Serine metabolism remodeling after platinum-based chemotherapy identifies vulnerabilities in a subgroup of resistant ovarian cancers
Van Nyen, Tom; Planque, Mélanie; van Wagensveld, Lilian; Duarte, Joao A.G.; Zaal, Esther A.; Talebi, Ali; Rossi, Matteo; Körner, Pierre René; Rizzotto, Lara; Moens, Stijn; De Wispelaere, Wout; Baiden-Amissah, Regina E.M.; Sonke, Gabe S.; Horlings, Hugo M.; Eelen, Guy; Berardi, Emanuele; Swinnen, Johannes V.; Berkers, Celia R.; Carmeliet, Peter; Lambrechts, Diether; Davidson, Ben; Agami, Reuven; Fendt, Sarah Maria; Annibali, Daniela; Amant, Frédéric
(2022) Nature Communications, volume 13, issue 1, pp. 1 - 19
(Article)
Abstract
Resistance to platinum-based chemotherapy represents a major clinical challenge for many tumors, including epithelial ovarian cancer. Patients often experience several response-relapse events, until tumors become resistant and life expectancy drops to 12–15 months. Despite improved knowledge of the molecular determinants of platinum resistance, the lack of clinical applicability limits exploitation
... read more
of many potential targets, leaving patients with limited options. Serine biosynthesis has been linked to cancer growth and poor prognosis in various cancer types, however its role in platinum-resistant ovarian cancer is not known. Here, we show that a subgroup of resistant tumors decreases phosphoglycerate dehydrogenase (PHGDH) expression at relapse after platinum-based chemotherapy. Mechanistically, we observe that this phenomenon is accompanied by a specific oxidized nicotinamide adenine dinucleotide (NAD+) regenerating phenotype, which helps tumor cells in sustaining Poly (ADP-ribose) polymerase (PARP) activity under platinum treatment. Our findings reveal metabolic vulnerabilities with clinical implications for a subset of platinum resistant ovarian cancers.
show less
Download/Full Text
Keywords: General Chemistry, General Biochemistry,Genetics and Molecular Biology, General, General Physics and Astronomy
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Funding Information: We are grateful to all past and present members of the Amant, Fendt and Agami laboratories for invaluable discussions and advice, and acknowledge the technical help of Tina Everaert and Rossana Maria Benedetto. We thank Mr. Arild Holth for the IHC staining of the effusion samples of the Norwegian cohort. We would like to acknowledge the NKI-AVL Core Facility Molecular Pathology & Biobanking (CFMPB) for supplying NKI-AVL Biobank material and lab support, for the staining of the Dutch cohort samples. We also thank TRACE, the KU Leuven PDX Platform, for technical assistance with the in vivo experiments. We would like to thank Jonas Dehairs and Frank Vanderhoydonc of the KU Leuven lipidomics core facility Lipometrix for performing lipidomics analysis. Finally, we would like to thank the Genomics Core Facilities of the Netherlands Cancer Institute and the UZ Leuven for RNA-seq analysis and WES analysis, respectively. Some schematic art pieces in Fig. and Supplementary Fig. were used and modified from Servier Medical Art ( http://smart.servier.com/ ). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License ( https://creativecommons.org/licenses/by/3.0/ ). Chemical structures in Supplementary Fig. are generated using PubChem Sketcher. This study was supported by research grants from Kom Op Tegen Kanker—The Flemish Cancer Society (3M150511, to F.A., S.M.F. and D.L.) and KWF Kanker Bestrijding (11574, to R.A., F.A. and D.A.). F.A. is a senior researcher for Research Foundation—Flanders (FWO). T.V.N. is recipient of an Emmanuel van der Schueren fellowship from Kom op Tegen Kanker—The Flemish Cancer Society. M.R. has received consecutive postdoctoral fellowships from FWO and Stichting tegen Kanker, and J.A.G.D. was supported by FWO. S.M.F. acknowledges funding from the European Research Council under the ERC Consolidator Grant Agreement n. 771486–MetaRegulation, FWO—Research Projects (G088318N), KU Leuven FTBO, Fonds Baillet Latour, King Baudouin Foundation and the Beug Foundation. TRACE staff is supported by Stichting Tegen Kanker grant 2016-054. P.C. is supported by Grants from Methusalem funding (Flemish government), the Fund for Scientific Research-Flanders (FWO-Vlaanderen), ERC Advanced Research Grant EU- (ERC743074), and a NNF Laureate Research Grant from Novo Nordisk Foundation (Denmark). Funding Information: S.M.F. has received funding from Bayer, Merck and BlackBelt Therapeutics and has consulted for Fund+. G.S.S. reports institutional research support from AstraZeneca, Merck, Novartis, and Roche, unrelated to this work. All the other authors declare no competing interests. Funding Information: We are grateful to all past and present members of the Amant, Fendt and Agami laboratories for invaluable discussions and advice, and acknowledge the technical help of Tina Everaert and Rossana Maria Benedetto. We thank Mr. Arild Holth for the IHC staining of the effusion samples of the Norwegian cohort. We would like to acknowledge the NKI-AVL Core Facility Molecular Pathology & Biobanking (CFMPB) for supplying NKI-AVL Biobank material and lab support, for the staining of the Dutch cohort samples. We also thank TRACE, the KU Leuven PDX Platform, for technical assistance with the in vivo experiments. We would like to thank Jonas Dehairs and Frank Vanderhoydonc of the KU Leuven lipidomics core facility Lipometrix for performing lipidomics analysis. Finally, we would like to thank the Genomics Core Facilities of the Netherlands Cancer Institute and the UZ Leuven for RNA-seq analysis and WES analysis, respectively. Some schematic art pieces in Fig. 5d and Supplementary Fig. 2d were used and modified from Servier Medical Art (http://smart.servier.com/). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/). Chemical structures in Supplementary Fig. 3h are generated using PubChem Sketcher60. This study was supported by research grants from Kom Op Tegen Kanker—The Flemish Cancer Society (3M150511, to F.A., S.M.F. and D.L.) and KWF Kanker Bestrijding (11574, to R.A., F.A. and D.A.). F.A. is a senior researcher for Research Foundation—Flanders (FWO). T.V.N. is recipient of an Emmanuel van der Schueren fellowship from Kom op Tegen Kanker—The Flemish Cancer Society. M.R. has received consecutive postdoctoral fellowships from FWO and Stichting tegen Kanker, and J.A.G.D. was supported by FWO. S.M.F. acknowledges funding from the European Research Council under the ERC Consolidator Grant Agreement n. 771486–MetaRegulation, FWO—Research Projects (G088318N), KU Leuven FTBO, Fonds Baillet Latour, King Baudouin Foundation and the Beug Foundation. TRACE staff is supported by Stichting Tegen Kanker grant 2016-054. P.C. is supported by Grants from Methusalem funding (Flemish government), the Fund for Scientific Research-Flanders (FWO-Vlaanderen), ERC Advanced Research Grant EU- (ERC743074), and a NNF Laureate Research Grant from Novo Nordisk Foundation (Denmark). Publisher Copyright: © 2022, The Author(s).
(Peer reviewed)
