Mueller, Fabienne, Lim, Jonathan K. M., Bebber, Christina M., Seidel, Eric ORCID: 0000-0003-3334-3950, Tishina, Sofya, Dahlhaus, Alina, Stroh, Jenny, Beck, Julia, Yapici, Fatma Isil, Nakayama, Keiko ORCID: 0000-0003-0134-6401, Fernandez, Lucia Torres, Braegelmann, Johannes, Leprivier, Gabriel and von Karstedt, Silvia . Elevated FSP1 protects KRAS-mutated cells from ferroptosis during tumor initiation. Cell Death Differ.. LONDON: SPRINGERNATURE. ISSN 1476-5403

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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-KRAS(G12D) 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Mueller, FabienneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lim, Jonathan K. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bebber, Christina M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seidel, EricUNSPECIFIEDorcid.org/0000-0003-3334-3950UNSPECIFIED
Tishina, SofyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dahlhaus, AlinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stroh, JennyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beck, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yapici, Fatma IsilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nakayama, KeikoUNSPECIFIEDorcid.org/0000-0003-0134-6401UNSPECIFIED
Fernandez, Lucia TorresUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braegelmann, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leprivier, GabrielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Karstedt, SilviaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-677092
DOI: 10.1038/s41418-022-01096-8
Journal or Publication Title: Cell Death Differ.
Publisher: SPRINGERNATURE
Place of Publication: LONDON
ISSN: 1476-5403
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
RAS SIGNALING PATHWAYS; MEDIATED RNA DECAY; TARGETING RAS; CANCER; DEATH; P38; IDENTIFICATION; PROLIFERATION; INHIBITION; OXIDASEMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/67709

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