd
- UCL Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, United Kingdom
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17
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Hirbe AC, Dehner CA, Dombi E, Eulo V, Gross AM, Sundby T, Lazar AJ, Widemann BC. Contemporary Approach to Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors. Am Soc Clin Oncol Educ Book 2024; 44:e432242. [PMID: 38710002 PMCID: PMC11656191 DOI: 10.1200/edbk_432242] [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] [Indexed: 05/08/2024]
Abstract
Most malignant peripheral nerve sheath tumors (MPNSTs) are clinically aggressive high-grade sarcomas, arising in individuals with neurofibromatosis type 1 (NF1) at a significantly elevated estimated lifetime frequency of 8%-13%. In the setting of NF1, MPNSTs arise from malignant transformation of benign plexiform neurofibroma and borderline atypical neurofibromas. Composed of neoplastic cells from the Schwannian lineage, these cancers recur in approximately 50% of individuals, and most patients die within five years of diagnosis, despite surgical resection, radiation, and chemotherapy. Treatment for metastatic disease is limited to cytotoxic chemotherapy and investigational clinical trials. In this article, we review the pathophysiology of this aggressive cancer and current approaches to surveillance and treatment.
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Affiliation(s)
- Angela C Hirbe
- Division of Oncology, Department of Medicine, Siteman Cancer Center, Barnes Jewish Hospital and Washington University School of Medicine, St Louis, MO
| | - Carina A Dehner
- Department of Anatomic Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN
| | - Eva Dombi
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Vanessa Eulo
- Division of Oncology, Department of Medicine, University of Alabama, Birmingham, AL
| | - Andrea M Gross
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Taylor Sundby
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Alexander J Lazar
- Departments of Pathology & Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Brigitte C Widemann
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
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18
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Na B, Shah SR, Vasudevan HN. Past, Present, and Future Therapeutic Strategies for NF-1-Associated Tumors. Curr Oncol Rep 2024; 26:706-713. [PMID: 38709422 PMCID: PMC11169015 DOI: 10.1007/s11912-024-01527-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/27/2024] [Indexed: 05/07/2024]
Abstract
PURPOSE OF REVIEW Neurofibromatosis type 1 (NF-1) is a cancer predisposition syndrome caused by mutations in the NF1 tumor suppressor gene that encodes the neurofibromin protein, which functions as a negative regulator of Ras signaling. We review the past, current, and future state of therapeutic strategies for tumors associated with NF-1. RECENT FINDINGS Therapeutic efforts for NF-1-associated tumors have centered around inhibiting Ras output, leading to the clinical success of downstream MEK inhibition for plexiform neurofibromas and low-grade gliomas. However, MEK inhibition and similar molecular monotherapy approaches that block Ras signaling do not work for all patients and show limited efficacy for more aggressive cancers such as malignant peripheral nerve sheath tumors and high-grade gliomas, motivating novel treatment approaches. We highlight the current therapeutic landscape for NF-1-associated tumors, broadly categorizing treatment into past strategies for serial Ras pathway blockade, current approaches targeting parallel oncogenic and tumor suppressor pathways, and future avenues of investigation leveraging biologic and technical innovations in immunotherapy, pharmacology, and gene delivery.
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Affiliation(s)
- Brian Na
- Department of Neurology, UCLA Neuro-Oncology Program, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Shilp R Shah
- Samueli School of Engineering, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Harish N Vasudevan
- Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, 94143, USA.
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, 94143, USA.
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19
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Nguyen HTL, Kohl E, Bade J, Eng SE, Tosevska A, Al Shihabi A, Tebon PJ, Hong JJ, Dry S, Boutros PC, Panossian A, Gosline SJC, Soragni A. A platform for rapid patient-derived cutaneous neurofibroma organoid establishment and screening. CELL REPORTS METHODS 2024; 4:100772. [PMID: 38744290 PMCID: PMC11133839 DOI: 10.1016/j.crmeth.2024.100772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 02/10/2024] [Accepted: 04/19/2024] [Indexed: 05/16/2024]
Abstract
Localized cutaneous neurofibromas (cNFs) are benign tumors that arise in the dermis of patients affected by neurofibromatosis type 1 syndrome. cNFs are benign lesions: they do not undergo malignant transformation or metastasize. Nevertheless, they can cover a significant proportion of the body, with some individuals developing hundreds to thousands of lesions. cNFs can cause pain, itching, and disfigurement resulting in substantial socio-emotional repercussions. Currently, surgery and laser desiccation are the sole treatment options but may result in scarring and potential regrowth from incomplete removal. To identify effective systemic therapies, we introduce an approach to establish and screen cNF organoids. We optimized conditions to support the ex vivo growth of genomically diverse cNFs. Patient-derived cNF organoids closely recapitulate cellular and molecular features of parental tumors as measured by immunohistopathology, methylation, RNA sequencing, and flow cytometry. Our cNF organoid platform enables rapid screening of hundreds of compounds in a patient- and tumor-specific manner.
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Affiliation(s)
- Huyen Thi Lam Nguyen
- Department of Orthopaedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Emily Kohl
- Department of Orthopaedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Jessica Bade
- Pacific Northwest National Laboratories, Seattle, WA, USA
| | - Stefan E Eng
- Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA
| | - Anela Tosevska
- Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Ahmad Al Shihabi
- Department of Orthopaedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Peyton J Tebon
- Department of Orthopaedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Jenny J Hong
- Division of Hematology-Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Sarah Dry
- Department of Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Paul C Boutros
- Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA; Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA
| | | | - Sara J C Gosline
- Pacific Northwest National Laboratories, Seattle, WA, USA; Department of Biomedical Engineering, Oregon Health and Sciences University, Portland, OR, USA.
| | - Alice Soragni
- Department of Orthopaedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA.
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20
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Tian Z, Du Z, Bai G, Gong Q, You Y, Xu G, Liu J, Xiao M, Wang Y, He Y. Schwann cell derived pleiotrophin stimulates fibroblast for proliferation and excessive collagen deposition in plexiform neurofibroma. Cancer Gene Ther 2024; 31:627-640. [PMID: 38302728 DOI: 10.1038/s41417-024-00727-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 12/21/2023] [Accepted: 01/08/2024] [Indexed: 02/03/2024]
Abstract
Neurofibromatosis type 1 associated plexiform neurofibroma (pNF) is characterized by abundant fibroblasts and dense collagen, yet the intricate interactions between tumor-origin cells (Schwann cells) and neurofibroma-associated fibroblasts (NFAFs) remain elusive. Employing single-cell RNA sequencing on human pNF samples, we generated a comprehensive transcriptomics dataset and conducted cell-cell communication analysis to unravel the molecular dynamics between Schwann cells and NFAFs. Our focus centered on the pleiotrophin (PTN)/nucleolin (NCL) axis as a pivotal ligand-receptor pair orchestrating this interaction. Validation of PTN involvement was affirmed through coculture models and recombinant protein experiments. Functional and mechanistic investigations, employing assays such as CCK8, EdU, Western Blot, ELISA, Hydroxyproline Assay, and Human phospho-kinase array, provided critical insights. We employed siRNA or inhibitors to intercept the PTN/NCL/proline-rich Akt substrate of 40 kDa (PRAS40) axis, validating the associated molecular mechanism. Our analysis highlighted a subset of Schwann cells closely linked to collagen deposition, underscoring their significance in pNF development. The PTN/NCL axis emerged as a key mediator of the Schwann cell-NFAF interaction. Furthermore, our study demonstrated that elevated PTN levels enhanced NFAF proliferation and collagen synthesis, either independently or synergistically with TGF-β1 in vitro. Activation of the downstream molecule PRAS40 was noted in NFAFs upon PTN treatment. Crucially, by targeting NCL and PRAS40, we successfully reversed collagen synthesis within NFAFs. In conclusion, our findings unveil the pivotal role of the PTN/NCL/PRAS40 axis in driving pNF development by promoting NFAFs proliferation and function. Targeting this pathway emerges as a potential therapeutic strategy for pNF. This study contributes novel insights into the molecular mechanisms governing pNF pathogenesis.
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Affiliation(s)
- Zhuowei Tian
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai, China
- Department of Oral Maxillofacial-Head and Neck Oncology, Fengcheng Hospital, Shanghai, China
| | - Zhong Du
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Guo Bai
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Qiyu Gong
- Institute of Immunology, Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuanhe You
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Guisong Xu
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Jialiang Liu
- Department of Oral Maxillofacial Surgery, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, China
| | - Meng Xiao
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai, China.
- Department of Oral Maxillofacial-Head and Neck Oncology, Fengcheng Hospital, Shanghai, China.
| | - Yanan Wang
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai, China.
| | - Yue He
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai, China.
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21
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Maresca G, Bonanno C, Veneziani I, Buono VL, Latella D, Quartarone A, Marino S, Formica C. The Lack of Ad Hoc Neuropsychological Assessment in Adults with Neurofibromatosis: A Systematic Review. J Clin Med 2024; 13:1432. [PMID: 38592693 PMCID: PMC10931953 DOI: 10.3390/jcm13051432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 02/26/2024] [Accepted: 02/28/2024] [Indexed: 04/10/2024] Open
Abstract
Background: Neurofibromatosis Type 1 (NF1) is a genetic autosomal dominant disorder that affects both the central and peripheral nervous systems. Children and adolescents with NF1 commonly experience neuropsychological, motor, and behavioral deficits. The cognitive profile hallmark of this disorder includes visuospatial and executive function impairments. These cognitive disorders may persist into adulthood. This study aims to analyze previous research studies that have described cognitive dysfunctions in adults with NF1. The purpose of this analysis is to review the neuropsychological and psychological assessment methods used. Methods: A total of 327 articles were identified based on the search terms in their titles and abstracts. The evaluation was conducted by scrutinizing each article's title, abstract, and text. Results: Only 16 articles were found to be eligible for inclusion based on the pre-defined criteria. The selected studies primarily focus on the development of diagnostic protocols for individuals with NF1. Conclusions: The management of NF1 disease requires a multidisciplinary approach to address symptoms, preserve neurological functions, and ensure the best possible quality of life. However, cognitive impairment can negatively affect psychological well-being. This study suggested that cognitive functions in NF1 patients were not tested using specific measures, but rather were evaluated through intelligence scales. Additionally, the findings revealed that there is no standardized neuropsychological assessment for adults with NF1. To address this gap, it would be helpful to create a specific neuropsychological battery to study cognitive function in NF1 patients during clinical studies. This battery could also serve as a tool to design models for cognitive rehabilitation by using reliable and sensitive measures of cognitive outcomes.
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Affiliation(s)
- Giuseppa Maresca
- IRCCS Centro Neurolesi Bonino Pulejo, S.S. 113-Via Palermo, C.da Casazza, 98124 Messina, Italy; (G.M.); (C.B.); (V.L.B.); (A.Q.); (S.M.); (C.F.)
| | - Carmen Bonanno
- IRCCS Centro Neurolesi Bonino Pulejo, S.S. 113-Via Palermo, C.da Casazza, 98124 Messina, Italy; (G.M.); (C.B.); (V.L.B.); (A.Q.); (S.M.); (C.F.)
| | - Isabella Veneziani
- Department of Nervous System and Behavioural Sciences, Psychology Section, University of Pavia, Piazza Botta, 11, 27100 Pavia, Italy;
| | - Viviana Lo Buono
- IRCCS Centro Neurolesi Bonino Pulejo, S.S. 113-Via Palermo, C.da Casazza, 98124 Messina, Italy; (G.M.); (C.B.); (V.L.B.); (A.Q.); (S.M.); (C.F.)
| | - Desirèe Latella
- IRCCS Centro Neurolesi Bonino Pulejo, S.S. 113-Via Palermo, C.da Casazza, 98124 Messina, Italy; (G.M.); (C.B.); (V.L.B.); (A.Q.); (S.M.); (C.F.)
| | - Angelo Quartarone
- IRCCS Centro Neurolesi Bonino Pulejo, S.S. 113-Via Palermo, C.da Casazza, 98124 Messina, Italy; (G.M.); (C.B.); (V.L.B.); (A.Q.); (S.M.); (C.F.)
| | - Silvia Marino
- IRCCS Centro Neurolesi Bonino Pulejo, S.S. 113-Via Palermo, C.da Casazza, 98124 Messina, Italy; (G.M.); (C.B.); (V.L.B.); (A.Q.); (S.M.); (C.F.)
| | - Caterina Formica
- IRCCS Centro Neurolesi Bonino Pulejo, S.S. 113-Via Palermo, C.da Casazza, 98124 Messina, Italy; (G.M.); (C.B.); (V.L.B.); (A.Q.); (S.M.); (C.F.)
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22
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White EE, Rhodes SD. The NF1+/- Immune Microenvironment: Dueling Roles in Neurofibroma Development and Malignant Transformation. Cancers (Basel) 2024; 16:994. [PMID: 38473354 PMCID: PMC10930863 DOI: 10.3390/cancers16050994] [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: 01/15/2024] [Revised: 02/12/2024] [Accepted: 02/16/2024] [Indexed: 03/14/2024] Open
Abstract
Neurofibromatosis type 1 (NF1) is a common genetic disorder resulting in the development of both benign and malignant tumors of the peripheral nervous system. NF1 is caused by germline pathogenic variants or deletions of the NF1 tumor suppressor gene, which encodes the protein neurofibromin that functions as negative regulator of p21 RAS. Loss of NF1 heterozygosity in Schwann cells (SCs), the cells of origin for these nerve sheath-derived tumors, leads to the formation of plexiform neurofibromas (PNF)-benign yet complex neoplasms involving multiple nerve fascicles and comprised of a myriad of infiltrating stromal and immune cells. PNF development and progression are shaped by dynamic interactions between SCs and immune cells, including mast cells, macrophages, and T cells. In this review, we explore the current state of the field and critical knowledge gaps regarding the role of NF1(Nf1) haploinsufficiency on immune cell function, as well as the putative impact of Schwann cell lineage states on immune cell recruitment and function within the tumor field. Furthermore, we review emerging evidence suggesting a dueling role of Nf1+/- immune cells along the neurofibroma to MPNST continuum, on one hand propitiating PNF initiation, while on the other, potentially impeding the malignant transformation of plexiform and atypical neurofibroma precursor lesions. Finally, we underscore the potential implications of these discoveries and advocate for further research directed at illuminating the contributions of various immune cells subsets in discrete stages of tumor initiation, progression, and malignant transformation to facilitate the discovery and translation of innovative diagnostic and therapeutic approaches to transform risk-adapted care.
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Affiliation(s)
- Emily E. White
- Medical Scientist Training Program, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Steven D. Rhodes
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Division of Pediatric Hematology/Oncology/Stem Cell Transplant, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- IU Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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23
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Ko WS, Kim SJ. Direct comparison of the diagnostic accuracy of 2-[ 18F]-fluoro-2-deoxy-d-glucose PET/CT and MRI for the differentiation of malignant peripheral nerve sheath tumour in neurofibromatosis type I: a meta-analysis. Clin Radiol 2024; 79:142-149. [PMID: 37968227 DOI: 10.1016/j.crad.2023.10.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 09/06/2023] [Accepted: 10/18/2023] [Indexed: 11/17/2023]
Abstract
AIM To compare the diagnostic test of integrated 2-[18F]-fluoro-2-deoxy-d-glucose positron-emission tomography/computed tomography (FDG PET/CT) with that of magnetic resonance imaging (MRI) for the differentiation of malignant peripheral nerve sheath tumours (MPNSTs) in neurofibromatosis type 1 (NF1) patients. MATERIALS AND METHODS A systematic search was performed in PubMed and EMBASE (last updated in 30 November 2022). Studies investigating the performance of FDG PET/CT and MRI for differentiation of MPNSTs were eligible for inclusion. Only studies reporting a direct comparison between these imaging methods were considered to establish precise summary estimates in the same setting of patients. RESULTS The pooled estimate of sensitivity of FDG PET/CT was 0.99 and a pooled specificity of 0.53. The pooled estimate of sensitivity of MRI was 0.85 and a pooled specificity of 0.85. CONCLUSION Analysis of the available studies indicated that FDG PET/CT and MRI had similar diagnostic performances for differentiation of MPNSTs in patients with NF1; however, either technique can be a complement to the other rather than being used singly.
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Affiliation(s)
- W S Ko
- Department of Internal Medicine, Pusan National University Hospital, Ami-dong, Seo-gu, Busan, 49241, Republic of Korea
| | - S-J Kim
- Department of Nuclear Medicine, Pusan National University School of Medicine, Busandaehak-ro 49, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do, 50612, Republic of Korea; BioMedical Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, 50612, Republic of Korea.
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24
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Staedtke V, Anstett K, Bedwell D, Giovannini M, Keeling K, Kesterson R, Kim Y, Korf B, Leier A, McManus ML, Sarnoff H, Vitte J, Walker JA, Plotkin SR, Wallis D. Gene-targeted therapy for neurofibromatosis and schwannomatosis: The path to clinical trials. Clin Trials 2024; 21:51-66. [PMID: 37937606 DOI: 10.1177/17407745231207970] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2023]
Abstract
Numerous successful gene-targeted therapies are arising for the treatment of a variety of rare diseases. At the same time, current treatment options for neurofibromatosis 1 and schwannomatosis are limited and do not directly address loss of gene/protein function. In addition, treatments have mostly focused on symptomatic tumors, but have failed to address multisystem involvement in these conditions. Gene-targeted therapies hold promise to address these limitations. However, despite intense interest over decades, multiple preclinical and clinical issues need to be resolved before they become a reality. The optimal approaches to gene-, mRNA-, or protein restoration and to delivery to the appropriate cell types remain elusive. Preclinical models that recapitulate manifestations of neurofibromatosis 1 and schwannomatosis need to be refined. The development of validated assays for measuring neurofibromin and merlin activity in animal and human tissues will be critical for early-stage trials, as will the selection of appropriate patients, based on their individual genotypes and risk/benefit balance. Once the safety of gene-targeted therapy for symptomatic tumors has been established, the possibility of addressing a wide range of symptoms, including non-tumor manifestations, should be explored. As preclinical efforts are underway, it will be essential to educate both clinicians and those affected by neurofibromatosis 1/schwannomatosis about the risks and benefits of gene-targeted therapy for these conditions.
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Affiliation(s)
- Verena Staedtke
- Department of Neurology, Johns Hopkins University, Baltimore, MD, USA
| | - Kara Anstett
- Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA
| | - David Bedwell
- Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Marco Giovannini
- Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA and Jonsson Comprehensive Cancer Center (JCCC), University of California Los Angeles, Los Angeles, CA, USA
| | - Kim Keeling
- Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Robert Kesterson
- Department of Cancer Precision Medicine, Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - YooRi Kim
- Gilbert Family Foundation, Detroit, MI, USA
| | - Bruce Korf
- Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - André Leier
- Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA
| | | | | | - Jeremie Vitte
- Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA and Jonsson Comprehensive Cancer Center (JCCC), University of California Los Angeles, Los Angeles, CA, USA
| | - James A Walker
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Scott R Plotkin
- Department of Neurology and Cancer Center, Massachusetts General Hospital, Boston, MA, USA
| | - Deeann Wallis
- Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA
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25
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Furnari FB, Anastasaki C, Bian S, Fine HA, Koga T, Le LQ, Rodriguez FJ, Gutmann DH. Stem cell modeling of nervous system tumors. Dis Model Mech 2024; 17:dmm050533. [PMID: 38353122 PMCID: PMC10886724 DOI: 10.1242/dmm.050533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Accepted: 12/18/2023] [Indexed: 02/16/2024] Open
Abstract
Nervous system tumors, particularly brain tumors, represent the most common tumors in children and one of the most lethal tumors in adults. Despite decades of research, there are few effective therapies for these cancers. Although human nervous system tumor cells and genetically engineered mouse models have served as excellent platforms for drug discovery and preclinical testing, they have limitations with respect to accurately recapitulating important aspects of the pathobiology of spontaneously arising human tumors. For this reason, attention has turned to the deployment of human stem cell engineering involving human embryonic or induced pluripotent stem cells, in which genetic alterations associated with nervous system cancers can be introduced. These stem cells can be used to create self-assembling three-dimensional cerebral organoids that preserve key features of the developing human brain. Moreover, stem cell-engineered lines are amenable to xenotransplantation into mice as a platform to investigate the tumor cell of origin, discover cancer evolutionary trajectories and identify therapeutic vulnerabilities. In this article, we review the current state of human stem cell models of nervous system tumors, discuss their advantages and disadvantages, and provide consensus recommendations for future research.
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Affiliation(s)
- Frank B Furnari
- Department of Medicine, University of California, San Diego, San Diego, CA 92037, USA
| | - Corina Anastasaki
- Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Shan Bian
- Institute for Regenerative Medicine, School of Life Sciences and Technology, Tongji University, 200070 Shanghai, China
| | - Howard A Fine
- Department of Neurology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Tomoyuki Koga
- Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA
| | - Lu Q Le
- Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Fausto J Rodriguez
- Division of Neuropathology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - David H Gutmann
- Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA
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26
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Kallionpää RA, Peltonen S, Le KM, Martikkala E, Jääskeläinen M, Fazeli E, Riihilä P, Haapaniemi P, Rokka A, Salmi M, Leivo I, Peltonen J. Characterization of Immune Cell Populations of Cutaneous Neurofibromas in Neurofibromatosis 1. J Transl Med 2024; 104:100285. [PMID: 37949359 DOI: 10.1016/j.labinv.2023.100285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 10/20/2023] [Accepted: 11/03/2023] [Indexed: 11/12/2023] Open
Abstract
Cutaneous neurofibromas (cNFs) are characteristic of neurofibromatosis 1 (NF1), yet their immune microenvironment is incompletely known. A total of 61 cNFs from 10 patients with NF1 were immunolabeled for different types of T cells and macrophages, and the cell densities were correlated with clinical characteristics. Eight cNFs and their overlying skin were analyzed for T cell receptor CDR domain sequences, and mass spectrometry of 15 cNFs and the overlying skin was performed to study immune-related processes. Intratumoral T cells were detected in all cNFs. Tumors from individuals younger than the median age of the study participants (33 years), growing tumors, and tumors smaller than the data set median showed increased T cell density. Most samples displayed intratumoral or peritumoral aggregations of CD3-positive cells. T cell receptor sequencing demonstrated that the skin and cNFs host distinct T cell populations, whereas no dominant cNF-specific T cell clones were detected. Unique T cell clones were fewer in cNFs than in skin, and mass spectrometry suggested lower expression of proteins related to T cell-mediated immunity in cNFs than in skin. CD163-positive cells, suggestive of M2 macrophages, were abundant in cNFs. Human cNFs have substantial T cell and macrophage populations that may be tumor-specific.
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Affiliation(s)
- Roope A Kallionpää
- Institute of Biomedicine, University of Turku, Turku, Finland; FICAN West Cancer Centre, University of Turku and Turku University Hospital, Turku, Finland
| | - Sirkku Peltonen
- Department of Dermatology and Venereology, University of Turku, Turku, Finland; Department of Dermatology, Turku University Hospital, Turku, Finland; Department of Dermatology and Venereology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Dermatology and Venereology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Dermatology and Allergology, University of Helsinki, Helsinki, Finland; Skin and Allergy Hospital, Helsinki University Hospital, Helsinki, Finland
| | - Kim My Le
- Institute of Biomedicine, University of Turku, Turku, Finland
| | - Eija Martikkala
- Institute of Biomedicine, University of Turku, Turku, Finland
| | | | - Elnaz Fazeli
- Institute of Biomedicine, University of Turku, Turku, Finland; Biomedicum Imaging Unit, Faculty of Medicine and HiLIFE, University of Helsinki, Helsinki, Finland
| | - Pilvi Riihilä
- Department of Dermatology and Venereology, University of Turku, Turku, Finland; Department of Dermatology, Turku University Hospital, Turku, Finland; FICAN West Cancer Research Laboratory, University of Turku and Turku University Hospital, Turku, Finland
| | - Pekka Haapaniemi
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Anne Rokka
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Marko Salmi
- Institute of Biomedicine, University of Turku, Turku, Finland; MediCity Research Laboratory, and InFLAMES Research Flagship Center, University of Turku, Turku, Finland
| | - Ilmo Leivo
- Institute of Biomedicine, University of Turku, Turku, Finland
| | - Juha Peltonen
- Institute of Biomedicine, University of Turku, Turku, Finland; FICAN West Cancer Centre, University of Turku and Turku University Hospital, Turku, Finland.
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27
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Wang WN, Koguchi-Yoshioka H, Nimura K, Watanabe R, Tanemura A, Fujimoto M, Wataya-Kaneda M. Distinct Transcriptional Profiles in the Different Phenotypes of Neurofibroma from the Same Subject with Neurofibromatosis 1. J Invest Dermatol 2024; 144:133-141.e4. [PMID: 37301319 DOI: 10.1016/j.jid.2023.03.1688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 03/24/2023] [Accepted: 03/27/2023] [Indexed: 06/12/2023]
Abstract
Neurofibromatosis 1 is a prevalent hereditary neurocutaneous disorder. Among the clinical phenotypes of neurofibromatosis 1, cutaneous neurofibroma (cNF) and plexiform neurofibroma (pNF) have distinct clinical manifestations, and pNF should be closely monitored owing to its malignant potential. However, the detailed distinct features of neurofibromatosis 1 phenotypes remain unknown. To determine whether the transcriptional features and microenvironment of cNF and pNF differ, single-cell RNA sequencing was performed on isolated cNF and pNF cells from the same patient. Six cNF and five pNF specimens from different subjects were also immunohistochemically analyzed. Our findings revealed that cNF and pNF had distinct transcriptional profiles even within the same subject. pNF is enriched in Schwann cells with characteristics similar to those of their malignant counterpart, fibroblasts, with a cancer-associated fibroblast-like phenotype, angiogenic endothelial cells, and M2-like macrophages, whereas cNF is enriched in CD8 T cells with tissue residency markers. The results of immunohistochemical analyses performed on different subjects agreed with those of single-cell RNA sequencing. This study found that cNF and pNF, the different neurofibromatosis phenotypes in neurofibromatosis 1, from the same subject are transcriptionally distinct in terms of the cell types involved, including T cells.
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Affiliation(s)
- Wei-Ning Wang
- Department of Dermatology, Course of Integrated Medicine, Graduate School of Medicine/Faculty of Medicine, Osaka University, Osaka, Japan
| | - Hanako Koguchi-Yoshioka
- Department of Dermatology, Course of Integrated Medicine, Graduate School of Medicine/Faculty of Medicine, Osaka University, Osaka, Japan; Division of Health Science, Department of Neurocutaneous Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Keisuke Nimura
- Division of Gene Therapy Science, Department of Genome Biology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Rei Watanabe
- Department of Dermatology, Course of Integrated Medicine, Graduate School of Medicine/Faculty of Medicine, Osaka University, Osaka, Japan; Department of Integrative Medicine for Allergic and Immunological Diseases, Course of Integrated Medicine, Graduate School of Medicine/Faculty of Medicine, Osaka University, Osaka, Japan
| | - Atsushi Tanemura
- Department of Dermatology, Course of Integrated Medicine, Graduate School of Medicine/Faculty of Medicine, Osaka University, Osaka, Japan
| | - Manabu Fujimoto
- Department of Dermatology, Course of Integrated Medicine, Graduate School of Medicine/Faculty of Medicine, Osaka University, Osaka, Japan
| | - Mari Wataya-Kaneda
- Department of Dermatology, Course of Integrated Medicine, Graduate School of Medicine/Faculty of Medicine, Osaka University, Osaka, Japan; Division of Health Science, Department of Neurocutaneous Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.
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28
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Lakes YB, Moye SL, Mo J, Tegtmeyer M, Nehme R, Charlton M, Salinas G, McKay RM, Eggan K, Le LQ. Econazole selectively induces cell death in NF1-homozygous mutant tumor cells. Cell Rep Med 2023; 4:101309. [PMID: 38086379 PMCID: PMC10772348 DOI: 10.1016/j.xcrm.2023.101309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 10/06/2023] [Accepted: 11/12/2023] [Indexed: 12/22/2023]
Abstract
Cutaneous neurofibromas (cNFs) are tumors that develop in more than 99% of individuals with neurofibromatosis type 1 (NF1). They develop in the dermis and can number in the thousands. cNFs can be itchy and painful and negatively impact self-esteem. There is no US Food and Drug Administration (FDA)-approved drug for their treatment. Here, we screen a library of FDA-approved drugs using a cNF cell model derived from human induced pluripotent stem cells (hiPSCs) generated from an NF1 patient. We engineer an NF1 mutation in the second allele to mimic loss of heterozygosity, differentiate the NF1+/- and NF1-/- hiPSCs into Schwann cell precursors (SCPs), and use them to screen a drug library to assess for inhibition of NF1-/- but not NF1+/- cell proliferation. We identify econazole nitrate as being effective against NF1-/- hiPSC-SCPs. Econazole cream selectively induces apoptosis in Nf1-/- murine nerve root neurosphere cells and human cNF xenografts. This study supports further testing of econazole for cNF treatment.
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Affiliation(s)
- Yenal B Lakes
- Department of Stem Cell and Regenerative Medicine, Harvard University, Boston, MA, USA
| | - Stefanie L Moye
- Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Juan Mo
- Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Matthew Tegtmeyer
- Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Ralda Nehme
- Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Maura Charlton
- Department of Stem Cell and Regenerative Medicine, Harvard University, Boston, MA, USA
| | - Gabrielle Salinas
- Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Renee M McKay
- Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Kevin Eggan
- Department of Stem Cell and Regenerative Medicine, Harvard University, Boston, MA, USA.
| | - Lu Q Le
- Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; O'Donnell Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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29
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Roy V, Paquet A, Touzel-Deschênes L, Khuong HT, Dupré N, Gros-Louis F. Heterozygous NF1 dermal fibroblasts modulate exosomal content to promote angiogenesis in a tissue-engineered skin model of neurofibromatosis type-1. J Neurochem 2023; 167:556-570. [PMID: 37837197 DOI: 10.1111/jnc.15982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 09/01/2023] [Accepted: 09/23/2023] [Indexed: 10/15/2023]
Abstract
Neovascularization is a critical process in tumor progression and malignant transformation associated with neurofibromatosis type 1 (NF1). Indeed, fibroblasts are known to play a key role in the tumoral microenvironment modification by producing an abundant collagenous matrix, but their contribution in paracrine communication pathways is poorly understood. Here, we hypothesized that NF1 heterozygosis in human dermal fibroblasts could promote angiogenesis through exosomes secretion. The purposes of this study are to identify the NF1 fibroblast-derived exosome protein contents and to determine their proangiogenic activity. Angiogenic proteome measurement confirmed the overexpression of VEGF and other proteins involved in vascularization. Tube formation of microvascular endothelial cells was also enhanced in presence of exosomes derived from NF1 skin fibroblasts. NF1 tissue-engineered skin (NF1-TES) generation showed a significantly denser microvessels networks compared to healthy controls. The reduction of exosomes production with an inhibitor treatment demonstrated a drastic decrease in blood vessel formation within the dermis. Our results suggest that NF1 haploinsufficiency alters the dermal fibroblast function and creates a pro-angiogenic signal via exosomes, which increases the capillary formation. This study highlights the potential of targeting exosome secretion and angiogenesis for therapeutic interventions in NF1.
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Affiliation(s)
- Vincent Roy
- Department of Surgery, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada
- Division of Regenerative Medicine, CHU de Quebec Research Center, Laval University, Quebec City, Quebec, Canada
| | - Alexandre Paquet
- Department of Surgery, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada
- Division of Regenerative Medicine, CHU de Quebec Research Center, Laval University, Quebec City, Quebec, Canada
| | - Lydia Touzel-Deschênes
- Department of Surgery, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada
- Division of Regenerative Medicine, CHU de Quebec Research Center, Laval University, Quebec City, Quebec, Canada
| | - Hélène T Khuong
- Department of Surgery, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada
- Division of Regenerative Medicine, CHU de Quebec Research Center, Laval University, Quebec City, Quebec, Canada
| | - Nicolas Dupré
- Division of Regenerative Medicine, CHU de Quebec Research Center, Laval University, Quebec City, Quebec, Canada
- Department of Neurological Sciences, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada
| | - Francois Gros-Louis
- Department of Surgery, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada
- Division of Regenerative Medicine, CHU de Quebec Research Center, Laval University, Quebec City, Quebec, Canada
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30
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Pillay-Smiley N, Fletcher JS, de Blank P, Ratner N. Shedding New Light: Novel Therapies for Common Disorders in Children with Neurofibromatosis Type I. Pediatr Clin North Am 2023; 70:937-950. [PMID: 37704352 DOI: 10.1016/j.pcl.2023.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/15/2023]
Abstract
Neurofibromatosis type I (NF1) is a common dominantly inherited disorder, and one of the most common of the RASopathies. Most individuals with NF1 develop plexiform neurofibromas and cutaneous neurofibromas, nerve tumors caused by NF1 loss of function in Schwann cells. Cell culture models and mouse models of NF1 are being used to test drug efficacy in preclinical trials, which led to Food and Drug Administration approval for use of MEK inhibitors to shrink most inoperable plexiform neurofibromas. This article details methods used for testing in preclinical models, and outlines newer models that may identify additional, curative, strategies.
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Affiliation(s)
- Natasha Pillay-Smiley
- University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-0731, USA; Cancer and Blood Diseases Institute, The Cure Starts Now Foundation Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Jonathan S Fletcher
- Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-0731, USA; Cancer and Blood Diseases Institute, The Cure Starts Now Foundation Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Current Address: Division of Hematology-Oncology, University of Texas Southwestern, Dallas, TX, USA
| | - Peter de Blank
- University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-0731, USA; Cancer and Blood Diseases Institute, The Cure Starts Now Foundation Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Nancy Ratner
- Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-0731, USA; Cancer and Blood Diseases Institute, The Cure Starts Now Foundation Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
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31
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McLean DT, Meudt JJ, Lopez Rivera LD, Schomberg DT, Pavelec DM, Duellman TT, Buehler DG, Schwartz PB, Graham M, Lee LM, Graff KD, Reichert JL, Bon-Durant SS, Konsitzke CM, Ronnekleiv-Kelly SM, Shanmuganayagam D, Rubinstein CD. Single-cell RNA sequencing of neurofibromas reveals a tumor microenvironment favorable for neural regeneration and immune suppression in a neurofibromatosis type 1 porcine model. Front Oncol 2023; 13:1253659. [PMID: 37817770 PMCID: PMC10561395 DOI: 10.3389/fonc.2023.1253659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 09/11/2023] [Indexed: 10/12/2023] Open
Abstract
Neurofibromatosis Type 1 (NF1) is one of the most common genetically inherited disorders that affects 1 in 3000 children annually. Clinical manifestations vary widely but nearly always include the development of cutaneous, plexiform and diffuse neurofibromas that are managed over many years. Recent single-cell transcriptomics profiling efforts of neurofibromas have begun to reveal cell signaling processes. However, the cell signaling networks in mature, non-cutaneous neurofibromas remain unexplored. Here, we present insights into the cellular composition and signaling within mature neurofibromas, contrasting with normal adjacent tissue, in a porcine model of NF1 using single-cell RNA sequencing (scRNA-seq) analysis and histopathological characterization. These neurofibromas exhibited classic diffuse-type histologic morphology and expected patterns of S100, SOX10, GFAP, and CD34 immunohistochemistry. The porcine mature neurofibromas closely resemble human neurofibromas histologically and contain all known cellular components of their human counterparts. The scRNA-seq confirmed the presence of all expected cell types within these neurofibromas and identified novel populations of fibroblasts and immune cells, which may contribute to the tumor microenvironment by suppressing inflammation, promoting M2 macrophage polarization, increasing fibrosis, and driving the proliferation of Schwann cells. Notably, we identified tumor-associated IDO1 +/CD274+ (PD-L1) + dendritic cells, which represent the first such observation in any NF1 animal model and suggest the role of the upregulation of immune checkpoints in mature neurofibromas. Finally, we observed that cell types in the tumor microenvironment are poised to promote immune evasion, extracellular matrix reconstruction, and nerve regeneration.
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Affiliation(s)
- Dalton T. McLean
- Biotechnology Center, University of Wisconsin–Madison, Madison, WI, United States
- Molecular & Environmental Toxicology Program, University of Wisconsin–Madison, Madison, WI, United States
| | - Jennifer J. Meudt
- Biomedical & Genomic Research Group, Department of Animal and Dairy Sciences, University of Wisconsin–Madison, Madison, WI, United States
| | - Loren D. Lopez Rivera
- Molecular & Environmental Toxicology Program, University of Wisconsin–Madison, Madison, WI, United States
| | - Dominic T. Schomberg
- Biomedical & Genomic Research Group, Department of Animal and Dairy Sciences, University of Wisconsin–Madison, Madison, WI, United States
| | - Derek M. Pavelec
- Biotechnology Center, University of Wisconsin–Madison, Madison, WI, United States
| | - Tyler T. Duellman
- Biotechnology Center, University of Wisconsin–Madison, Madison, WI, United States
| | - Darya G. Buehler
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Patrick B. Schwartz
- Molecular & Environmental Toxicology Program, University of Wisconsin–Madison, Madison, WI, United States
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Melissa Graham
- Research Animal Resources and Compliance (RARC), Office of the Vice Chancellor for Research and Graduate Education, University of Wisconsin–Madison, Madison, WI, United States
| | - Laura M. Lee
- Research Animal Resources and Compliance (RARC), Office of the Vice Chancellor for Research and Graduate Education, University of Wisconsin–Madison, Madison, WI, United States
| | - Keri D. Graff
- Swine Research and Teaching Center, Department of Animal and Dairy Sciences, University of Wisconsin–Madison, Madison, WI, United States
| | - Jamie L. Reichert
- Swine Research and Teaching Center, Department of Animal and Dairy Sciences, University of Wisconsin–Madison, Madison, WI, United States
| | - Sandra S. Bon-Durant
- Biotechnology Center, University of Wisconsin–Madison, Madison, WI, United States
| | - Charles M. Konsitzke
- Biotechnology Center, University of Wisconsin–Madison, Madison, WI, United States
| | - Sean M. Ronnekleiv-Kelly
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Dhanansayan Shanmuganayagam
- Molecular & Environmental Toxicology Program, University of Wisconsin–Madison, Madison, WI, United States
- Biomedical & Genomic Research Group, Department of Animal and Dairy Sciences, University of Wisconsin–Madison, Madison, WI, United States
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
- Center for Biomedical Swine Research and Innovation, University of Wisconsin–Madison, Madison, WI, United States
| | - C. Dustin Rubinstein
- Biotechnology Center, University of Wisconsin–Madison, Madison, WI, United States
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32
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Flint AC, Mitchell DK, Angus SP, Smith AE, Bessler W, Jiang L, Mang H, Li X, Lu Q, Rodriguez B, Sandusky GE, Masters AR, Zhang C, Dang P, Koenig J, Johnson GL, Shen W, Liu J, Aggarwal A, Donoho GP, Willard MD, Bhagwat SV, Wade Clapp D, Rhodes SD. Combined CDK4/6 and ERK1/2 Inhibition Enhances Antitumor Activity in NF1-Associated Plexiform Neurofibroma. Clin Cancer Res 2023; 29:3438-3456. [PMID: 37406085 PMCID: PMC11060649 DOI: 10.1158/1078-0432.ccr-22-2854] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 04/06/2023] [Accepted: 06/29/2023] [Indexed: 07/07/2023]
Abstract
PURPOSE Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options remain limited. To identify novel therapeutic targets for PNF, we applied an integrated multi-omic approach to quantitatively profile kinome enrichment in a mouse model that has predicted therapeutic responses in clinical trials for NF1-associated PNF with high fidelity. EXPERIMENTAL DESIGN Utilizing RNA sequencing combined with chemical proteomic profiling of the functionally enriched kinome using multiplexed inhibitor beads coupled with mass spectrometry, we identified molecular signatures predictive of response to CDK4/6 and RAS/MAPK pathway inhibition in PNF. Informed by these results, we evaluated the efficacy of the CDK4/6 inhibitor, abemaciclib, and the ERK1/2 inhibitor, LY3214996, alone and in combination in reducing PNF tumor burden in Nf1flox/flox;PostnCre mice. RESULTS Converging signatures of CDK4/6 and RAS/MAPK pathway activation were identified within the transcriptome and kinome that were conserved in both murine and human PNF. We observed robust additivity of the CDK4/6 inhibitor, abemaciclib, in combination with the ERK1/2 inhibitor, LY3214996, in murine and human NF1(Nf1) mutant Schwann cells. Consistent with these findings, the combination of abemaciclib (CDK4/6i) and LY3214996 (ERK1/2i) synergized to suppress molecular signatures of MAPK activation and exhibited enhanced antitumor activity in Nf1flox/flox;PostnCre mice in vivo. CONCLUSIONS These findings provide rationale for the clinical translation of CDK4/6 inhibitors alone and in combination with therapies targeting the RAS/MAPK pathway for the treatment of PNF and other peripheral nerve sheath tumors in persons with NF1.
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Affiliation(s)
- Alyssa C. Flint
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Dana K. Mitchell
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Steven P. Angus
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center
| | - Abbi E. Smith
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Waylan Bessler
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Li Jiang
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Henry Mang
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Xiaohong Li
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Qingbo Lu
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Brooke Rodriguez
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - George E. Sandusky
- Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Andi R. Masters
- Clinical Pharmacology Analytical Core, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Chi Zhang
- Center for Computational Biology and Bioinformatics and Department of Medical and Molecular Genetics, Indiana University School of Medicine
| | - Pengtao Dang
- Center for Computational Biology and Bioinformatics and Department of Medical and Molecular Genetics, Indiana University School of Medicine
| | - Jenna Koenig
- Medical Scientist Training Program, Indiana University School of Medicine, Indianapolis, IN USA
| | - Gary L. Johnson
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Weihua Shen
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - Jiangang Liu
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - Amit Aggarwal
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - Gregory P. Donoho
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - Melinda D. Willard
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - Shripad V. Bhagwat
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - D. Wade Clapp
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center
| | - Steven D. Rhodes
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center
- Division of Pediatric Hematology-Oncology, Indiana University School of Medicine, Indianapolis, IN, USA
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33
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Rhodes SD, McCormick F, Cagan RL, Bakker A, Staedtke V, Ly I, Steensma MR, Lee SY, Romo CG, Blakeley JO, Sarin KY. RAS Signaling Gone Awry in the Skin: The Complex Role of RAS in Cutaneous Neurofibroma Pathogenesis, Emerging Biological Insights. J Invest Dermatol 2023; 143:1358-1368. [PMID: 37245145 PMCID: PMC10409534 DOI: 10.1016/j.jid.2023.01.043] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 01/13/2023] [Accepted: 01/20/2023] [Indexed: 05/29/2023]
Abstract
Cutaneous neurofibromas (cNFs) are the most common tumor in people with the rasopathy neurofibromatosis type 1. They number in hundreds or even thousands throughout the body, and currently, there are no effective interventions to prevent or treat these skin tumors. To facilitate the identification of novel and effective therapies, essential studies including a more refined understanding of cNF biology and the role of RAS signaling and downstream effector pathways responsible for cNF initiation, growth, and maintenance are needed. This review highlights the current state of knowledge of RAS signaling in cNF pathogenesis and therapeutic development for cNF treatment.
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Affiliation(s)
- Steven D Rhodes
- Division of Hematology-Oncology, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA; Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Frank McCormick
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA; Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
| | - Ross L Cagan
- School of Cancer Sciences, University of Glasgow, Glasgow, Scotland
| | | | - Verena Staedtke
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Ina Ly
- Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Matthew R Steensma
- Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan, USA; Helen DeVos Children's Hospital, Spectrum Health System, Grand Rapids, Michigan, USA; College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA
| | - Sang Y Lee
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Carlos G Romo
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jaishri O Blakeley
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Kavita Y Sarin
- Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA.
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34
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Jiang C, McKay RM, Lee SY, Romo CG, Blakeley JO, Haniffa M, Serra E, Steensma MR, Largaespada D, Le LQ. Cutaneous Neurofibroma Heterogeneity: Factors that Influence Tumor Burden in Neurofibromatosis Type 1. J Invest Dermatol 2023; 143:1369-1377. [PMID: 37318402 PMCID: PMC11173230 DOI: 10.1016/j.jid.2022.12.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 12/01/2022] [Accepted: 12/05/2022] [Indexed: 06/16/2023]
Abstract
Neurofibromatosis type 1 is one of the most common genetic disorders of the nervous system and predisposes patients to develop benign and malignant tumors. Cutaneous neurofibromas (cNFs) are NF1-associated benign tumors that affect nearly 100% of patients with NF1. cNFs dramatically reduce patients' QOL owing to their unaesthetic appearance, physical discomfort, and corresponding psychological burden. There is currently no effective drug therapy option, and treatment is restricted to surgical removal. One of the greatest hurdles for cNF management is the variability of clinical expressivity in NF1, resulting in intrapatient and interpatient cNF tumor burden heterogeneity, that is, the variability in the presentation and evolution of these tumors. There is growing evidence that a wide array of factors are involved in the regulation of cNF heterogeneity. Understanding the mechanisms underlying this heterogeneity of cNF at the molecular, cellular, and environmental levels can facilitate the development of innovative and personalized treatment regimens.
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Affiliation(s)
- Chunhui Jiang
- Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Renée M McKay
- Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Sang Y Lee
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Carlos G Romo
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jaishri O Blakeley
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Muzlifah Haniffa
- Biosciences Institute, Newcastle University, Newcastle Upon Tyne, United Kingdom; NIHR Newcastle Biomedical Research Center Dermatology, Newcastle University, Newcastle Upon Tyne, United Kingdom
| | - Eduard Serra
- Hereditary Cancer Group, Germans Trias i Pujol Research Institute (IGTP), Barcelona, Spain
| | - Matthew R Steensma
- Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan, USA
| | - David Largaespada
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA; Division of Hematology and Oncology, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Lu Q Le
- Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Comprehensive Neurofibromatosis Clinic, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA; O'Donnell Brain Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
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35
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Jiang C, Kumar A, Yu Z, Shipman T, Wang Y, McKay RM, Xing C, Le LQ. Basement membrane proteins in extracellular matrix characterize NF1 neurofibroma development and response to MEK inhibitor. J Clin Invest 2023; 133:e168227. [PMID: 37140985 PMCID: PMC10266775 DOI: 10.1172/jci168227] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 05/02/2023] [Indexed: 05/05/2023] Open
Abstract
Neurofibromatosis type 1 (NF1) is one of the most common tumor-predisposing genetic disorders. Neurofibromas are NF1-associated benign tumors. A hallmark feature of neurofibromas is an abundant collagen-rich extracellular matrix (ECM) that constitutes more than 50% of the tumor dry weight. However, little is known about the mechanism underlying ECM deposition during neurofibroma development and treatment response. We performed a systematic investigation of ECM enrichment during plexiform neurofibroma (pNF) development and identified basement membrane (BM) proteins, rather than major collagen isoforms, as the most upregulated ECM component. Following MEK inhibitor treatment, the ECM profile displayed an overall downregulation signature, suggesting ECM reduction as a therapeutic benefit of MEK inhibition. Through these proteomic studies, TGF-β1 signaling was identified as playing a role in ECM dynamics. Indeed, TGF-β1 overexpression promoted pNF progression in vivo. Furthermore, by integrating single-cell RNA sequencing, we found that immune cells including macrophages and T cells produce TGF-β1 to induce Schwann cells to produce and deposit BM proteins for ECM remodeling. Following Nf1 loss, neoplastic Schwann cells further increased BM protein deposition in response to TGF-β1. Our data delineate the regulation governing ECM dynamics in pNF and suggest that BM proteins could serve as biomarkers for disease diagnosis and treatment response.
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Affiliation(s)
| | - Ashwani Kumar
- Eugene McDermott Center for Human Growth and Development
| | - Ze Yu
- Eugene McDermott Center for Human Growth and Development
| | | | | | | | - Chao Xing
- Eugene McDermott Center for Human Growth and Development
- Lyda Hill Department of Bioinformatics
| | - Lu Q. Le
- Department of Dermatology
- Simmons Comprehensive Cancer Center
- UTSW Comprehensive Neurofibromatosis Clinic
- Hamon Center for Regenerative Science and Medicine, and
- O’Donnell Brain Institute, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
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36
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Wataya-Kaneda M, Watanabe Y, Nakamura A, Yamamoto K, Okada K, Maeda S, Nimura K, Saga K, Katayama I. Pilot study for the treatment of cutaneous neurofibromas in neurofibromatosis type 1 patients using topical sirolimus gel. J Am Acad Dermatol 2023; 88:877-880. [PMID: 36334988 DOI: 10.1016/j.jaad.2022.08.066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 08/03/2022] [Accepted: 08/09/2022] [Indexed: 11/05/2022]
Affiliation(s)
- Mari Wataya-Kaneda
- Department of Dermatology, Graduate School of Medicine, Osaka University, Suita, Japan; Department of Neurocutaneous Medicine, Division of Health Sciences, Graduate School of Medicine, Osaka University, Suita, Japan.
| | - Yoshiyuki Watanabe
- Department of Radiology, Graduate School of Medicine, Osaka University, Suita, Japan; Department of Radiology, Shiga University of Medical Science, Otsu, Japan
| | - Ayumi Nakamura
- Department of Pharmacy, Osaka University Hospital, Suita, Japan
| | - Kouji Yamamoto
- Department of Biostatistics Yokohama City University, School of Medicine, Yokohama, Japan
| | - Kiyoshi Okada
- Strategic Global Partnership Cross-Innovation Initiative, Osaka University Graduate School of Medicine, Faculty of Medicine, Osaka University Hospital, Suita, Japan
| | - Shinichiro Maeda
- Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan
| | - Keisuke Nimura
- Division of Gene Therapy Science, Department of Genome Biology, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Kotaro Saga
- Division of Gene Therapy Science, Department of Genome Biology, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Ichiro Katayama
- Department of Dermatology, Graduate School of Medicine, Osaka University, Suita, Japan
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37
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Na Y, Hall A, Yu Y, Hu L, Choi K, Burgard JA, Szabo S, Huang G, Ratner N, Wu J. Runx1/3-driven adaptive endoplasmic reticulum stress pathways contribute to neurofibromagenesis. Oncogene 2023; 42:1038-1047. [PMID: 36759572 PMCID: PMC10194627 DOI: 10.1038/s41388-023-02620-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 01/28/2023] [Accepted: 01/31/2023] [Indexed: 02/11/2023]
Abstract
Neurofibromatosis type 1 (NF1) patients are predisposed to develop plexiform neurofibromas (PNFs). Three endoplasmic reticulum (ER) stress response pathways restore cellular homeostasis. The unfolded protein response (UPR) sensors contribute to tumor initiation in many cancers. We found that all three UPR pathways were activated in mouse and human PNFs, with protein kinase RNA [PKR]-like ER kinase (PERK) the most highly expressed. We tested if neurofibroma cells adapt to ER stress, leading to their growth. Pharmacological or genetic inhibition of PERK reduced mouse neurofibroma-sphere number, and genetic inhibition in PERK in Schwann cell precursors (SCPs) decreased tumor-like lesion numbers in a cell transplantation model. Further, in a PNF mouse model, deletion of PERK in Schwann cells (SCs) and SCPs reduced tumor size, number, and increased survival. Mechanistically, loss of Nf1 activated PERK-eIF2α-ATF4 signaling and increased ATF4 downstream target gene p21 translocation from nucleus to cytoplasm. This nucleus-cytoplasm translocation was mediated by exportin-1. Runx transcriptionally activated ribosome gene expression and increased protein synthesis to allow SCs to adapt to ER stress and tumor formation. We propose that targeting proteostasis might provide cytotoxic and/or potentially durable novel therapy for PNFs.
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Affiliation(s)
- Youjin Na
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
| | - Ashley Hall
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
| | - Yanan Yu
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
- College of Life Science, Xuzhou Medical University, 221004, Jiangsu, P. R. China
| | - Liang Hu
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
| | - Kwangmin Choi
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
| | - Jake A Burgard
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
| | - Sara Szabo
- Department of Pediatrics and Department of Pediatric Pathology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA
| | - Gang Huang
- Department of Cell Systems & Anatomy and Department of Pathology & Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio, San Antonio, TX, USA
- Department of Pathology & Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio, San Antonio, TX, 78229, USA
| | - Nancy Ratner
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
| | - Jianqiang Wu
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA.
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
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38
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Duan J, Wang Y. Modeling nervous system tumors with human stem cells and organoids. CELL REGENERATION (LONDON, ENGLAND) 2023; 12:4. [PMID: 36854987 PMCID: PMC9975125 DOI: 10.1186/s13619-022-00150-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 11/05/2022] [Indexed: 03/02/2023]
Abstract
Nervous system cancers are the 10th leading cause of death worldwide, many of which are difficult to diagnose and exhibit varying degrees of treatment resistance. The limitations of existing cancer models, such as patient-derived xenograft (PDX) models and genetically engineered mouse (GEM) models, call for the development of novel preclinical cancer models to more faithfully mimic the patient's cancer and offer additional insights. Recent advances in human stem cell biology, organoid, and genome-editing techniques allow us to model nervous system tumors in three types of next-generation tumor models: cell-of-origin models, tumor organoids, and 3D multicellular coculture models. In this review, we introduced and compared different human stem cell/organoid-derived models, and comprehensively summarized and discussed the recently developed models for various primary tumors in the central and peripheral nervous systems, including glioblastoma (GBM), H3K27M-mutant Diffuse Midline Glioma (DMG) and H3G34R-mutant High-grade Glioma (HGG), Low-grade Glioma (LGG), Neurofibromatosis Type 1 (NF1), Neurofibromatosis Type 2 (NF2), Medulloblastoma (MB), Atypical Teratoid/rhabdoid Tumor (AT/RT), and meningioma. We further compared these models with PDX and GEM models, and discussed the opportunities and challenges of precision nervous cancer modeling with human stem cells and organoids.
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Affiliation(s)
- Jie Duan
- grid.412901.f0000 0004 1770 1022Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and National Collaborative Innovation Center, Chengdu, 610041 China
| | - Yuan Wang
- Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and National Collaborative Innovation Center, Chengdu, 610041, China.
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Ioannou M, Zhang L, Schatz K, Rodriguez FJ, Ahlawat S, Gocke CD, Rhee DS, Staedtke V, Pratilas CA. Plexiform neurofibroma of the liver, with malignant transformation to MPNST, in a pediatric patient without neurofibromatosis type 1. Neurooncol Adv 2023; 5:vdad125. [PMID: 37841697 PMCID: PMC10576510 DOI: 10.1093/noajnl/vdad125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2023] Open
Affiliation(s)
- Maria Ioannou
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Lindy Zhang
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Krista Schatz
- Department of Genetic Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Fausto J Rodriguez
- Department of Pathology, University of California Los Angeles, Los Angeles, California, USA
| | - Shivani Ahlawat
- Russell H. Morgan Department of Radiology & Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Christopher D Gocke
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Daniel S Rhee
- Department of Pediatric Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Verena Staedtke
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Christine A Pratilas
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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40
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Muacevic A, Adler JR, Landge S, Pundkar A, Chandanwale R. Unusual Solitary Neurofibroma of Common Peroneal Nerve in a Child. Cureus 2022; 14:e33039. [PMID: 36721607 PMCID: PMC9881391 DOI: 10.7759/cureus.33039] [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: 10/26/2022] [Accepted: 12/28/2022] [Indexed: 12/29/2022] Open
Abstract
Neurofibroma (NF) is a tumour of peripheral nerves, which would be seldom seen in the limbs, particularly in children's limbs. Soft, skin-coloured papules or small sub-mucosal nodules appear as these lesions. Neurofibroma is classified into three types: localized, diffuse, and plexiform. The vast majority of nerve injury is sporadic and localized, with an incredibly low risk of tumour formation. Neurofibromatosis can present as multiple skin lesions along with bone deformities in which a full investigation is critical where an undiscovered widespread illness may arise. This case study describes a neurofibroma on the common peroneal nerve of the left lower limb in a 6-year-old child who visited our hospital with chief complaints of pain and swelling around the left proximal leg.
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Reed CB, Feltri ML, Wilson ER. Peripheral glia diversity. J Anat 2022; 241:1219-1234. [PMID: 34131911 PMCID: PMC8671569 DOI: 10.1111/joa.13484] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 05/20/2021] [Accepted: 05/26/2021] [Indexed: 12/13/2022] Open
Abstract
Recent years have seen an evolving appreciation for the role of glial cells in the nervous system. As we move away from the typical neurocentric view of neuroscience, the complexity and variability of central nervous system glia is emerging, far beyond the three main subtypes: astrocytes, oligodendrocytes, and microglia. Yet the diversity of the glia found in the peripheral nervous system remains rarely discussed. In this review, we discuss the developmental origin, morphology, and function of the different populations of glia found in the peripheral nervous system, including: myelinating Schwann cells, Remak Schwann cells, repair Schwann cells, satellite glia, boundary cap-derived glia, perineurial glia, terminal Schwann cells, glia found in the skin, olfactory ensheathing cells, and enteric glia. The morphological and functional heterogeneity of glia found in the periphery reflects the diverse roles the nervous system performs throughout the body. Further, it highlights a complexity that should be appreciated and considered when it comes to a complete understanding of the peripheral nervous system in health and disease.
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Affiliation(s)
- Chelsey B. Reed
- Hunter James Kelly Research InstituteJacobs School of Medicine and Biomedical Sciences StateUniversity of New York at BuffaloBuffaloNew YorkUSA
- Department of NeurologyJacobs School of Medicine and Biomedical SciencesState University of New York at BuffaloBuffaloNew YorkUSA
| | - M. Laura Feltri
- Hunter James Kelly Research InstituteJacobs School of Medicine and Biomedical Sciences StateUniversity of New York at BuffaloBuffaloNew YorkUSA
- Department of NeurologyJacobs School of Medicine and Biomedical SciencesState University of New York at BuffaloBuffaloNew YorkUSA
- Department of BiochemistryJacobs School of Medicine and Biomedical SciencesState University of New York at BuffaloBuffaloNew YorkUSA
| | - Emma R. Wilson
- Hunter James Kelly Research InstituteJacobs School of Medicine and Biomedical Sciences StateUniversity of New York at BuffaloBuffaloNew YorkUSA
- Department of BiochemistryJacobs School of Medicine and Biomedical SciencesState University of New York at BuffaloBuffaloNew YorkUSA
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42
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Ge LL, Xing MY, Zhang HB, Wang ZC. Neurofibroma Development in Neurofibromatosis Type 1: Insights from Cellular Origin and Schwann Cell Lineage Development. Cancers (Basel) 2022; 14:cancers14184513. [PMID: 36139671 PMCID: PMC9497298 DOI: 10.3390/cancers14184513] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 09/11/2022] [Accepted: 09/14/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Neurofibromatosis type 1 (NF1), a genetic tumor predisposition syndrome that affects about 1 in 3000 newborns, is caused by mutations in the NF1 gene and subsequent inactivation of its encoded neurofibromin. Neurofibromin is a tumor suppressor protein involved in the downregulation of Ras signaling. Despite a diverse clinical spectrum, one of several hallmarks of NF1 is a peripheral nerve sheath tumor (PNST), which comprises mixed nervous and fibrous components. The distinct spatiotemporal characteristics of plexiform and cutaneous neurofibromas have prompted hypotheses about the origin and developmental features of these tumors, involving various cellular transition processes. METHODS We retrieved published literature from PubMed, EMBASE, and Web of Science up to 21 June 2022 and searched references cited in the selected studies to identify other relevant papers. Original articles reporting the pathogenesis of PNSTs during development were included in this review. We highlighted the Schwann cell (SC) lineage shift to better present the evolution of its corresponding cellular origin hypothesis and its important effects on the progression and malignant transformation of neurofibromas. CONCLUSIONS In this review, we summarized the vast array of evidence obtained on the full range of neurofibroma development based on cellular and molecular pathogenesis. By integrating findings relating to tumor formation, growth, and malignancy, we hope to reveal the role of SC lineage shift as well as the combined impact of additional determinants in the natural history of PNSTs.
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Affiliation(s)
- Ling-Ling Ge
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People′s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Ming-Yan Xing
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200011, China
| | - Hai-Bing Zhang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200011, China
- Correspondence: (H.-B.Z.); or (Z.-C.W.); Tel.: +86-021-54920988 (H.-B.Z.); +86-021-53315120 (Z.-C.W.)
| | - Zhi-Chao Wang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People′s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
- Correspondence: (H.-B.Z.); or (Z.-C.W.); Tel.: +86-021-54920988 (H.-B.Z.); +86-021-53315120 (Z.-C.W.)
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Wang X, Zhao C, Huang D, Liu Z, Liu M, Lin F, Lu Y, Jia J, Lin L, Lin X, Li H, Chen Z. A Novel M6A-Related Genes Signature Can Impact the Immune Status and Predict the Prognosis and Drug Sensitivity of Lung Adenocarcinoma. Front Immunol 2022; 13:923533. [PMID: 35860262 PMCID: PMC9289247 DOI: 10.3389/fimmu.2022.923533] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 06/01/2022] [Indexed: 01/22/2023] Open
Abstract
Lung adenocarcinoma (LUAD) is a primary cause of cancer-related death around the world and has a poor outcome and high incidence. Treatment options are, however, restricted. One of the most critical factors in cancer and metastasis is the N6-methyladenine (m6A) alteration on RNA. This modification could alter gene expression and even function at numerous levels, such as the stability, translocation and translation of RNA splicing. This study aimed to construct an m6A-related genes signature to accurately predict the prognosis of LUAD patients. From TCGA datasets, the LUAD patient data and m6A-related genes were retrieved. LUAD patients’ mutational features and differentially expressed genes (DEGs) were investigated. An univariate and LASSO model with m6A-related genes were constructed for the prediction of outcomes in LUAD. It was possible to develop a prognostic nomogram that could quantitatively predict LUAD patients’ overall survival chances at 1, 3, and 5 years. Research into biological processes and cell pathways was carried out using GSEA. This study found six m6A-related DEGs in LUAD patients, and three of these DEGs(HNRNPC, IGFBP3 and IGF2BP1) were linked to the clinical outcomes of LUAD patients. We found that the overall survival rate for all LUAD patients with high-risk subgroup was considerably lower. According to ROC curves, the prognostic signature demonstrated a high degree of accuracy in predicting future outcomes. In addition, we created a novel nomogram achieved great accuracy with this one as well. The researchers also found that the novel signature might favorably modulate the immune response, and high-risk scores samples were more susceptible to numerous chemotherapeutic medicines. Overall, we developed a m6A-related gene prognostic signature that effectively predicted outcomes of LUAD patients and gave an immunological perspective for creating customized therapeutics.
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Affiliation(s)
- Xuewen Wang
- Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, China
| | - Chengfei Zhao
- Department of Pharmacy, School of Pharmacy and Medical Technology, Putian University, Putian, China
| | - Dandan Huang
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Zhoujie Liu
- Department of Pharmacy, First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Mengmeng Liu
- Department of Pharmacy, First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Fei Lin
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Yingyu Lu
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Jing Jia
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Liqing Lin
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Xinhua Lin
- Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China
- Key Laboratory of Nanomedical Technology (Education Department of Fujian Province), School of Pharmacy, Nano Medical Technology Research Institute, Fujian Medical University, Fuzhou, China
- *Correspondence: Zhiwei Chen, ; Huangyuan Li, ; Xinhua Lin,
| | - Huangyuan Li
- Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, China
- Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, China
- *Correspondence: Zhiwei Chen, ; Huangyuan Li, ; Xinhua Lin,
| | - Zhiwei Chen
- Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, China
- Fuzhou Center for Disease Control and Prevention, Fuzhou, China
- *Correspondence: Zhiwei Chen, ; Huangyuan Li, ; Xinhua Lin,
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Diffuse Type Neurofibroma of the Forearm. PLASTIC AND RECONSTRUCTIVE SURGERY-GLOBAL OPEN 2022; 10:e4341. [PMID: 35620496 PMCID: PMC9126514 DOI: 10.1097/gox.0000000000004341] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Accepted: 04/01/2022] [Indexed: 11/26/2022]
Abstract
Nerve sheath tumors comprise 5% of soft tissue masses of the upper limb in adults. Neurofibromas are divided into three types: localized, diffuse, and plexi- form. The diffuse type is rare and is typically found in the head and neck region. We present a rare case of diffuse type neurofibroma found in the forearm, presented to our clinic as a slowly enlarging mass of the left forearm of 3 years duration. The lesion was suspicious in the magnetic resonance imaging, and biopsy revealed diffuse type neurofibroma. We opted for total excision of the lesion that was found to be not possible due to involvement of the major nerves. The final pathology report showed no malignancy. Nerve tumors of the upper limb can be either benign or malignant. Neurofibroma associated with neurofibromatosis has malignant potential. The diffuse type is rare, and it most commonly occurs in the head and neck region. It has a low malignant transformation rate. Magnetic resonance imaging is the diagnostic modality of choice; however, it can be inconclusive. Biopsy should be taken to confirm the diagnosis and plan for management. Our case was managed by near total excision in order to preserve the major forearm nerves because of high clinical suspicion.
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45
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Iriki H, Umegaki-Arao N, Kakuta R, Fujita H, Aoki S, Amagai M, Sasaki T, Hamamoto Y, Nakayama R, Kubo A. Superimposition of checkerboard distribution of ephelides and neurofibromas in a segmental neurofibromatosis patient. JAAD Case Rep 2022; 25:89-92. [PMID: 35799684 PMCID: PMC9253525 DOI: 10.1016/j.jdcr.2022.05.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Affiliation(s)
- Hisato Iriki
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
| | - Noriko Umegaki-Arao
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
- Department of Dermatology, Tokyo Women's Medical University Adachi Medical Center, Tokyo, Japan
| | - Risa Kakuta
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
| | - Harumi Fujita
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
- KOSÉ Endowed Program for Skin Care and Allergy Prevention, Keio University School of Medicine, Tokyo, Japan
| | - Satomi Aoki
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
| | - Masayuki Amagai
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
- KOSÉ Endowed Program for Skin Care and Allergy Prevention, Keio University School of Medicine, Tokyo, Japan
| | - Takashi Sasaki
- Center for Supercentenarian Medical Research, Keio University School of Medicine, Tokyo, Japan
| | - Yasuo Hamamoto
- Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan
| | - Robert Nakayama
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Akiharu Kubo
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
- Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Japan
- Correspondence to: Akiharu Kubo, MD, PhD, Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
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46
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Chaker-Margot M, Werten S, Dunzendorfer-Matt T, Lechner S, Ruepp A, Scheffzek K, Maier T. Structural basis of activation of the tumor suppressor protein neurofibromin. Mol Cell 2022; 82:1288-1296.e5. [PMID: 35353986 DOI: 10.1016/j.molcel.2022.03.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 01/14/2022] [Accepted: 03/03/2022] [Indexed: 12/15/2022]
Abstract
Mutations in the NF1 gene cause the familial genetic disease neurofibromatosis type I, as well as predisposition to cancer. The NF1 gene product, neurofibromin, is a GTPase-activating protein and acts as a tumor suppressor by negatively regulating the small GTPase, Ras. However, structural insights into neurofibromin activation remain incompletely defined. Here, we provide cryoelectron microscopy (cryo-EM) structures that reveal an extended neurofibromin homodimer in two functional states: an auto-inhibited state with occluded Ras-binding site and an asymmetric open state with an exposed Ras-binding site. Mechanistically, the transition to the active conformation is stimulated by nucleotide binding, which releases a lock that tethers the catalytic domain to an extended helical repeat scaffold in the occluded state. Structure-guided mutational analysis supports functional relevance of allosteric control. Disease-causing mutations are mapped and primarily impact neurofibromin stability. Our findings suggest a role for nucleotides in neurofibromin regulation and may lead to therapeutic modulation of Ras signaling.
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Affiliation(s)
| | - Sebastiaan Werten
- Institute of Biological Chemistry, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria
| | | | - Stefan Lechner
- Institute of Biological Chemistry, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria
| | - Angela Ruepp
- Institute of Biological Chemistry, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria
| | - Klaus Scheffzek
- Institute of Biological Chemistry, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria.
| | - Timm Maier
- Biozentrum, University of Basel, 4056 Basel, Switzerland.
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47
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Somatilaka BN, Sadek A, McKay RM, Le LQ. Malignant peripheral nerve sheath tumor: models, biology, and translation. Oncogene 2022; 41:2405-2421. [PMID: 35393544 PMCID: PMC9035132 DOI: 10.1038/s41388-022-02290-1] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 03/16/2022] [Accepted: 03/21/2022] [Indexed: 01/29/2023]
Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, invasive cancer that comprise around 10% of all soft tissue sarcomas and develop in about 8-13% of patients with Neurofibromatosis Type 1. They are associated with poor prognosis and are the leading cause of mortality in NF1 patients. MPNSTs can also develop sporadically or following exposure to radiation. There is currently no effective targeted therapy to treat MPNSTs and surgical removal remains the mainstay treatment. Unfortunately, surgery is not always possible due to the size and location of the tumor, thus, a better understanding of MPNST initiation and development is required to design novel therapeutics. Here, we provide an overview of MPNST biology and genetics, discuss findings regarding the developmental origin of MPNST, and summarize the various model systems employed to study MPNST. Finally, we discuss current management strategies for MPNST, as well as recent developments in translating basic research findings into potential therapies.
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Affiliation(s)
- Bandarigoda N. Somatilaka
- Department of Dermatology, University of Texas Southwestern
Medical Center at Dallas, Dallas, Texas, 75390-9069, USA
| | - Ali Sadek
- Department of Dermatology, University of Texas Southwestern
Medical Center at Dallas, Dallas, Texas, 75390-9069, USA
| | - Renee M. McKay
- Department of Dermatology, University of Texas Southwestern
Medical Center at Dallas, Dallas, Texas, 75390-9069, USA
| | - Lu Q. Le
- Department of Dermatology, University of Texas Southwestern
Medical Center at Dallas, Dallas, Texas, 75390-9069, USA,Simmons Comprehensive Cancer Center, University of Texas
Southwestern Medical Center at Dallas, Dallas, Texas, 75390-9069, USA,UTSW Comprehensive Neurofibromatosis Clinic, University of
Texas Southwestern Medical Center at Dallas, Dallas, Texas, 75390-9069, USA,Hamon Center for Regenerative Science and Medicine,
University of Texas Southwestern Medical Center at Dallas, Dallas, Texas,
75390-9069, USA,O’Donnell Brain Institute, University of Texas
Southwestern Medical Center at Dallas, Dallas, Texas, 75390-9069, USA
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48
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Sinegubov A, Andreeva D, Burzak N, Vasyutina M, Murashova L, Dyachuk V. Heterogeneity and Potency of Peripheral Glial Cells in Embryonic Development and Adults. Front Mol Neurosci 2022; 15:737949. [PMID: 35401107 PMCID: PMC8990813 DOI: 10.3389/fnmol.2022.737949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 02/08/2022] [Indexed: 11/13/2022] Open
Abstract
This review describes the heterogeneity of peripheral glial cell populations, from the emergence of Schwann cells (SCs) in early development, to their involvement, and that of their derivatives in adult glial populations. We focus on the origin of the first glial precursors from neural crest cells (NCCs), and their ability to differentiate into several cell types during development. We also discuss the heterogeneity of embryonic glia in light of the latest data from genetic tracing and transcriptome analysis. Special attention has been paid to the biology of glial populations in adult animals, by highlighting common features of different glial cell types and molecular differences that modulate their functions. Finally, we consider the communication of glial cells with axons of neurons in normal and pathological conditions. In conclusion, the present review details how information available on glial cell types and their functions in normal and pathological conditions may be utilized in the development of novel therapeutic strategies for the treatment of patients with neurodiseases.
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Patritti Cram J, Wu J, Coover RA, Rizvi TA, Chaney KE, Ravindran R, Cancelas JA, Spinner RJ, Ratner N. P2RY14 cAMP signaling regulates Schwann cell precursor self-renewal, proliferation, and nerve tumor initiation in a mouse model of neurofibromatosis. eLife 2022; 11:73511. [PMID: 35311647 PMCID: PMC8959601 DOI: 10.7554/elife.73511] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 01/19/2022] [Indexed: 01/05/2023] Open
Abstract
Neurofibromatosis type 1 (NF1) is characterized by nerve tumors called neurofibromas, in which Schwann cells (SCs) show deregulated RAS signaling. NF1 is also implicated in regulation of cAMP. We identified the G-protein-coupled receptor (GPCR) P2ry14 in human neurofibromas, neurofibroma-derived SC precursors (SCPs), mature SCs, and mouse SCPs. Mouse Nf1-/- SCP self-renewal was reduced by genetic or pharmacological inhibition of P2ry14. In a mouse model of NF1, genetic deletion of P2ry14 rescued low cAMP signaling, increased mouse survival, delayed neurofibroma initiation, and improved SC Remak bundles. P2ry14 signals via Gi to increase intracellular cAMP, implicating P2ry14 as a key upstream regulator of cAMP. We found that elevation of cAMP by either blocking the degradation of cAMP or by using a P2ry14 inhibitor diminished NF1-/- SCP self-renewal in vitro and neurofibroma SC proliferation in in vivo. These studies identify P2ry14 as a critical regulator of SCP self-renewal, SC proliferation, and neurofibroma initiation.
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Affiliation(s)
- Jennifer Patritti Cram
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, United States.,Neuroscience Graduate Program, University of Cincinnati College of Medicine, Cincinnati, United States
| | - Jianqiang Wu
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, United States.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, United States
| | - Robert A Coover
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
| | - Tilat A Rizvi
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
| | - Katherine E Chaney
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
| | - Ramya Ravindran
- Molecular and Developmental Biology, Cincinnati Children's Hospital, Cincinnati, United States
| | - Jose A Cancelas
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, United States.,Hoxworth Blood Center, College of Medicine, University of Cincinnati, Cincinnati, United States
| | - Robert J Spinner
- Department of Neurosurgery, Mayo Clinic, Rochester, United States
| | - Nancy Ratner
- Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, United States.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, United States
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50
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Mattox AK, Douville C, Silliman N, Ptak J, Dobbyn L, Schaefer J, Popoli M, Blair C, Judge K, Pollard K, Pratilas C, Blakeley J, Rodriguez F, Papadopoulos N, Belzberg A, Bettegowda C. Detection of malignant peripheral nerve sheath tumors in patients with neurofibromatosis using aneuploidy and mutation identification in plasma. eLife 2022; 11:e74238. [PMID: 35244537 PMCID: PMC9094745 DOI: 10.7554/elife.74238] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 02/01/2022] [Indexed: 11/28/2022] Open
Abstract
Malignant peripheral nerve sheath tumors (MPNST) are the deadliest cancer that arises in individuals diagnosed with neurofibromatosis and account for nearly 5% of the 15,000 soft tissue sarcomas diagnosed in the United States each year. Comprised of neoplastic Schwann cells, primary risk factors for developing MPNST include existing plexiform neurofibromas (PN), prior radiotherapy treatment, and expansive germline mutations involving the entire NF1 gene and surrounding genes. PN develop in nearly 30-50% of patients with neurofibromatosis type 1 (NF1) and most often grow rapidly in the first decade of life. One of the most important aspects of clinical care for NF1 patients is monitoring PN for signs of malignant transformation to MPNST that occurs in 10-15% of patients. We perform aneuploidy analysis on ctDNA from 883 ostensibly healthy individuals and 28 patients with neurofibromas, including 7 patients with benign neurofibroma, 9 patients with PN and 12 patients with MPNST. Overall sensitivity for detecting MPNST using genome wide aneuploidy scoring was 33%, and analysis of sub-chromosomal copy number alterations (CNAs) improved sensitivity to 50% while retaining a high specificity of 97%. In addition, we performed mutation analysis on plasma cfDNA for a subset of patients and identified mutations in NF1, NF2, RB1, TP53BP2, and GOLGA2. Given the high throughput and relatively low sequencing coverage required by our assay, liquid biopsy represents a promising technology to identify incipient MPNST.
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Affiliation(s)
- Austin K Mattox
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Christopher Douville
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Natalie Silliman
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Janine Ptak
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Lisa Dobbyn
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Joy Schaefer
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Maria Popoli
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Cherie Blair
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Kathy Judge
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Kai Pollard
- Department of Pediatrics, Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Oncology, Sidney Kimmel Comprehensive Cancer, Johns Hopkins UniversityBaltimoreUnited States
| | - Christine Pratilas
- Department of Pediatrics, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Jaishri Blakeley
- Department of Neurology, Johns Hopkins University School of Medicine, MD School of MedicineBaltimoreUnited States
| | - Fausto Rodriguez
- Department of Pathology, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Nickolas Papadopoulos
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Oncology, Sidney Kimmel Comprehensive Cancer, Johns Hopkins UniversityBaltimoreUnited States
- Department of Pathology, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Allan Belzberg
- Department of Neurosurgery, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Chetan Bettegowda
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Oncology, Sidney Kimmel Comprehensive Cancer, Johns Hopkins UniversityBaltimoreUnited States
- Department of Neurosurgery, Johns Hopkins University School of MedicineBaltimoreUnited States
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