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Proline metabolism supports metastasis formation and could be inhibited to selectively target metastasizing cancer cells

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  • Ilaria Elia

    (Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology
    Laboratory of Cellular Metabolism and Metabolic Regulation, KU Leuven and Leuven Cancer Institute (LKI))

  • Dorien Broekaert

    (Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology
    Laboratory of Cellular Metabolism and Metabolic Regulation, KU Leuven and Leuven Cancer Institute (LKI))

  • Stefan Christen

    (Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology
    Laboratory of Cellular Metabolism and Metabolic Regulation, KU Leuven and Leuven Cancer Institute (LKI))

  • Ruben Boon

    (Stem Cell Institute, KU Leuven)

  • Enrico Radaelli

    (Center for the Biology of Disease, VIB Leuven and Center for Human Genetics, KU Leuven)

  • Martin F. Orth

    (Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology)

  • Catherine Verfaillie

    (Stem Cell Institute, KU Leuven)

  • Thomas G. P. Grünewald

    (Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology)

  • Sarah-Maria Fendt

    (Laboratory of Cellular Metabolism and Metabolic Regulation, VIB Center for Cancer Biology
    Laboratory of Cellular Metabolism and Metabolic Regulation, KU Leuven and Leuven Cancer Institute (LKI))

Abstract

Metastases are the leading cause of mortality in patients with cancer. Metastasis formation requires cancer cells to adapt their cellular phenotype. However, how metabolism supports this adaptation of cancer cells is poorly defined. We use 2D versus 3D cultivation to induce a shift in the cellular phenotype of breast cancer cells. We discover that proline catabolism via proline dehydrogenase (Prodh) supports growth of breast cancer cells in 3D culture. Subsequently, we link proline catabolism to in vivo metastasis formation. In particular, we find that PRODH expression and proline catabolism is increased in metastases compared to primary breast cancers of patients and mice. Moreover, inhibiting Prodh is sufficient to impair formation of lung metastases in the orthotopic 4T1 and EMT6.5 mouse models, without adverse effects on healthy tissue and organ function. In conclusion, we discover that Prodh is a potential drug target for inhibiting metastasis formation.

Suggested Citation

  • Ilaria Elia & Dorien Broekaert & Stefan Christen & Ruben Boon & Enrico Radaelli & Martin F. Orth & Catherine Verfaillie & Thomas G. P. Grünewald & Sarah-Maria Fendt, 2017. "Proline metabolism supports metastasis formation and could be inhibited to selectively target metastasizing cancer cells," Nature Communications, Nature, vol. 8(1), pages 1-11, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15267
    DOI: 10.1038/ncomms15267
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    Cited by:

    1. Tom Nyen & Mélanie Planque & Lilian Wagensveld & Joao A. G. Duarte & Esther A. Zaal & Ali Talebi & Matteo Rossi & Pierre-René Körner & Lara Rizzotto & Stijn Moens & Wout Wispelaere & Regina E. M. Baid, 2022. "Serine metabolism remodeling after platinum-based chemotherapy identifies vulnerabilities in a subgroup of resistant ovarian cancers," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. Tal Levy & Kai Voeltzke & Laura Hruby & Khawla Alasad & Zuelal Bas & Marteinn Snaebjörnsson & Ran Marciano & Katerina Scharov & Mélanie Planque & Kim Vriens & Stefan Christen & Cornelius M. Funk & Chr, 2024. "mTORC1 regulates cell survival under glucose starvation through 4EBP1/2-mediated translational reprogramming of fatty acid metabolism," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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