A NOTCH feed-forward loop drives reprogramming from adrenergic to mesenchymal state in neuroblastoma

Groningen, Tim van; Akogul, Nurdan; Westerhout, Ellen M.; Chan, Alvin; Hasselt, Nancy E.; Zwijnenburg, Danny; Broekmans, Marloes E.C.; Stroeken, Peter; Haneveld, Franciska; Hooijer, Gerrit K J; Savcı-Heijink, C. Dilara; Lakeman, Arjan; Volckmann, Richard; Sluis, Peter van; Valentijn, Linda J.; Koster, Jan; Versteeg, Rogier; Nes, Johan van

doi:10.1038/s41467-019-09470-w

Cited by 117 publications

(164 citation statements)

References 35 publications

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“…10 The Notch signaling pathway plays an important role in the maintenance of CSCs 565,566 and can induce CSC differentiation. Abnormal activity of the Notch signaling pathway has been observed in many cancers, such as leukemia, 567 glioblastoma, 568,569 breast cancer, 570 lung cancer, 571 ovarian cancer, 572 pancreatic cancer, 573 and colon cancer. 574 At present, there are three major clinical methods used to inhibit Notch signaling, secretase inhibition (γ-secretase inhibitor (GSI)), Notch receptor or ligand antibodies, and combination therapy with other pathways.…”

Section: Agents Targeting Csc-associated Signaling Pathways In Clinicmentioning

confidence: 99%

“…576 MK-0752 is well tolerated and shows targeted inhibition in recurrent pediatric central nervous system tumors. 577 In addition, combining MK-0752 with cisplatin treatment for ovarian cancer, 578,579 docetaxel treatment for locally advanced or metastatic breast cancer, 569 and gemcitabine treatment for ductal adenocarcinoma of the pancreas 580 has shown good efficacy. However, the clinical effect was minimal in patients with advanced solid tumors, 576,581 including metastatic pancreatic cancer.…”

Section: Agents Targeting Csc-associated Signaling Pathways In Clinicmentioning

confidence: 99%

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Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

1,113

998

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Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.Signal Transduction and Targeted Therapy (2020) 5:8; https://doi.

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Section: Agents Targeting Csc-associated Signaling Pathways In Clinicmentioning

confidence: 99%

Section: Agents Targeting Csc-associated Signaling Pathways In Clinicmentioning

confidence: 99%

Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

1,113

998

View full text Add to dashboard Cite

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“…Prior studies have speculated that adrenergic/noradrenergic cells transdifferentiate to mesenchymal/neural crest cells and vice versa 7,8,36,37,41 . This theory was primarily based on spontaneous state polarization of isogenic pairs of cells and forced overexpression experiments using strong lineage associated transcription factors to reprogram cell phenotype such as PHOX2B, PRRX1, ASCL1 and NOTCH3 7,8,36,41 . Our trajectory modelling using single-cell RNA-seq data, and our reclassification approach for H3K27ac landscapes in neuroblastoma cell lines is in support of this theory, albeit by a slightly more complex mechanism involving transitional cells as a transdifferentiation intermediate cell state.…”

Section: Pntsmentioning

confidence: 99%

Single-cell RNA-sequencing of peripheral neuroblastic tumors reveals an aggressive transitional cell state at the junction of an adrenergic-mesenchymal transdifferentiation trajectory

Yuan

Seneviratne

et al. 2020

Preprint

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Peripheral neuroblastic tumors (PNTs) are the most common extracranial solid tumors in early childhood.They represent a spectrum of neural crest derived tumors including neuroblastoma, ganglioneuroblastoma and ganglioneuroma. PNTs exhibit heterogeneity due to interconverting malignant cell states described as adrenergic/nor-adrenergic or mesenchymal/neural crest cell in origin. The factors determining individual patient levels of tumor heterogeneity, their impact on the malignant phenotype, and the presence of other cell states are unknown. Here, single-cell RNA-sequencing analysis of 4267 cells from 7 PNTs demonstrated extensive transcriptomic heterogeneity. Trajectory modelling showed that malignant neuroblasts move between adrenergic and mesenchymal cell states via a novel state that we termed a "transitional" phenotype. Transitional cells are characterized by gene expression programs linked to a sympathoadrenal development, and aggressive tumor phenotypes such as rapid proliferation and tumor dissemination. Among primary bulk tumor patient cohorts, high expression of the transitional gene signature was highly predictive of poor prognosis when compared to adrenergic and mesenchymal expression patterns. High transitional gene expression in neuroblastoma cell lines identified a similar transitional H3K27-acetylation super-enhancer landscape, supporting the concept that PNTs have phenotypic plasticity and transdifferentiation capacity. Additionally, examination of PNT microenvironments, found that neuroblastomas contained low immune cell infiltration, high levels of non-inflammatory macrophages, and low cytotoxic T lymphocyte levels compared with more benign PNT subtypes. Modeling of cell-cell signaling in the tumor microenvironment predicted specific paracrine effects toward the various subtypes of malignant cells, suggesting further cell-extrinsic influences on malignant cell phenotype. Collectively, our study reveals the presence of a previously unrecognized transitional cell state with high malignant potential and an immune cell architecture which serve both as potential biomarkers and therapeutic targets.Introduction Peripheral neuroblastic tumors (PNTs) represent a spectrum of tumors derived from the neural crest and account up to 8-10% of all pediatric malignancies. A salient feature of PNTs is a heterogeneous clinical course ranging from spontaneous regression to persistent disease progression 1 . Histologically, PNTs comprise four variants, including neuroblastoma (NB), ganglioneuroblastoma nodular (GNBn), ganglioneuroblastoma intermixed (GNBi), and ganglioneuroma (GN) 1 . GN and GNBi are low-grade in nature and usually curable by surgical resection alone 2 . In contrast, the most common subtype; NB is often lethal. Despite intensive treatments, the long-term survival of high-risk NB is less than 50% 3 .Around half of high-risk patients relapse after initial treatment response, and salvage therapies for relapsed patients are rarely effective 1 . Moreover, genomics studies comparing longitudinal samples f...

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“…The ability of the two lineages to interconvert may contribute further to therapeutic resistance. In vitro studies of cell lines suggest that adrenergic-to-mesenchymal transitions may be enabled by activation of the NOTCH signaling pathway which is also involved in cell identity choices in development 7 . Despite the clinical relevance, however, the mechanisms underlying plasticity of neuroblastoma tumors remain poorly understood.…”

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confidence: 99%

Malignant Schwann cell precursors mediate intratumoral plasticity in human neuroblastoma

Olsen

Otte

Mei

et al. 2020

Preprint

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Neuroblastoma is a heterogeneous embryonal malignancy and the most deadly tumor of childhood, although a minor subset may show spontaneous differentiation. It arises from the multipotent neural crest lineage during development. Some of this multipotency is retained in neuroblastoma, which can give rise to both adrenergic and mesenchymal tumor cells. The mechanisms enabling such dual fates are unknown, but likely help neuroblastoma to evade existing therapies. To understand neuroblastoma plasticity, we analyzed patient tumors using single-cell transcriptomics. In addition to the heterogeneous adrenergic and mesenchymal

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A NOTCH feed-forward loop drives reprogramming from adrenergic to mesenchymal state in neuroblastoma

Cited by 117 publications

References 35 publications

Targeting cancer stem cell pathways for cancer therapy

Targeting cancer stem cell pathways for cancer therapy

Single-cell RNA-sequencing of peripheral neuroblastic tumors reveals an aggressive transitional cell state at the junction of an adrenergic-mesenchymal transdifferentiation trajectory

Malignant Schwann cell precursors mediate intratumoral plasticity in human neuroblastoma

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