Title | Reciprocal impacts of telomerase activity and ADRN/MES differentiation state in neuroblastoma tumor biology. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Yu EYoung, Zahid SS, Aloe S, Falck-Pedersen E, Zhou XKathy, Cheung N-KV, Lue NF |
Journal | Commun Biol |
Volume | 4 |
Issue | 1 |
Pagination | 1315 |
Date Published | 2021 Nov 19 |
ISSN | 2399-3642 |
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. |
DOI | 10.1038/s42003-021-02821-8 |
Alternate Journal | Commun Biol |
PubMed ID | 34799676 |
Grant List | N/A / / Cornell University / N/A / / Cornell University / N/A / / Cornell University / 1UL1 TR002384-01 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / |
Submitted by jom4013 on November 22, 2021 - 11:43am