Schwann cell plasticity regulates neuroblastic tumor cell differentiation via epidermal growth factor-like protein 8

Abstract

The remarkable plasticity of Schwann cells (SCs) enables the acquisition of repair-specific functions essential for peripheral nerve regeneration. We hypothesized that this plastic potential is manifested in stromal SCs found within mostly benign-behaving peripheral neuroblastic tumors. To shed light on the cellular state and impact of stromal SCs, we performed transcriptome profiling of human ganglioneuromas and neuroblastomas, rich and poor in SC-stroma, respectively, as well as human injured nerves, rich in repair SCs. The results revealed a nerve repair-characteristic gene expression signature of stromal SCs. In turn, primary repair SCs had a pro-differentiating and anti-proliferative effect on aggressive neuroblastoma cell lines after direct and trans-well co-culture. Within the pool of secreted stromal/repair SC factors, we identified EGFL8, a matricellular protein with so far undescribed function, to induce neuronal differentiation of neuroblastoma cell lines. This study indicates that stromal SCs underwent an adaptive response to neuroblastic tumor cells and exert repairassociated functions in the microenvironment resulting in a benign tumor development.Further, SC-derived factors, such as EGFL8, may be of therapeutic value for aggressive, SCstroma poor neuroblastomas. SYNOPSISIn order to investigate the nature of stromal Schwann cells in benign peripheral neuroblastic tumors (ganglioneuromas), we compared the cellular state of stromal Schwann cells with repair-associated Schwann cells emerging in peripheral nerves after injury. • Stromal Schwann cells in ganglioneuromas and repair Schwann cells in injured nervesshare the expression of nerve repair-associated genes.• Neuroblastoma cell lines, derived from high-risk metastatic peripheral neuroblastic tumors (neuroblastomas), respond to primary repair Schwann cells and their secretome with increased neuronal differentiation and reduced proliferation. • Stromal and repair Schwann cells express the matricellular protein EGFL8, which is capable to induce neuronal differentiation of neuroblastoma cell lines in recombinant form. Human Schwann Cell Plasticity Weiss, Taschner-Mandl et al Page 4 of 48 ABBREVIATIONS SC … Schwann cell NT … peripheral neuroblastic tumor NB … neuroblastoma GNB … ganglioneuroblatoma GN … ganglioneuroma RT … room temperature IF … immunofluorescence THE PAPER EXPLAINED ProblemIn response to peripheral nerve damage, Schwann cells (SCs) are able to transform into specialized repair cells essential for nerve cell regeneration. Our previous studies indicated that this reactive/adaptive potential of human SCs is not restricted to injured nerve cells but also emerges in response to peripheral neuroblastic tumor cells. The usually benign subtypes of peripheral neuroblastic tumors, i.e. ganglioneuroblastomas and ganglioneuromas, contain neuronal differentiating tumor cells and are pervaded by various portions of stromal SCs. Of note, the amount of stromal SCs correlates with a favorable tumor behavior and increased patient survival, whereas aggre...

Whole-exome sequencing in 16,511 individuals reveals a role of the HTRA1 protease and its substrate EGFL8 in brain white matter hyperintensities

“…The biological function of EGFL8, encoding 'EGF Like Domain Multiple 8', remains largely unexplored. A recent study (Weiss et al, 2021) found EGFL8 to act as neuritogen and to rewire cellular signaling by activating kinases involved in neurogenesis. Notably, EGFL7, a close paralogue of EGFL8, which is likewise expressed in brain vessels, has been implicated in various vascular functions including angiogenesis and elastogenesis (Parker et al, 2004;Lelievre et al, 2008;Nichol and Stuhlmann, 2012).…”

Artificial Tumor Microenvironments in Neuroblastoma

“…It has been suggested that neuroblastomas expressing NKT1 may recruit Schwann cells to the TME through secretion of neural growth factor and in turn, the migrated Schwann cells will promote differentiation of the tumor [ 48 ]. Weiss et al further show that the Schwann cells in the neuroblastoma TME promoted tumor cell apoptosis, inhibited proliferation, and supported neurite outgrowth (a marker of neuroblastoma differentiation) via epidermal growth factor-like protein 8 [ 49 ]. The interaction between neuroblastoma and Schwann cells is not always pro-differentiation, as neuroblastoma may secrete HGMB1 into the TME to induce autophagy of the Schwann cells and ultimately promote tumor proliferation [ 50 ].…”

Mechanisms involved in selecting and maintaining neuroblastoma cancer stem cell populations, and perspectives for therapeutic targeting

“…This suggests different origins for NBs that develop within the sympathetic chain and adrenal medulla, further supported by differences in dissemination and migratory behaviour, illustrated by the migratory behaviour of NB cells transplanted onto the avian embryo NC, which migrate to form primary tumours in sympathetic ganglia, then exhibit secondary migration along nerves and blood vessels, reminiscent of Schwann progenitor migratory behaviour[ 9 , 78 , 79 , 81 ]. Malignant Sox10 expressing Schwann cell progenitor subpopulations with stem cell-like features have also been reported in human NBs, connecting adrenergic and mesenchymal compartments through transitions, reminiscent of Schwann cell progenitors[ 82 ], and may or may not be involved in the formation of the Schwannian stroma that characterises favourable NBs and benign ganglioneuromas[ 83 , 84 ]. Therefore, NBs originate from either NCSCs, SA or Schwann cell progenitors or from NC cells converted into CNS SCs by aberrant N-Myc expression with full transformation within target tissues (Figure 3 ).…”