Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation

Wu, Jianqiang; Keng, Vincent W.; Patmore, Deanna M.; Kendall, Jed J.; Patel, Akhil; Jousma, Edwin; Jessen, Walter J.; Choi, Kwangmin; Tschida, Barbara R.; Silverstein, Kevin A.T.; Fan, Danhua; Schwartz, Eric; Fuchs, James R.; Zou, Yuanshu; Kim, Miok; Dombi, Eva; Levy, David E.; Huang, Gang; Cancelas, José A.; Stemmer‐Rachamimov, Anat; Spinner, Robert J.; Largaespada, David A.; Ratner, Nancy

doi:10.1016/j.celrep.2016.01.074

Cited by 54 publications

(59 citation statements)

References 40 publications

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“…In macrophages, perturbation of the balance between phospho-STAT1 and phospho-STAT3 can redirect signaling. In neurofibroma macrophages, neither Stat1 nor the Stat1 target gene Il10 were differentially expressed; however, phospho-STAT3 is elevated58. Given that IFN-γ is elevated in neurofibroma yet IL10 is not, an IFN-γ-dependent STAT1-independent pathway may be relevant59.…”

Section: Discussionmentioning

confidence: 93%

An inflammatory gene signature distinguishes neurofibroma Schwann cells and macrophages from cells in the normal peripheral nervous system

Choi

Komurov

Fletcher

et al. 2017

Sci Rep

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Neurofibromas are benign peripheral nerve tumors driven by NF1 loss in Schwann cells (SCs). Macrophages are abundant in neurofibromas, and macrophage targeted interventions may have therapeutic potential in these tumors. We generated gene expression data from fluorescence-activated cell sorted (FACS) SCs and macrophages from wild-type and mutant nerve and neurofibroma to identify candidate pathways involved in SC-macrophage cross-talk. While in 1-month-old Nf1 mutant nerve neither SCs nor macrophages significantly differed from their normal counterparts, both macrophages and SCs showed significantly altered cytokine gene expression in neurofibromas. Computationally reconstructed SC-macrophage molecular networks were enriched for inflammation-associated pathways. We verified that neurofibroma SC conditioned medium contains macrophage chemo-attractants including colony stimulation factor 1 (CSF1). Network analysis confirmed previously implicated pathways and predict novel paracrine and autocrine loops involving cytokines, chemokines, and growth factors. Network analysis also predicted a central role for decreased type-I interferon signaling. We validated type-I interferon expression in neurofibroma by protein profiling, and show that treatment of neurofibroma-bearing mice with polyethylene glycolyated (PEGylated) type-I interferon-α2b reduces the expression of many cytokines overexpressed in neurofibroma. These studies reveal numerous potential targetable interactions between Nf1 mutant SCs and macrophages for further analyses.

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Section: Discussionmentioning

confidence: 93%

An inflammatory gene signature distinguishes neurofibroma Schwann cells and macrophages from cells in the normal peripheral nervous system

Choi

Komurov

Fletcher

et al. 2017

Sci Rep

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“…35 STAT3 has been shown to stimulate expression of b-catenin and repress GSK3b transcription. [38][39][40] Such mechanisms would thus be likely candidates to explain the observed synergistic activation of b-catenin in human CD49f 1 CB cells exposed to the 5 GFs studied here.…”

Section: Cd49fmentioning

confidence: 88%

Distinct signaling programs control human hematopoietic stem cell survival and proliferation

Knapp

Hammond

Aghaeepour

et al. 2017

Blood

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“…For example, the neurofibroma model was used in an insertional mutagenesis screen to identify new effector pathways in NF1 -mutant tumors. Using this approach a Stat3-Arid1b/β-catenin pathway was found to be essential for neurofibroma formation (22), supporting the investigation of JAK/STAT and Wnt/β-catenin pathway inhibitors as potential therapeutic agents. Human genetic and mouse modeling studies also identified the epigenetic regulator, SUZ12, as an important tumor suppressor in MPNSTs (23).…”

Section: Successful Target Identification and Translationmentioning

confidence: 70%

A Collaborative Model for Accelerating the Discovery and Translation of Cancer Therapies

et al. 2017

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Preclinical studies using genetically engineered mouse models (GEMMs) have the potential to expedite the development of effective new therapies; however, they are not routinely integrated into drug development pipelines. GEMMs may be particularly valuable for investigating treatments for less common cancers, which frequently lack alternative faithful models. Here we describe a multi-center cooperative group that has successfully leveraged the expertise and resources from philanthropic foundations, academia, and industry to advance therapeutic discovery and translation using GEMMs as a preclinical platform. This effort, known as the Neurofibromatosis Preclinical Consortium (NFPC), was established to accelerate new treatments for tumors associated with neurofibromatosis type 1 (NF1). At its inception, there were no effective treatments for NF1 and few promising approaches on the horizon. Since 2008 participating labs have conducted 95 preclinical trials of 38 drugs or combinations through collaborations with 18 pharmaceutical companies. Importantly, these studies have identified 13 therapeutic targets, which have inspired 16 clinical trials. This review outlines the opportunities and challenges of building this type of consortium and highlights how it can accelerate clinical translation. We believe that this strategy of foundation-academic-industry partnering is generally applicable to many diseases and has the potential to markedly improve the success of therapeutic development.

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Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation

Cited by 54 publications

References 40 publications

An inflammatory gene signature distinguishes neurofibroma Schwann cells and macrophages from cells in the normal peripheral nervous system

An inflammatory gene signature distinguishes neurofibroma Schwann cells and macrophages from cells in the normal peripheral nervous system

Distinct signaling programs control human hematopoietic stem cell survival and proliferation

A Collaborative Model for Accelerating the Discovery and Translation of Cancer Therapies

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