Reciprocal impacts of telomerase activity and ADRN/MES differentiation state in neuroblastoma tumor biology

Eun Young Yu,Nai-Kong V Cheung,Xi Kathy Zhou,Erik Falck-Pedersen,Syed S Zahid,Sarah Aloe,Neal F Lue

doi:10.1038/s42003-021-02821-8

Eun Young Yu, Nai-Kong V Cheung + Show 5 more

Open Access

https://doi.org/10.1038/s42003-021-02821-8

Copy DOI

Abstract

Telomere maintenance and tumor cell differentiation have been separately implicated in neuroblastoma malignancy. Their mechanistic connection is unclear. We analyzed neuroblastoma cell lines and morphologic subclones representing the adrenergic (ADRN) and mesenchymal (MES) differentiation states and uncovered sharp differences in their telomere protein and telomerase activity levels. Pharmacologic conversion of ADRN into MES cells elicited consistent and robust changes in the expression of telomere-related proteins. Conversely, stringent down-regulation of telomerase activity triggers the differentiation of ADRN into MES cells, which was reversible upon telomerase up-regulation. Interestingly, the MES differentiation state is associated with elevated levels of innate immunity factors, including key components of the DNA-sensing pathway. Accordingly, MES but not ADRN cells can mount a robust response to viral infections in vitro. A gene expression signature based on telomere and cell lineage-related factors can cluster neuroblastoma tumor samples into predominantly ADRN or MES-like groups, with distinct clinical outcomes. Our findings establish a strong mechanistic connection between telomere and differentiation and suggest that manipulating telomeres may suppress malignancy not only by limiting the tumor growth potential but also by inducing tumor cell differentiation and altering its immunogenicity.

Highlights

Telomere maintenance and tumor cell differentiation have been separately implicated in neuroblastoma malignancy
One pair of cell lines is shared between the earlier and more recent studies and their designations support the N/ADRN and S/MES groupings5,10. (For consistency, the ADRN and MES designations are used throughout this study for cell lines that were initially classified according to the N/I/S classification scheme.) Notably, multiple studies implicate the state of tumor cell differentiation in disease progression and treatment response
These include three shelterin components that were over-expressed in ADRN cells relative to MES (TRF1, TRF2 and TPP1), and another component that was elevated in MES (POT1)

Summary

Introduction

Telomere maintenance and tumor cell differentiation have been separately implicated in neuroblastoma malignancy. We analyzed neuroblastoma cell lines and morphologic subclones representing the adrenergic (ADRN) and mesenchymal (MES) differentiation states and uncovered sharp differences in their telomere protein and telomerase activity levels. (For consistency, the ADRN and MES designations are used throughout this study for cell lines that were initially classified according to the N/I/S classification scheme.) Notably, multiple studies implicate the state of tumor cell differentiation in disease progression and treatment response. The ADRN cells tend to predominate at diagnosis and show greater sensitivity to chemotherapies[10,11] Another facet of NB biology that has been strongly implicated in disease progression is telomere maintenance[14,15].

Methods

Results

Conclusion