Intrinsic Interferon Signaling Regulates the Cell Death and Mesenchymal Phenotype of Glioblastoma Stem Cells

Sabbir Khan; Rajasekaran Mahalingam; Shayak Sen; Emmanuel Martinez-Ledesma; Arshad Khan; Kaitlin Gandy; Frederick F Lang; Erik P Sulman; Kristin D Alfaro-Munoz; Nazanin K Majd; Veerakumar Balasubramaniyan; John F de Groot

doi:10.3390/cancers13215284

Intrinsic Interferon Signaling Regulates the Cell Death and Mesenchymal Phenotype of Glioblastoma Stem Cells

Cancers (Basel). 2021 Oct 21;13(21):5284. doi: 10.3390/cancers13215284.

Authors

Affiliations

¹ Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
² Department of Symptom Research, MD Anderson Cancer Center, The University of Texas, Houston, TX 770030, USA.
³ Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Ave. Morones Prieto 3000, Monterrey 64710, Mexico.
⁴ Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, TX 77030, USA.
⁵ Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
⁶ Department of Radiation Oncology, New York University, New York, NY 10016, USA.
⁷ Department of Neuro-Oncology, University of California, San Francisco, CA 94143, USA.

Abstract

Interferon (IFN) signaling contributes to stemness, cell proliferation, cell death, and cytokine signaling in cancer and immune cells; however, the role of IFN signaling in glioblastoma (GBM) and GBM stem-like cells (GSCs) is unclear. Here, we investigated the role of cancer-cell-intrinsic IFN signaling in tumorigenesis in GBM. We report here that GSCs and GBM tumors exhibited differential cell-intrinsic type I and type II IFN signaling, and high IFN/STAT1 signaling was associated with mesenchymal phenotype and poor survival outcomes. In addition, chronic inhibition of IFN/STAT1 signaling decreased cell proliferation and mesenchymal signatures in GSCs with intrinsically high IFN/STAT1 signaling. IFN-β exposure induced apoptosis in GSCs with intrinsically high IFN/STAT1 signaling, and this effect was abolished by the pharmacological inhibitor ruxolitinib and STAT1 knockdown. We provide evidence for targeting IFN signaling in a specific sub-group of GBM patients. IFN-β may be a promising candidate for adjuvant GBM therapy.

Keywords: STAT1; apoptosis; cell proliferation; glioblastoma; glioma stem-like cell; interferon signaling.