The critical role that STAT3 plays in glioma-initiating cells: STAT3 addiction in glioma

Debolina Ganguly, Meiyun Fan, Chuan Yang, Blazej Zbytek, David Finkelstein, Martine F. Roussel, Lawrence Pfeffer

Research output: Contribution to journalArticle

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Abstract

Glioma-Initiating Cells (GICs) are thought to be responsible for tumor initiation, progression and recurrence in glioblastoma (GBM). In previous studies, we reported the constitutive phosphorylation of the STAT3 transcription factor in GICs derived from GBM patient-derived xenografts, and that STAT3 played a critical role in GBM tumorigenesis. In this study, we show that CRISPR/Cas9-mediated deletion of STAT3 in an established GBM cell line markedly inhibited tumorigenesis by intracranial injection but had little effect on cell proliferation in vitro. Tumorigenesis was rescued by the enforced expression of wild-type STAT3 in cells lacking STAT3. In contrast, GICs were highly addicted to STAT3 and upon STAT3 deletion GICs were non-viable. Moreover, we found that STAT3 was constitutively activated in GICs by phosphorylation on both tyrosine (Y705) and serine (S727) residues. Therefore, to study STAT3 function in GICs we established an inducible system to knockdown STAT3 expression (iSTAT3-KD). Using this approach, we demonstrated that Y705-STAT3 phosphorylation was critical and indispensable for GIC-induced tumor formation. Both phosphorylation sites in STAT3 promoted GIC proliferation in vitro. We further showed that S727-STAT3 phosphorylation was Y705-dependent. Targeted microarray and RNA sequencing revealed that STAT3 activated cell-cycle regulator genes, and downregulated genes involved in the interferon response, the hypoxia response, the TGFβ pathway, and remodeling of the extracellular matrix. Since STAT3 is an important oncogenic driver of GBM, the identification of these STAT3 regulated pathways in GICs will inform the development of better targeted therapies against STAT3 in GBM and other cancers.

Original languageEnglish (US)
Pages (from-to)22110-22127
Number of pages18
JournalOncotarget
Volume9
Issue number31
DOIs
StatePublished - Apr 24 2018

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Glioma
Glioblastoma
Phosphorylation
Carcinogenesis
Clustered Regularly Interspaced Short Palindromic Repeats
Cell Proliferation
RNA Sequence Analysis
cdc Genes
STAT3 Transcription Factor
Neoplastic Stem Cells
Regulator Genes
Heterografts
Serine
Interferons
Extracellular Matrix
Tyrosine
Neoplasms
Down-Regulation
Recurrence
Cell Line

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

The critical role that STAT3 plays in glioma-initiating cells : STAT3 addiction in glioma. / Ganguly, Debolina; Fan, Meiyun; Yang, Chuan; Zbytek, Blazej; Finkelstein, David; Roussel, Martine F.; Pfeffer, Lawrence.

In: Oncotarget, Vol. 9, No. 31, 24.04.2018, p. 22110-22127.

Research output: Contribution to journalArticle

Ganguly, Debolina ; Fan, Meiyun ; Yang, Chuan ; Zbytek, Blazej ; Finkelstein, David ; Roussel, Martine F. ; Pfeffer, Lawrence. / The critical role that STAT3 plays in glioma-initiating cells : STAT3 addiction in glioma. In: Oncotarget. 2018 ; Vol. 9, No. 31. pp. 22110-22127.
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