Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis
A major therapeutic barrier in melanoma is the coexistence of diverse cellular states marked by distinct metabolic traits. Transitioning from a proliferative to an invasive melanoma phenotype is coupled with increased ferroptosis vulnerability. However, the regulatory circuits controlling ferroptosis susceptibility across melanoma cell states are unknown. In this work, we identified Apolipoprotein E (<i>APOE</i>) as the top lipid-metabolism gene segregating the melanoma MITF<sup>high</sup>/AXL<sup>low</sup> proliferative/ferroptosis-resistant from MITF<sup>low</sup>/AXL<sup>high</sup> invasive/ferroptosis-sensitive state. Mechanistically, ApoE secreted by the MITF<sup>high</sup>/AXL<sup>low</sup> cells protects the invasive phenotype from ferroptosis-inducing agents by reducing the content of peroxidation-prone polyunsaturated fatty acids and boosting GPX4 levels both in vitro and in vivo. Whole-exome sequencing indicates that <i>APOE</i><sup>high</sup> expression in patients with melanoma is associated with resistance to ferroptosis, regardless of <i>APOE</i> germline status. In aggregate, we found a ferroptosis-resistance mechanism between melanoma cell states relying on secreted ApoE and <i>APOE</i><sup>high</sup> expression as a potential biomarker for poor ferroptosis response in melanoma.
Authors
- David Nittner (ORCID: https://orcid.org/0000-0002-2939-2453)
- Oliver Edgar Bechter (ORCID: https://orcid.org/0000-0003-0667-3284)
- Jean‐Christophe Marine (ORCID: https://orcid.org/0000-0003-2433-9837)
- Johannes V. Swinnen (ORCID: https://orcid.org/0000-0002-7720-5077)
- Ellen Vervoort (ORCID: https://orcid.org/0000-0001-5031-3150)
- Francesca M. Bosisio (ORCID: https://orcid.org/0000-0002-8874-2003)
- Brent R. Stockwell (ORCID: https://orcid.org/0000-0002-3532-3868)
- Sanket More (ORCID: https://orcid.org/0000-0003-3482-4414)
- D. J. Wouters (ORCID: https://orcid.org/0000-0002-8000-8023)
- Julie Bonnereau (ORCID: https://orcid.org/0000-0002-4750-9061)
- Xander Spotbeen (ORCID: https://orcid.org/0000-0002-1510-967X)
- Stefan Naulaerts (ORCID: https://orcid.org/0000-0002-1880-6374)
- Alejandro Sifrim (ORCID: https://orcid.org/0000-0001-8247-4020)
- Tom Venken (ORCID: https://orcid.org/0000-0003-0773-1810)
- Francesca Rizzollo (ORCID: https://orcid.org/0000-0002-5211-7281)
- Panagiotis Karras (ORCID: https://orcid.org/0000-0002-7642-0875)
- Diether Lambrechts (ORCID: https://orcid.org/0000-0002-3429-302X)
- Jelle Verhoeven (ORCID: https://orcid.org/0000-0003-1534-3340)
- Theo Killian (ORCID: https://orcid.org/0000-0002-7510-175X)
- Maarten Ganne (ORCID: https://orcid.org/0009-0007-9048-7957)
- Patrizia Agostinis (ORCID: https://orcid.org/0000-0003-1314-2115)
Institutions
- Universitair Ziekenhuis Leuven (BE)
- VIB-KU Leuven Center for Cancer Biology (BE)
- VIB-KU Leuven Center for Microbiology (BE)
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- Columbia University (US)
- KU Leuven (BE)
Publication Details
- Journal
- Science Advances
- Published
- 2024-10-16
- DOI
- https://doi.org/10.1126/sciadv.adp6164
- Citations
- 14
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 5.87