Single-cell atlas of developing murine adrenal gland reveals relation of Schwann cell precursor signature to neuroblastoma phenotype

Hanemaaijer, Evelyn S.; Margaritis, Thanasis; Sanders, Karin; Bos, Frank L.; Candelli, Tito; Al-Saati, Hanin; Noesel, Max M. van; Meyer‐Wentrup, Friederike; Wetering, Marc van de; Holstege, Frank C.P.; Clevers, Hans

doi:10.1073/pnas.2022350118

Cited by 66 publications

(63 citation statements)

References 60 publications

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“…The finding of extra-adrenal tissue reported in our study might also be relevant to the not infrequent occurrence of chromaffin cell tumours at extra-adrenal sites ( Tischler 2008 ). Although a correlation between the distribution of chromaffin tissue and paraganglioma has been reported ( Coupland 1965 ), our data raises the possibility that these extra-adrenal PGLs may arise due to impaired migration and differentiation of sympathetic precursors that would normally populate the adrenal primordia to acquire features of mature, adrenergic chromaffin cells during development ( Furlan et al 2017 , Hanemaaijer et al 2021 ).…”

Section: Discussionmentioning

confidence: 54%

“…TH + chromaffin cells migrate through the adrenal cortex to reach their final destination in the AM ( Furlan et al 2017 , Hanemaaijer et al 2021 ), during which time they acquire Pnmt expression in the final stages of maturation to become adrenergic ( Verhofstad et al 1979 ). We therefore considered whether the abnormally located TH + cells (both within and directly adjacent to the AG) represent abnormal migration of chromaffin cells and that the reduction in Pnmt might also reflect failure to acquire Pnmt due to dysregulated/arrested development with Phd2 inactivation.…”

Section: Resultsmentioning

confidence: 99%

“…We next considered whether this expression pattern extended to other genes which were dysregulated in AMs with loss of Phd2 . The following genes were selected for analysis: Hif-2α , since its upregulation is characteristic of VHL-associated neoplasia including PCCs ( Toledo 2017 ); Vegfa and Rgs5 , since these are reported HIF target genes ( Jin et al 2009 , Fielding et al 2018 ) and the latter is also a proposed regulator of chromaffin cell differentiation ( Chan et al 2019 , Hanemaaijer et al 2021 ). These experiments revealed a striking inverse pattern of gene expression, with Hif-2α and Rgs5 mRNA being expressed only in the normal AM cells that do not express Pnmt ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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Developmental role of PHD2 in the pathogenesis of pseudohypoxic pheochromocytoma

Eckardt

Prange-Barczynska

Hodson

et al. 2021

Endocrine-Related Cancer

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Despite a general role for the HIF hydroxylase system in cellular oxygen sensing and tumour hypoxia, cancer-associated mutations of genes in this pathway, including PHD2, PHD1, EPAS1 (encoding HIF-2α) are highly tissue-restricted, being observed in pseudohypoxic pheochromocytoma and paraganglioma (PPGL) but rarely, if ever, in other tumours. In an effort to understand that paradox and gain insights into the pathogenesis of pseudohypoxic PPGL, we constructed mice in which the principal HIF prolyl hydroxylase, Phd2, is inactivated in the adrenal medulla using TH-restricted Cre recombinase. Investigation of these animals revealed a gene expression pattern closely mimicking that of pseudohypoxic PPGL. Spatially resolved analyses demonstrated a binary distribution of two contrasting patterns of gene expression among adrenal medullary cells. Phd2 inactivation resulted in a marked shift in this distribution towards a Pnmt−/Hif-2α+/Rgs5+ population. This was associated with morphological abnormalities of adrenal development, including ectopic TH+ cells within the adrenal cortex and external to the adrenal gland. These changes were ablated by combined inactivation of Phd2 with Hif-2α, but not Hif-1α. However, they could not be reproduced by inactivation of Phd2 in adult life, suggesting that they arise from dysregulation of this pathway during adrenal development. Together with the clinical observation that pseudohypoxic PPGL manifests remarkably high heritability, our findings suggest that this type of tumour likely arises from dysregulation of a tissue-restricted action of the PHD2/HIF-2α pathway affecting adrenal development in early life and provides a model for the study of the relevant processes.

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Section: Discussionmentioning

confidence: 54%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Developmental role of PHD2 in the pathogenesis of pseudohypoxic pheochromocytoma

Eckardt

Prange-Barczynska

Hodson

et al. 2021

Endocrine-Related Cancer

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“…Presently, conflicting results have been published [ 57 , 58 , 59 , 60 , 61 ] regarding their developmental origin, but definitive results will certainly come in the next few years. As for the plasticity, it is interesting to note that already in 2007, Martinez et al described the presence of GD2+/CD45− cells with mesenchymal phenotype in the BM of children with NB [ 62 ].…”

Section: Bm-infiltrating Metastatic Nb Cellsmentioning

confidence: 99%

Bone Marrow Environment in Metastatic Neuroblastoma

Brignole

Pastorino

Perri

et al. 2021

Cancers

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The study of the interactions occurring in the BM environment has been facilitated by the peculiar nature of metastatic NB. In fact: (i) metastases are present at diagnosis; (ii) metastases are confined in a very specific tissue, the BM, suggestive of a strong attraction and possibility of survival; (iii) differently from adult cancers, NB metastases are available because the diagnostic procedures require morphological examination of BM; (iv) NB metastatic cells express surface antigens that allow enrichment of NB metastatic cells by immune–magnetic separation; and (v) patients with localized disease represent an internal control to discriminate specific alterations occurring in the metastatic niche from generic alterations determined by the neoplastic growth at the primary site. Here, we first review the information regarding the features of BM-infiltrating NB cells. Then, we focus on the alterations found in the BM of children with metastatic NB as compared to healthy children and children with localized NB. Specifically, information regarding all the BM cell populations and their sub-sets will be first examined in the context of BM microenvironment in metastatic NB. In the last part, the information regarding the soluble factors will be presented.

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“…While the majority of NBs are found in the adrenal gland, the cell of origin for NB has not been uncovered. Recent advances in single-cell profiling suggested that more benign neuroblastomas resemble Schwann cell precursors [ 2 ]. However, a large study comparing neuroblastoma and normal fetal adrenal tissue revealed a pan-neuroblastoma pattern, suggesting a common precursor of human NB [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

NTRK1/TrkA Signaling in Neuroblastoma Cells Induces Nuclear Reorganization and Intra-Nuclear Aggregation of Lamin A/C

Funke

Bracht

Oeck

et al. 2021

Cancers

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(1) Background: Neuroblastomas (NBs) are the most common extracranial solid tumors of children. The amplification of the Myc-N proto-oncogene (MYCN) is a major driver of NB aggressiveness, while high expression of the neurotrophin receptor NTRK1/TrkA is associated with mild disease courses. The molecular effects of NTRK1 signaling in MYCN-amplified NB, however, are still poorly understood and require elucidation. (2) Methods: Inducible NTRK1 expression was realized in four NB cell lines with (IMR5, NGP) or without MYCN amplification (SKNAS, SH-SY5Y). Proteome and phosphoproteome dynamics upon NTRK1 activation by its ligand, NGF, were analyzed in a time-dependent manner in IMR5 cells. Target validation by immunofluorescence staining and automated image processing was performed using the three other NB cell lines. (3) Results: In total, 230 proteins and 134 single phosphorylated class I phosphosites were found to be significantly regulated upon NTRK1 activation. Among known NTRK1 targets, Stathmin and the neurosecretory protein VGF were recovered. Additionally, we observed the upregulation and phosphorylation of Lamin A/C (LMNA) that accumulated inside nuclear foci. (4) Conclusions: We provide a comprehensive picture of NTRK1-induced proteome and phosphoproteome dynamics. The phosphorylation of LMNA within nucleic aggregates was identified as a prominent feature of NTRK1 signaling independent of the MYCN status of NB cells.

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Single-cell atlas of developing murine adrenal gland reveals relation of Schwann cell precursor signature to neuroblastoma phenotype

Cited by 66 publications

References 60 publications

Developmental role of PHD2 in the pathogenesis of pseudohypoxic pheochromocytoma

Developmental role of PHD2 in the pathogenesis of pseudohypoxic pheochromocytoma

Bone Marrow Environment in Metastatic Neuroblastoma

NTRK1/TrkA Signaling in Neuroblastoma Cells Induces Nuclear Reorganization and Intra-Nuclear Aggregation of Lamin A/C

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