Homeostatic iron regulatory protein drives glioblastoma growth via tumor cell-intrinsic and sex-specific responses
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Homeostatic iron regulatory protein drives glioblastoma growth via tumor cell-intrinsic and sex-specific responses. / Troike, Katie M.; Wang, Sabrina Z.; Silver, Daniel J.; Lee, Juyeun; Mulkearns-Hubert, Erin E.; Hajdari, Nicole; Ghosh, Prabar K.; Kay, Kristen E.; Beilis, Julia L.; Mitchell, Sofia E.; Bishop, Christopher W.; Hong, Ellen S.; Artomov, Mykyta; Hubert, Christopher G.; Rajappa, Prajwal; Connor, James R.; Fox, Paul L.; Kristensen, Bjarne W.; Lathia, Justin D.
In: Neuro-Oncology Advances, Vol. 6, No. 1, vdad154, 2024.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Homeostatic iron regulatory protein drives glioblastoma growth via tumor cell-intrinsic and sex-specific responses
AU - Troike, Katie M.
AU - Wang, Sabrina Z.
AU - Silver, Daniel J.
AU - Lee, Juyeun
AU - Mulkearns-Hubert, Erin E.
AU - Hajdari, Nicole
AU - Ghosh, Prabar K.
AU - Kay, Kristen E.
AU - Beilis, Julia L.
AU - Mitchell, Sofia E.
AU - Bishop, Christopher W.
AU - Hong, Ellen S.
AU - Artomov, Mykyta
AU - Hubert, Christopher G.
AU - Rajappa, Prajwal
AU - Connor, James R.
AU - Fox, Paul L.
AU - Kristensen, Bjarne W.
AU - Lathia, Justin D.
N1 - Publisher Copyright: © 2023 The Author(s). Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
PY - 2024
Y1 - 2024
N2 - Background: Glioblastoma (GBM) displays alterations in iron that drive proliferation and tumor growth. Iron regulation is complex and involves many regulatory mechanisms, including the homeostatic iron regulator (HFE) gene, which encodes the homeostatic iron regulatory protein. While HFE is upregulated in GBM and correlates with poor survival outcomes, the function of HFE in GBM remains unclear. Methods: We interrogated the impact of cell-intrinsic Hfe expression on proliferation and survival of intracranially implanted animals through genetic gain- and loss-of-function approaches in syngeneic mouse glioma models, along with in vivo immune assessments. We also determined the expression of iron-associated genes and their relationship to survival in GBM using public data sets and used transcriptional profiling to identify differentially expressed pathways in control compared to Hfe-knockdown cells. Results: Overexpression of Hfe accelerated GBM proliferation and reduced animal survival, whereas suppression of Hfe induced apoptotic cell death and extended survival, which was more pronounced in females and associated with attenuation of natural killer cells and CD8+ T cell activity. Analysis of iron gene signatures in Hfe-knockdown cells revealed alterations in the expression of several iron-associated genes, suggesting global disruption of intracellular iron homeostasis. Further analysis of differentially expressed pathways revealed oxidative stress as the top pathway upregulated following Hfe loss. Hfe knockdown indeed resulted in enhanced 55Fe uptake and generation of reactive oxygen species. Conclusions: These findings reveal an essential function for HFE in GBM cell growth and survival, as well as a sex-specific interaction with the immune response.
AB - Background: Glioblastoma (GBM) displays alterations in iron that drive proliferation and tumor growth. Iron regulation is complex and involves many regulatory mechanisms, including the homeostatic iron regulator (HFE) gene, which encodes the homeostatic iron regulatory protein. While HFE is upregulated in GBM and correlates with poor survival outcomes, the function of HFE in GBM remains unclear. Methods: We interrogated the impact of cell-intrinsic Hfe expression on proliferation and survival of intracranially implanted animals through genetic gain- and loss-of-function approaches in syngeneic mouse glioma models, along with in vivo immune assessments. We also determined the expression of iron-associated genes and their relationship to survival in GBM using public data sets and used transcriptional profiling to identify differentially expressed pathways in control compared to Hfe-knockdown cells. Results: Overexpression of Hfe accelerated GBM proliferation and reduced animal survival, whereas suppression of Hfe induced apoptotic cell death and extended survival, which was more pronounced in females and associated with attenuation of natural killer cells and CD8+ T cell activity. Analysis of iron gene signatures in Hfe-knockdown cells revealed alterations in the expression of several iron-associated genes, suggesting global disruption of intracellular iron homeostasis. Further analysis of differentially expressed pathways revealed oxidative stress as the top pathway upregulated following Hfe loss. Hfe knockdown indeed resulted in enhanced 55Fe uptake and generation of reactive oxygen species. Conclusions: These findings reveal an essential function for HFE in GBM cell growth and survival, as well as a sex-specific interaction with the immune response.
KW - glioblastoma
KW - HFE
KW - iron
KW - reactive oxygen species
KW - sex difference
U2 - 10.1093/noajnl/vdad154
DO - 10.1093/noajnl/vdad154
M3 - Journal article
C2 - 38239626
AN - SCOPUS:85182752963
VL - 6
JO - Neuro-Oncology Advances
JF - Neuro-Oncology Advances
SN - 2632-2498
IS - 1
M1 - vdad154
ER -
ID: 381059167