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Transcription Factor-Forced Astrocytic Differentiation Impairs Human Glioblastoma Growth In Vitro and In Vivo

Trovato, Francesco LU ; Stefani, Francesca Romana LU ; Li, Jiaxin LU ; Zetterdahl, Oskar G LU ; Canals, Isaac LU ; Ahlenius, Henrik LU and Bengzon, Johan LU (2023) In Molecular Cancer Therapeutics 22(2). p.274-286
Abstract

Direct cellular reprogramming has recently gained attention of cancer researchers for the possibility to convert undifferentiated cancer cells into more differentiated, postmitotic cell types. While a few studies have attempted reprogramming of glioblastoma (GBM) cells toward a neuronal fate, this approach has not yet been used to induce differentiation into other lineages and in vivo data on reduction in tumorigenicity are limited. Here, we employ cellular reprogramming to induce astrocytic differentiation as a therapeutic approach in GBM. To this end, we overexpressed key transcriptional regulators of astroglial development in human GBM and GBM stem cell lines. Treated cells undergo a remarkable shift in structure, acquiring an... (More)

Direct cellular reprogramming has recently gained attention of cancer researchers for the possibility to convert undifferentiated cancer cells into more differentiated, postmitotic cell types. While a few studies have attempted reprogramming of glioblastoma (GBM) cells toward a neuronal fate, this approach has not yet been used to induce differentiation into other lineages and in vivo data on reduction in tumorigenicity are limited. Here, we employ cellular reprogramming to induce astrocytic differentiation as a therapeutic approach in GBM. To this end, we overexpressed key transcriptional regulators of astroglial development in human GBM and GBM stem cell lines. Treated cells undergo a remarkable shift in structure, acquiring an astrocyte-like morphology with star-shaped bodies and radial branched processes. Differentiated cells express typical glial markers and show a marked decrease in their proliferative state. In addition, forced differentiation induces astrocytic functions such as induced calcium transients and ability to respond to inflammatory stimuli. Most importantly, forced differentiation substantially reduces tumorigenicity of GBM cells in an in vivo xenotransplantation model. The current study capitalizes on cellular plasticity with a novel application in cancer. We take advantage of the similarity between neural developmental processes and cancer hierarchy to mitigate, if not completely abolish, the malignant nature of tumor cells and pave the way for new intervention strategies.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Humans, Glioblastoma/drug therapy, Astrocytes, Transcription Factors/metabolism, Brain Neoplasms/drug therapy, Cell Line, Tumor, Cell Differentiation, Neoplastic Stem Cells/metabolism
in
Molecular Cancer Therapeutics
volume
22
issue
2
pages
274 - 286
publisher
American Association for Cancer Research
external identifiers
  • scopus:85147234359
  • pmid:36508391
ISSN
1538-8514
DOI
10.1158/1535-7163.MCT-21-0903
language
English
LU publication?
yes
additional info
©2022 The Authors; Published by the American Association for Cancer Research.
id
7676bba6-688b-4078-9f4a-8a4493e6bd4d
date added to LUP
2023-02-06 23:07:17
date last changed
2024-04-18 18:34:47
@article{7676bba6-688b-4078-9f4a-8a4493e6bd4d,
  abstract     = {{<p>Direct cellular reprogramming has recently gained attention of cancer researchers for the possibility to convert undifferentiated cancer cells into more differentiated, postmitotic cell types. While a few studies have attempted reprogramming of glioblastoma (GBM) cells toward a neuronal fate, this approach has not yet been used to induce differentiation into other lineages and in vivo data on reduction in tumorigenicity are limited. Here, we employ cellular reprogramming to induce astrocytic differentiation as a therapeutic approach in GBM. To this end, we overexpressed key transcriptional regulators of astroglial development in human GBM and GBM stem cell lines. Treated cells undergo a remarkable shift in structure, acquiring an astrocyte-like morphology with star-shaped bodies and radial branched processes. Differentiated cells express typical glial markers and show a marked decrease in their proliferative state. In addition, forced differentiation induces astrocytic functions such as induced calcium transients and ability to respond to inflammatory stimuli. Most importantly, forced differentiation substantially reduces tumorigenicity of GBM cells in an in vivo xenotransplantation model. The current study capitalizes on cellular plasticity with a novel application in cancer. We take advantage of the similarity between neural developmental processes and cancer hierarchy to mitigate, if not completely abolish, the malignant nature of tumor cells and pave the way for new intervention strategies.</p>}},
  author       = {{Trovato, Francesco and Stefani, Francesca Romana and Li, Jiaxin and Zetterdahl, Oskar G and Canals, Isaac and Ahlenius, Henrik and Bengzon, Johan}},
  issn         = {{1538-8514}},
  keywords     = {{Humans; Glioblastoma/drug therapy; Astrocytes; Transcription Factors/metabolism; Brain Neoplasms/drug therapy; Cell Line, Tumor; Cell Differentiation; Neoplastic Stem Cells/metabolism}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{2}},
  pages        = {{274--286}},
  publisher    = {{American Association for Cancer Research}},
  series       = {{Molecular Cancer Therapeutics}},
  title        = {{Transcription Factor-Forced Astrocytic Differentiation Impairs Human Glioblastoma Growth In Vitro and In Vivo}},
  url          = {{http://dx.doi.org/10.1158/1535-7163.MCT-21-0903}},
  doi          = {{10.1158/1535-7163.MCT-21-0903}},
  volume       = {{22}},
  year         = {{2023}},
}