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In vivo evidence for serine biosynthesis-defined sensitivity of lung metastasis, but not of primary breast tumors, to mTORC1 inhibition

In tumors, nutrient availability and metabolism are known to be important modulators of growth signaling. However, it remains elusive whether cancer cells that are growing out in the metastatic niche rely on the same nutrients and metabolic pathways to activate growth signaling as cancer cells withi...

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Main Authors: Rinaldi, Gianmarco (Author) , Pranzini, Erica (Author) , Van Elsen, Joke (Author) , Broekaert, Dorien (Author) , Funk, Cornelius M. (Author) , Planque, Mélanie (Author) , Doglioni, Ginevra (Author) , Altea-Manzano, Patricia (Author) , Rossi, Matteo (Author) , Geldhof, Vincent (Author) , Teoh, Shao Thing (Author) , Ross, Christina (Author) , Hunter, Kent W. (Author) , Lunt, Sophia Y. (Author) , Grünewald, Thomas G. P. (Author) , Fendt, Sarah-Maria (Author)
Format: Article (Journal)
Language:English
Published: 2021
In: Molecular cell
Year: 2021, Volume: 81, Issue: 2, Pages: 386-397,e1-e7
ISSN:1097-4164
DOI:10.1016/j.molcel.2020.11.027
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.molcel.2020.11.027
Verlag, lizenzpflichtig, Volltext: https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=DynamicDOIArticle&SrcApp=WOS&KeyAID=10.1016%2Fj.molcel.2020.11.027&DestApp=DOI&SrcAppSID=E4kvFEhPmo5xgbiIJtE&SrcJTitle=MOLECULAR+CELL&DestDOIRegistrantName=Elsevier
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Author Notes:Gianmarco Rinaldi, Erica Pranzini, Joke Van Elsen, Dorien Broekaert, Cornelius M. Funk, Mélanie Planque, Ginevra Doglioni, Patricia Altea-Manzano, Matteo Rossi, Vincent Geldhof, Shao Thing Teoh, Christina Ross, Kent W. Hunter, Sophia Y. Lunt, Thomas G.P. Grünewald, and Sarah-Maria Fendt
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Summary:In tumors, nutrient availability and metabolism are known to be important modulators of growth signaling. However, it remains elusive whether cancer cells that are growing out in the metastatic niche rely on the same nutrients and metabolic pathways to activate growth signaling as cancer cells within the primary tumor. We discovered that breast-cancer-derived lung metastases, but not the corresponding primary breast tumors, use the serine biosynthesis pathway to support mTORC1 growth signaling. Mechanistically, pyruvate uptake through Mct2 supported mTORC1 signaling by fueling serine biosynthesis-derived a-ketoglutarate production in breast-cancer-derived lung metastases. Consequently, expression of the serine biosynthesis enzyme PHGDH was required for sensitivity to the mTORC1 inhibitor rapamycin in breast-cancer-derived lung tumors, but not in primary breast tumors. In summary, we provide in vivo evidence that the metabolic and nutrient requirements to activate growth signaling differ between the lung metastatic niche and the primary breast cancer site.
Item Description:Available online 18 December 2020
Gesehen am 15.09.2021
Physical Description:Online Resource
ISSN:1097-4164
DOI:10.1016/j.molcel.2020.11.027

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