NF1 heterozygosity fosters de novo tumorigenesis but impairs malignant transformation

Brosseau, Jean Philippe; Liao, Chung Ping; Wang, Yong; Ramani, Vijay; Vandergriff, Travis; Lee, Michelle; Patel, Abhinav; Ariizumi, Kiyoshi; Le, Lu Q.

doi:10.1038/s41467-018-07452-y

Cited by 38 publications

(35 citation statements)

References 64 publications

(73 reference statements)

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“…They also suggested the presence of T cells in human tumor samples. This has previously been described in mouse models of NF1 tumors [75]. In humans, systemic T cell burden has been found to correlate with NF1 nerve sheath tumor progression; T cell presence has also been observed in NF1 gliomas [10,76].…”

Section: Discussionmentioning

confidence: 53%

Integrative Analysis Identifies Candidate Tumor Microenvironment and Intracellular Signaling Pathways that Define Tumor Heterogeneity in NF1

Banerjee

Allaway

Taroni

et al. 2020

Genes

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Neurofibromatosis type 1 (NF1) is a monogenic syndrome that gives rise to numerous symptoms including cognitive impairment, skeletal abnormalities, and growth of benign nerve sheath tumors. Nearly all NF1 patients develop cutaneous neurofibromas (cNFs), which occur on the skin surface, whereas 40–60% of patients develop plexiform neurofibromas (pNFs), which are deeply embedded in the peripheral nerves. Patients with pNFs have a ~10% lifetime chance of these tumors becoming malignant peripheral nerve sheath tumors (MPNSTs). These tumors have a severe prognosis and few treatment options other than surgery. Given the lack of therapeutic options available to patients with these tumors, identification of druggable pathways or other key molecular features could aid ongoing therapeutic discovery studies. In this work, we used statistical and machine learning methods to analyze 77 NF1 tumors with genomic data to characterize key signaling pathways that distinguish these tumors and identify candidates for drug development. We identified subsets of latent gene expression variables that may be important in the identification and etiology of cNFs, pNFs, other neurofibromas, and MPNSTs. Furthermore, we characterized the association between these latent variables and genetic variants, immune deconvolution predictions, and protein activity predictions.

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Section: Discussionmentioning

confidence: 53%

Integrative Analysis Identifies Candidate Tumor Microenvironment and Intracellular Signaling Pathways that Define Tumor Heterogeneity in NF1

Banerjee

Allaway

Taroni

et al. 2020

Genes

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“…On the other hand, independent laboratories have demonstrated that the microenvironment modulates neurofibroma development, thus making it a potential target for treatment. Mice with a heterozygous mutation for Nf1 (mimicking NF1 patients) develop neurofibroma faster than their wild type littermates [3][4][5]. The cellular and molecular mechanisms by which the microenvironment promotes neurofibroma development, however, is unclear [6].…”

Section: Introductionmentioning

confidence: 99%

Human cutaneous neurofibroma matrisome revealed by single-cell RNA sequencing

Brosseau

Sathe

Wang

et al. 2021

acta neuropathol commun

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Neurofibromatosis Type I (NF1) is a neurocutaneous genetic syndrome characterized by a wide spectrum of clinical presentations, including benign peripheral nerve sheath tumor called neurofibroma. These tumors originate from the Schwann cell lineage but other cell types as well as extracellular matrix (ECM) in the neurofibroma microenvironment constitute the majority of the tumor mass. In fact, collagen accounts for up to 50% of the neurofibroma’s dry weight. Although the presence of collagens in neurofibroma is indisputable, the exact repertoire of ECM genes and ECM-associated genes (i.e. the matrisome) and their functions are unknown. Here, transcriptome profiling by single-cell RNA sequencing reveals the matrisome of human cutaneous neurofibroma (cNF). We discovered that classic pro-fibrogenic collagen I myofibroblasts are rare in neurofibroma. In contrast, collagen VI, a pro-tumorigenic ECM, is abundant and mainly secreted by neurofibroma fibroblasts. This study also identified potential cell type-specific markers to further elucidate the biology of the cNF microenvironment.

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“…They also suggested the presence of T cells in human tumor samples. This has previously been described in mouse models of NF1 tumors [57] . Furthermore, in humans, systemic T-cell burden has been found to correlate with NF1 nerve sheath tumor progression; T-cells have also been observed in NF1 gliomas [10,58] .…”

Section: Discussionmentioning

confidence: 54%

Integrative analysis identifies candidate tumor microenvironment and intracellular signaling pathways that define tumor heterogeneity in NF1

Banerjee

Allaway

Taroni

et al. 2020

Preprint

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Neurofibromatosis type 1 is a monogenic syndrome that gives rise to numerous symptoms including cognitive impairment, skeletal abnormalities, and growth of benign nerve sheath tumors. Nearly all NF1 patients develop cutaneous neurofibromas (cNFs), which occur on the skin surface, while 40-60% of patients develop plexiform neurofibromas (pNFs) which are deeply embedded in the peripheral nerves. Patients with pNFs have a ~10% lifetime chance of these tumors becoming malignant peripheral nerve sheath tumors (MPNSTs). These tumors have a severe prognosis and few treatment options other than surgery. Given the lack of therapeutic options available to patients with these tumors, identification of druggable pathways or other key molecular features could aid ongoing therapeutic discovery studies. In this work, we used statistical and machine learning methods to analyze 77 NF1 tumors with genomic data to characterize key signaling pathways that distinguish these tumors and identify candidates for drug development. We identified subsets of latent gene expression variables that may be important in the identification and etiology of cNFs, pNFs, other neurofibromas, and MPNSTs. Furthermore, we characterized the association between these latent variables and genetic variants, immune deconvolution predictions, and protein activity predictions.

show abstract

NF1 heterozygosity fosters de novo tumorigenesis but impairs malignant transformation

Cited by 38 publications

References 64 publications

Integrative Analysis Identifies Candidate Tumor Microenvironment and Intracellular Signaling Pathways that Define Tumor Heterogeneity in NF1

Integrative Analysis Identifies Candidate Tumor Microenvironment and Intracellular Signaling Pathways that Define Tumor Heterogeneity in NF1

Human cutaneous neurofibroma matrisome revealed by single-cell RNA sequencing

Integrative analysis identifies candidate tumor microenvironment and intracellular signaling pathways that define tumor heterogeneity in NF1

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