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Palma, M.* ; Chaufan, M.* ; Breuer, C.B.* ; Müller, S.* ; Sabatier, M.* ; Fraser, C.S.* ; Szylo, K.J.* ; Yavari, M.* ; Carmona, A.* ; Kaur, M.* ; Melo, L.M.N.* ; Cansiz, F.* ; Monge-Lorenzo, J.* ; Flores, M.A.E.* ; Mishima, E. ; Nakamura, T. ; Proneth, B. ; Labrado, M.* ; Liang, Y.* ; Cayting, N.* ; Zheng, L.* ; Cañeque, T.* ; Colombeau, L.* ; Wahida, A. ; Friedmann Angeli, J.P.* ; Tasdogan, A.* ; Hui, S.T.* ; Rodriguez, R.* ; Conrad, M. ; Reticker-Flynn, N.E.* ; Ubellacker, J.M.*

Lymph node environment drives FSP1 targetability in metastasizing melanoma.

Nature, DOI: 10.1038/s41586-025-09709-1 (2025)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Ferroptosis has emerged as an actionable target to eliminate therapy-resistant and metastatic cancers1. However, which ferroptosis surveillance systems may offer a therapeutic window to leverage redox maladaptation in cancer remains unclear. In melanoma, glutathione peroxidase 4 (GPX4) impedes ferroptosis during haematogenous metastasis, but is dispensable during lymphatic metastasis2. Here, using a metastatic mouse melanoma model selected for lymph node metastasis, we show that lymph-node-derived metastatic cells exhibit markedly diminished expression of glutamate-cysteine ligase (GCLC) and reduced glutathione (GSH) levels relative to their parental counterparts. This metabolic shift occurs within the hypoxic lymphatic niche. Under comparable low-oxygen conditions, GPX4 undergoes ubiquitination and proteasomal degradation. In response, lymph node metastatic cells acquire increased reliance on ferroptosis suppressor protein 1 (FSP1), which is localized with perinuclear lysosomes. These findings reveal that the reduced reliance on the GPX4 axis enables melanoma cells to shift toward FSP1 dependency. Notably, intratumoural monotherapy with selective FSP1 inhibitors (viFSP1 and FSEN1) effectively suppresses melanoma growth in lymph nodes, but not in subcutaneous tumours, emphasizing a microenvironment-specific dependency on FSP1. Thus, targeting FSP1 in the lymph nodes holds strong potential for blocking melanoma progression.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Oxidative Stress; Ferroptosis; Gpx4; Form
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Zeitschrift Nature
Verlag Nature Publishing Group
Verlagsort London
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Metabolism and Cell Death (MCD)
Förderungen Agence Nationale de la Recherche
Institut National du Cancer
Fondation Bettencourt Schueller
Deutsche Forschungsgemeinschaft (DFG)
Fondation Charles Defforey-Institut de France
Ligue Contre le Cancer (Equipe Labellisee)
NCI
Arc Institute Fellowship
METAvivor Early Career Investigator Award
Cause Breast Cancer Foundation
NIH
Melanoma Research Foundation Young Career Investigators Award
Ludwig Center at Harvard
European Research Council
DFG Priority Program SPP 2306

EU-H2020
ERC starting grant
Ministry of Culture and Science of the State of North Rhine-Westphalia
German Research Foundation
European Research Council (ERC)
CRC TRR 353
Melanoma Research Program Department of Defense Team Science Award