Research Papers:

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

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

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Oncotarget. 2018; 9:22095-22112. https://doi.org/10.18632/oncotarget.25188

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Debolina Ganguly1, Meiyun Fan1, Chuan He Yang1, Blazej Zbytek2, David Finkelstein3, Martine F. Roussel4 and Lawrence M. Pfeffer1

1Department of Pathology and Laboratory Medicine, and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA

2Pathology Group of the Midsouth, Germantown, TN, USA

3Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA

4Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA

Correspondence to:

Lawrence M. Pfeffer, email: [email protected]

Keywords: STAT3; glioblastoma; phosphorylation; gene expression; tumorigenesis

Received: March 19, 2018     Accepted: April 02, 2018     Published: April 24, 2018


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.

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