MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis

Hamed Alborzinia, Andrés F Flórez, Sina Kreth, Lena M Brückner, Umut Yildiz, Moritz Gartlgruber, Dorett I Odoni, Gernot Poschet, Karolina Garbowicz, Chunxuan Shao, Corinna Klein, Jasmin Meier, Petra Zeisberger, Michal Nadler-Holly, Matthias Ziehm, Franziska Paul, Jürgen Burhenne, Emma Bell, Marjan Shaikhkarami, Roberto WürthSabine A Stainczyk, Elisa M Wecht, Jochen Kreth, Michael Büttner, Naveed Ishaque, Matthias Schlesner, Barbara Nicke, Carlo Stresemann, María Llamazares-Prada, Jan H Reiling, Matthias Fischer, Ido Amit, Matthias Selbach, Carl Herrmann, Stefan Wölfl, Kai-Oliver Henrich, Thomas Höfer, Andreas Trumpp, Frank Westermann

Research output: Contribution to journalArticlepeer-review

Abstract

Aberrant expression of MYC transcription factor family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYCN induces massive lipid peroxidation on depletion of cysteine, the rate-limiting amino acid for glutathione (GSH) biosynthesis, and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and iron-dependent type of cell death. The high cysteine demand of MYCN-amplified childhood neuroblastoma is met by uptake and transsulfuration. When uptake is limited, cysteine usage for protein synthesis is maintained at the expense of GSH triggering ferroptosis and potentially contributing to spontaneous tumor regression in low-risk neuroblastomas. Pharmacological inhibition of both cystine uptake and transsulfuration combined with GPX4 inactivation resulted in tumor remission in an orthotopic MYCN-amplified neuroblastoma model. These findings provide a proof of concept of combining multiple ferroptosis targets as a promising therapeutic strategy for aggressive MYCN-amplified tumors.

Original languageEnglish
Pages (from-to)471-485
Number of pages15
JournalNature Cancer
Volume3
Issue number4
DOIs
StatePublished - Apr 2022

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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