2. Academic Validation
  3. Elevated FSP1 protects KRAS-mutated cells from ferroptosis during tumor initiation

Elevated FSP1 protects KRAS-mutated cells from ferroptosis during tumor initiation

  • Cell Death Differ. 2022 Nov 29. doi: 10.1038/s41418-022-01096-8.
Fabienne Müller 1 2,  Jonathan K M Lim 3,  Christina M Bebber 1 2,  Eric Seidel 1 2,  Sofya Tishina 1 2,  Alina Dahlhaus 1 2,  Jenny Stroh 1 2,  Julia Beck 1 2,  Fatma Isil Yapici 1 2,  Keiko Nakayama 4,  Lucia Torres Fernández 1,  Johannes Brägelmann 1 5 6,  Gabriel Leprivier 3,  Silvia von Karstedt 7 8 9
Affiliations

Affiliations

  • 1 University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany.
  • 2 CECAD Cluster of Excellence, University of Cologne, Cologne, Germany.
  • 3 Heinrich Heine University, Medical Faculty and University Hospital Düsseldorf, Institute of Neuropathology, Düsseldorf, Germany.
  • 4 Division of Cell Proliferation, ART, Graduate School of Medicine, Tohoku University, Sendai, Japan.
  • 5 University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, Cologne, Germany.
  • 6 Mildred Scheel School of Oncology Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
  • 7 University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany. s.vonkarstedt@uni-koeln.de.
  • 8 CECAD Cluster of Excellence, University of Cologne, Cologne, Germany. s.vonkarstedt@uni-koeln.de.
  • 9 University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, Cologne, Germany. s.vonkarstedt@uni-koeln.de.
PMID: 36443441 DOI: 10.1038/s41418-022-01096-8
Abstract

Oncogenic KRAS is the key driver oncogene for several of the most aggressive human cancers. One key feature of oncogenic KRAS expression is an early increase in cellular Reactive Oxygen Species (ROS) which promotes cellular transformation if cells manage to escape cell death, mechanisms of which remain incompletely understood. Here, we identify that expression of oncogenic as compared to WT KRAS in isogenic cellular systems renders cells more resistant to Ferroptosis, a recently described type of regulated necrosis. Mechanistically, we find that cells with mutant KRAS show a specific lack of ferroptosis-induced lipid peroxidation. Interestingly, KRAS-mutant cells upregulate expression of Ferroptosis suppressor protein 1 (FSP1). Indeed, elevated levels of FSP1 in KRAS-mutant cells are responsible for mediating Ferroptosis resistance and FSP1 is upregulated as a consequence of MAPK and NRF2 pathway activation downstream of KRAS. Strikingly, FSP1 activity promotes cellular transformation in soft agar and its overexpression is sufficient to promote spheroid growth in 3D in KRAS WT cells. Moreover, FSP1 expression and its activity in Ferroptosis inhibition accelerates tumor onset of KRAS WT cells in the absence of oncogenic KRAS in vivo. Consequently, we find that pharmacological induction of Ferroptosis in pancreatic organoids derived from the LsL-KRASG12D expressing mouse model is only effective in combination with FSP1 inhibition. Lastly, FSP1 is upregulated in non-small cell lung Cancer (NSCLC), colorectal Cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) as compared to the respective normal tissue of origin and correlates with NRF2 expression in PDAC patient datasets. Based on these data, we propose that KRAS-mutant cells must navigate a Ferroptosis checkpoint by upregulating FSP1 during tumor establishment. Consequently, ferroptosis-inducing therapy should be combined with FSP1 inhibitors for efficient therapy of KRAS-mutant cancers.

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