PDGF signaling inhibits mitophagy in glioblastoma stem cells through N6-methyladenosine

Deguan Lv; Ryan C Gimple; Cuiqing Zhong; Qiulian Wu; Kailin Yang; Briana C Prager; Bhaskar Godugu; Zhixin Qiu; Linjie Zhao; Guoxin Zhang; Deobrat Dixit; Derrick Lee; Jia Z Shen; Xiqing Li; Qi Xie; Xiuxing Wang; Sameer Agnihotri; Jeremy N Rich

doi:10.1016/j.devcel.2022.05.007

PDGF signaling inhibits mitophagy in glioblastoma stem cells through N⁶-methyladenosine

Dev Cell. 2022 Jun 20;57(12):1466-1481.e6. doi: 10.1016/j.devcel.2022.05.007. Epub 2022 Jun 3.

Authors

Deguan Lv¹, Ryan C Gimple², Cuiqing Zhong³, Qiulian Wu⁴, Kailin Yang⁵, Briana C Prager⁶, Bhaskar Godugu⁷, Zhixin Qiu¹, Linjie Zhao¹, Guoxin Zhang⁸, Deobrat Dixit⁸, Derrick Lee¹, Jia Z Shen⁹, Xiqing Li¹⁰, Qi Xie¹¹, Xiuxing Wang¹², Sameer Agnihotri¹³, Jeremy N Rich¹⁴

Affiliations

¹ Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA; Division of Regenerative Medicine, School of Medicine, University of California San Diego, CA 92037, USA.
² Division of Regenerative Medicine, School of Medicine, University of California San Diego, CA 92037, USA; Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
³ Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA; Gene Expression Laboratory, Salk Institute for Biological Studies, San Diego, CA 92037, USA.
⁴ Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA.
⁵ Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH 44195, USA.
⁶ Division of Regenerative Medicine, School of Medicine, University of California San Diego, CA 92037, USA; Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA.
⁷ Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
⁸ Division of Regenerative Medicine, School of Medicine, University of California San Diego, CA 92037, USA.
⁹ Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA 92037, USA.
¹⁰ Division of Regenerative Medicine, School of Medicine, University of California San Diego, CA 92037, USA; Department of Oncology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, Henan 450003, China.
¹¹ Division of Regenerative Medicine, School of Medicine, University of California San Diego, CA 92037, USA; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang 310024, China.
¹² Division of Regenerative Medicine, School of Medicine, University of California San Diego, CA 92037, USA; School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
¹³ Department of Neurological Surgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.
¹⁴ Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA; Division of Regenerative Medicine, School of Medicine, University of California San Diego, CA 92037, USA; Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA. Electronic address: drjeremyrich@gmail.com.

Abstract

Dysregulated growth factor receptor pathways, RNA modifications, and metabolism each promote tumor heterogeneity. Here, we demonstrate that platelet-derived growth factor (PDGF) signaling induces N⁶-methyladenosine (m⁶A) accumulation in glioblastoma (GBM) stem cells (GSCs) to regulate mitophagy. PDGF ligands stimulate early growth response 1 (EGR1) transcription to induce methyltransferase-like 3 (METTL3) to promote GSC proliferation and self-renewal. Targeting the PDGF-METTL3 axis inhibits mitophagy by regulating m⁶A modification of optineurin (OPTN). Forced OPTN expression phenocopies PDGF inhibition, and OPTN levels portend longer survival of GBM patients; these results suggest a tumor-suppressive role for OPTN. Pharmacologic targeting of METTL3 augments anti-tumor efficacy of PDGF receptor (PDGFR) and mitophagy inhibitors in vitro and in vivo. Collectively, we define PDGF signaling as an upstream regulator of oncogenic m⁶A regulation, driving tumor metabolism to promote cancer stem cell maintenance, highlighting PDGF-METTL3-OPTN signaling as a GBM therapeutic target.

Keywords: (m(6)A); METTL3; N6-methyladenosine; OPTN; PDGF; PDGFRβ; cancer stem cell; glioblastoma; glioblastoma stem cell; mitophagy; optineurin.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Adenosine / analogs & derivatives
Brain Neoplasms* / metabolism
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Glioblastoma* / genetics
Glioblastoma* / metabolism
Glioblastoma* / pathology
Humans
Methyltransferases / metabolism
Mitophagy
Neoplastic Stem Cells / pathology
Platelet-Derived Growth Factor / metabolism
Platelet-Derived Growth Factor / pharmacology

Substances

Platelet-Derived Growth Factor
N-methyladenosine
Methyltransferases
METTL3 protein, human
Adenosine

Abstract

Publication types

MeSH terms

Substances

Grants and funding