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

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

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

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.

Original language	English (US)
Article number	5284
Journal	Cancers
Volume	13
Issue number	21
DOIs	https://doi.org/10.3390/cancers13215284
State	Published - Nov 1 2021

Keywords

Apoptosis
Cell proliferation
Glioblastoma
Glioma stem-like cell
Interferon signaling
STAT1

ASJC Scopus subject areas

Oncology
Cancer Research

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title = "Intrinsic interferon signaling regulates the cell death and mesenchymal phenotype of glioblastoma stem cells",

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 = "Apoptosis, Cell proliferation, Glioblastoma, Glioma stem-like cell, Interferon signaling, STAT1",

author = "Sabbir Khan and Rajasekaran Mahalingam and Shayak Sen and Emmanuel Martinez-Ledesma and Arshad Khan and Kaitlin Gandy and Lang, {Frederick F.} and Sulman, {Erik P.} and Alfaro-Munoz, {Kristin D.} and Majd, {Nazanin K.} and Veerakumar Balasubramaniyan and {de Groot}, {John F.}",

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year = "2021",

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doi = "10.3390/cancers13215284",

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AU - Khan, Sabbir

AU - Mahalingam, Rajasekaran

AU - Sen, Shayak

AU - Martinez-Ledesma, Emmanuel

AU - Khan, Arshad

AU - Gandy, Kaitlin

AU - Lang, Frederick F.

AU - Sulman, Erik P.

AU - Alfaro-Munoz, Kristin D.

AU - Majd, Nazanin K.

AU - Balasubramaniyan, Veerakumar

AU - de Groot, John F.

PY - 2021/11/1

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N2 - 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.

AB - 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.

KW - Apoptosis

KW - Cell proliferation

KW - Glioblastoma

KW - Glioma stem-like cell

KW - Interferon signaling

KW - STAT1

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Intrinsic interferon signaling regulates the cell death and mesenchymal phenotype of glioblastoma stem cells

Abstract

Keywords

ASJC Scopus subject areas

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