Targeting chemotherapy induced metabolic escape mechanisms to reduce cancer metastasis
Biochemistry
Public Health, Healthcare Research, Social and Occupational Medicine
Cell Biology
Final Report Abstract
Today, the most common cause of death in cancer patients is metastatic disease progression. Despite significant progress, the cellular mechanisms that lead to the metastatic spread of cancer cells are still not completely understood. As metastasis formation can also occur as tumour relapse after chemotherapy, it was important to investigate whether certain chemotherapies themselves can induce cellular changes that promote this metastatic spread. Here, it has become more and more clear over the past decade that especially the rewiring of cellular metabolism is essential for tumour progression and metastatic outspread to meet the varying biomass and energy demands of cancer cells along the metastatic cascade. With this DFG fellowship my intent was to gain proficiency in the field of cancer metabolism and understand its relevance for metastatic cancer disease. I specifically aimed to analyse how changes in cellular metabolism during chemotherapy may induce mechanisms of cellular adaptation that prime cancer cells for enhanced motility, invasiveness and subsequently metastasis formation. Defining such metabolic rewiring at the root of metastasis formation offers the possibility to define potential therapeutic interventions with the aim to prevent metastatic disease progression during chemotherapy. With the help of this fellowship, I was able to elucidate mechanistic details of the folate mediated one-carbon (1C) cycle, a metabolic pathway that is essential for cancer cell division and survival. I showed that the 1C cycle is specifically important for the migration of cancer cells under chemotherapy and that a targeted intervention with mitochondrial 1C cycle activity in growth-inhibited cancer cells under chemotherapy holds promise to prevent cancer cell migration. Due to this initial discovery, I was interested in defining additional targeted interventions of 1C cycle activity and was able to metabolically characterize a newly developed drug for its inhibitory activity on 1C cycle. While this drug turned out to not be ideal for the desired inhibition of mitochondrial 1C cycle activity, we nevertheless were able to characterize its metabolic mechanism of action, identify until then unknown mechanistic details of 1C cycle and define strategies with which the drug can be used for cancer cell killing. My research during this fellowship has implications for the fundamental knowledge on metabolic pathway regulation in cancer cells and gives indications how this knowledge may be applied in targeted therapies to enhance cancer cell killing and prevent metastatic progression under chemotherapy. The next steps will include the further characterization of the defined therapeutic interventions in mouse models to define their potential for clinical application.
Link to the final report
https://repository.publisso.de/resource/frl:6526939
Publications
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Mitochondria preserve an autarkic one-carbon cycle to confer growth-independent cancer cell migration and metastasis. Nature Communications, 13(1).
Kiweler, Nicole; Delbrouck, Catherine; Pozdeev, Vitaly I.; Neises, Laura; Soriano-Baguet, Leticia; Eiden, Kim; Xian, Feng; Benzarti, Mohaned; Haase, Lara; Koncina, Eric; Schmoetten, Maryse; Jaeger, Christian; Noman, Muhammad Zaeem; Vazquez, Alexei; Janji, Bassam; Dittmar, Gunnar; Brenner, Dirk; Letellier, Elisabeth & Meiser, Johannes
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress. Nature Cancer, 3(2), 156-172.
Bonagas, Nadilly; Gustafsson, Nina M. S.; Henriksson, Martin; Marttila, Petra; Gustafsson, Robert; Wiita, Elisée; Borhade, Sanjay; Green, Alanna C.; Vallin, Karl S. A.; Sarno, Antonio; Svensson, Richard; Göktürk, Camilla; Pham, Therese; Jemth, Ann-Sofie; Loseva, Olga; Cookson, Victoria; Kiweler, Nicole; Sandberg, Lars; Rasti, Azita ... & Helleday, Thomas
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Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells. Nature Metabolism, 5(4), 642-659.
Green, Alanna C.; Marttila, Petra; Kiweler, Nicole; Chalkiadaki, Christina; Wiita, Elisée; Cookson, Victoria; Lesur, Antoine; Eiden, Kim; Bernardin, François; Vallin, Karl S. A.; Borhade, Sanjay; Long, Maeve; Ghahe, Elahe Kamali; Jiménez-Alonso, Julio J.; Jemth, Ann-Sofie; Loseva, Olga; Mortusewicz, Oliver; Meyers, Marianne; Viry, Elodie ... & Meiser, Johannes
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Formate promotes invasion and metastasis in reliance on lipid metabolism. Cell Reports, 42(9), 113034.
Delbrouck, Catherine; Kiweler, Nicole; Chen, Oleg; Pozdeev, Vitaly I.; Haase, Lara; Neises, Laura; Oudin, Anaïs; Fouquier, d.’Hérouël Aymeric; Shen, Ruolin; Schlicker, Lisa; Halder, Rashi; Lesur, Antoine; Schuster, Anne; Lorenz, Nadja I.; Jaeger, Christian; Feucherolles, Maureen; Frache, Gilles; Szpakowska, Martyna; Chevigne, Andy ... & Meiser, Johannes
