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Neurofibromatosis Type 1 (NF1) Related Tumors
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Neurofibromatosis Type 1 (NF1) Related Tumors

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: 31 March 2025 | Viewed by 8428

Special Issue Editors

Dr. Daochun Sun

E-Mail Website
Guest Editor
Department of Cell Biology, Neurobiology and Anatomy, The Medical College of Wisconsin, Milwaukee, WI 53226, USA
Interests: NF1-associated tumors; plexiform neurofibromas; glioblastoma multiforme
Dr. Sameer Farouk Sait

E-Mail Website
Guest Editor
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Interests: NF1 tumor; pediatric brain tumors; spinal cord tumors

Special Issue Information

Dear Colleagues,

We are pleased to announce the Special Issue of Cancers entitled “Neurofibromatosis Type 1 (NF1) Related Tumors“.

Neurofibromatosis Type 1 (NF1) is a cancer predisposition syndrome with afflicted patients developing benign and/or malignant tumors at distinct developmental stages. The pathognomonic feature is the development of nerve sheath tumors, cutaneous neurofibromas, and plexiform neurofibromas, with the latter capable of transformation into malignant peripheral nerve sheath tumor (MPNST), an incurable sarcoma with metastatic potential. Central nervous system (CNS) tumors are also frequently encountered in children including optic pathway gliomas (OPGs) and brainstem low-grade gliomas (LGGs), while an increased incidence of high-grade gliomas (HGGs) in adolescents and young adults compared to the general population has also been reported. With the identification of NF1 and co-operating driver alterations through collaborative multi-omics studies and the development of genetically engineered mouse models that accurately recapitulate these tumor phenotypes, therapies targeting the underlying molecular pathophysiology (i.e., RAS signaling and downstream effectors) for neurofibromatosis type 1 are becoming available and have demonstrated success in benign plexiform neurofibromas and optic pathway gliomas. In addition, NF1 patients show increased risk for leukemia, sarcomas, breast cancer, pheochromocytoma and gastrointestinal stromal tumors, among others. NF1-associated tumors demonstrate significant tumor heterogeneity, an enriched tumor microenvironment, and versatile epigenetic regulations which create significant challenges in the development of new drug and treatment strategies and often contribute to worse outcomes relative to sporadic NF1 wildtype tumors. Recent advances in the NF1 field demonstrate stem-like tumor populations driving heterogeneity, characterize the immune microenvironment and inflammatory signatures, and elucidate the crystal structure of neurofibromin. These new angles enable further characterizing NF1-associated tumors and inspire new ideas to devise treatment. Clinical trials evaluating targeted therapy (i.e., MEK inhibitors) versus standard approaches are ongoing and may potentially result in a paradigm shift in the treatment of benign NF1 tumors, while combinatorial approaches will likely be required for the management of high-grade tumors.

In this Special Issue, we aim to summarize, explore, and characterize the features of NF1-related tumors, covering both basic and (pre)clinical aspects to advance our understanding of targeting these complex diseases.

We look forward to receiving your contributions.

Dr. Daochun Sun
Dr. Sameer Farouk Sait
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • NF1
  • tumorigenesis
  • cancer stem cells
  • targeted therapy
  • tumor microenvironment
  • epigenetics
  • case report
  • metastasis
  • clinical trials

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Published Papers (5 papers)

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Research

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16 pages, 1107 KiB  
Article
Genotype–Phenotype Correlation in Neurofibromatosis Type 1: Evidence for a Mild Phenotype Associated with Splicing Variants Leading to In-Frame Skipping of NF1 Exon 24 [19a]
by Yunjia Chen, Yulong Fu, Magdalena Koczkowska, Tom Callens, Alicia Gomes, Jian Liu, William Bradley, Bryce Brown, Brandon Shaw, Daniela D’Agostino, Chuanhua Fu and Deeann Wallis
Cancers 2024, 16(13), 2406; https://doi.org/10.3390/cancers16132406 - 29 Jun 2024
Viewed by 1220
Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder caused by loss-of-function variants in the NF1 gene. As of 20 November 2023, over 5000 distinct pathogenic or likely pathogenic variants have been reported in public databases. However, only a few NF1 genotype–phenotype [...] Read more.
Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder caused by loss-of-function variants in the NF1 gene. As of 20 November 2023, over 5000 distinct pathogenic or likely pathogenic variants have been reported in public databases. However, only a few NF1 genotype–phenotype correlations have been established so far. In this study, we present findings on 40 individuals with NF1, comprising 26 unrelated probands and 14 affected relatives, who carry one of nine NF1 heterozygous pathogenic splicing variants, all of which result in the in-frame skipping of exon 24 [19a] (NM_000267.3:r.3114_3197del, p.Asn1039_Arg1066del). These variants include c.3114-2A>G, c.3114-1G>A, c.3196A>G, c.3197G>A, c.3197G>T, c.3197+1G>A, c.3197+1G>T, c.3197+2T>C, and c.3197+3A>T. Among individuals with these variants, none exhibit externally visible plexiform neurofibromas, histopathologically confirmed cutaneous or subcutaneous neurofibromas, symptomatic spinal neurofibromas, or symptomatic optic pathway gliomas. The most prevalent, and sometimes sole, clinical feature observed in this cohort is multiple café-au-lait macules, with or without skinfold freckles: 85% and 60.5% of the individuals display six or more café-au-lait macules and freckles, respectively. In comparison to established NF1 genotype–phenotype correlations, these patients demonstrate highly similar clinical presentations to those associated with the NF1 pathogenic variant c.2970_2972del (p.Met992del), known for resulting in the mildest clinical features. Despite the generally mild phenotype, cognitive impairment, developmental delay, and/or learning difficulties are still observed in 33.3% of these patients, suggesting that learning challenges remain a prominent aspect of the phenotypic presentation in these individuals and necessitate specialized care. This newly established genotype–phenotype correlation will assist clinicians in improving the management of patients harboring NF1 exon 24 [19a] skipping variants and provide a new therapeutic target for NF1 treatment. Full article
(This article belongs to the Special Issue Neurofibromatosis Type 1 (NF1) Related Tumors)
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22 pages, 4098 KiB  
Article
Synergistic Suppression of NF1 Malignant Peripheral Nerve Sheath Tumor Cell Growth in Culture and Orthotopic Xenografts by Combinational Treatment with Statin and Prodrug Farnesyltransferase Inhibitor PAMAM G4 Dendrimers
by John J. Reiners, Jr., Patricia A. Mathieu, Mary Gargano, Irene George, Yimin Shen, John F. Callaghan, Richard F. Borch and Raymond R. Mattingly
Cancers 2024, 16(1), 89; https://doi.org/10.3390/cancers16010089 - 23 Dec 2023
Viewed by 1245
Abstract
Neurofibromatosis type 1 (NF1) is a disorder in which RAS is constitutively activated due to the loss of the Ras-GTPase-activating activity of neurofibromin. RAS must be prenylated (i.e., farnesylated or geranylgeranylated) to traffic and function properly. Previous studies showed that the anti-growth properties [...] Read more.
Neurofibromatosis type 1 (NF1) is a disorder in which RAS is constitutively activated due to the loss of the Ras-GTPase-activating activity of neurofibromin. RAS must be prenylated (i.e., farnesylated or geranylgeranylated) to traffic and function properly. Previous studies showed that the anti-growth properties of farnesyl monophosphate prodrug farnesyltransferase inhibitors (FTIs) on human NF1 malignant peripheral nerve sheath tumor (MPNST) cells are potentiated by co-treatment with lovastatin. Unfortunately, such prodrug FTIs have poor aqueous solubility. In this study, we synthesized a series of prodrug FTI polyamidoamine generation 4 (PAMAM G4) dendrimers that compete with farnesyl pyrophosphate for farnesyltransferase (Ftase) and assessed their effects on human NF1 MPNST S462TY cells. The prodrug 3-tert-butylfarnesyl monophosphate FTI-dendrimer (i.e., IG 2) exhibited improved aqueous solubility. Concentrations of IG 2 and lovastatin (as low as 0.1 μM) having little to no effect when used singularly synergistically suppressed cell proliferation, colony formation, and induced N-RAS, RAP1A, and RAB5A deprenylation when used in combination. Combinational treatment had no additive or synergistic effects on the proliferation/viability of immortalized normal rat Schwann cells, primary rat hepatocytes, or normal human mammary epithelial MCF10A cells. Combinational, but not singular, in vivo treatment markedly suppressed the growth of S462TY xenografts established in the sciatic nerves of immune-deficient mice. Hence, prodrug farnesyl monophosphate FTIs can be rendered water-soluble by conjugation to PAMAM G4 dendrimers and exhibit potent anti-tumor activity when combined with clinically achievable statin concentrations. Full article
(This article belongs to the Special Issue Neurofibromatosis Type 1 (NF1) Related Tumors)
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19 pages, 2807 KiB  
Article
Drug Responses in Plexiform Neurofibroma Type I (PNF1) Cell Lines Using High-Throughput Data and Combined Effectiveness and Potency
by Paul O. Zamora, Gabriel Altay, Ulisses Santamaria, Nathan Dwarshuis, Hari Donthi, Chang In Moon, Dana Bakalar and Matthew Zamora
Cancers 2023, 15(24), 5811; https://doi.org/10.3390/cancers15245811 - 12 Dec 2023
Viewed by 1944
Abstract
Background: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by heterozygous germline NF1 gene mutations that predispose patients to developing plexiform neurofibromas, which are benign but often disfiguring tumors of the peripheral nerve sheath induced by loss of heterozygosity at the [...] Read more.
Background: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by heterozygous germline NF1 gene mutations that predispose patients to developing plexiform neurofibromas, which are benign but often disfiguring tumors of the peripheral nerve sheath induced by loss of heterozygosity at the NF1 locus. These can progress to malignant peripheral nerve sheath tumors (MPNSTs). There are no approved drug treatments for adults with NF1-related inoperable plexiform neurofibromas, and only one drug (selumetinib), which is an FDA-approved targeted therapy for the treatment of symptomatic pediatric plexiform neurofibromas, highlighting the need for additional drug screening and development. In high-throughput screening, the effectiveness of drugs against cell lines is often assessed by measuring in vitro potency (AC50) or the area under the curve (AUC). However, the variability of dose–response curves across drugs and cell lines and the frequency of partial effectiveness suggest that these measures alone fail to provide a full picture of overall efficacy. Methods: Using concentration–response data, we combined response effectiveness (EFF) and potency (AC50) into (a) a score characterizing the effect of a compound on a single cell line, S = log[EFF/AC50], and (b) a relative score, ΔS, characterizing the relative difference between a reference (e.g., non-tumor) and test (tumor) cell line. ΔS was applied to data from high-throughput screening (HTS) of a drug panel tested on NF1−/− tumor cells, using immortalized non-tumor NF1+/− cells as a reference. Results: We identified drugs with sensitivity, targeting expected pathways, such as MAPK-ERK and PI3K-AKT, as well as serotonin-related targets, among others. The ΔS technique used here, in tandem with a supplemental ΔS web tool, simplifies HTS analysis and may provide a springboard for further investigations into drug response in NF1-related cancers. The tool may also prove useful for drug development in a variety of other cancers. Full article
(This article belongs to the Special Issue Neurofibromatosis Type 1 (NF1) Related Tumors)
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Review

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11 pages, 503 KiB  
Review
Leveraging Neural Crest-Derived Tumors to Identify NF1 Cancer Stem Cell Signatures
by Sajjad Khan, Donia Alson, Li Sun, Caroline Maloney and Daochun Sun
Cancers 2024, 16(21), 3639; https://doi.org/10.3390/cancers16213639 - 29 Oct 2024
Viewed by 643
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Neurofibromatosis Type 1 (NF1) Related Tumors)
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18 pages, 1646 KiB  
Review
The NF1+/- Immune Microenvironment: Dueling Roles in Neurofibroma Development and Malignant Transformation
by Emily E. White and Steven D. Rhodes
Cancers 2024, 16(5), 994; https://doi.org/10.3390/cancers16050994 - 29 Feb 2024
Cited by 1 | Viewed by 2441
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Neurofibromatosis Type 1 (NF1) Related Tumors)
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