In Vivo Evidence for Serine Biosynthesis-Defined Sensitivity of Lung Metastasis, but Not of Primary Breast Tumors, to mTORC1 Inhibition.
Mol Cell
; 81(2): 386-397.e7, 2021 01 21.
Article
en En
| MEDLINE
| ID: mdl-33340488
ABSTRACT
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 α-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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Serina
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Neoplasias de la Mama
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Regulación Neoplásica de la Expresión Génica
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Fosfoglicerato-Deshidrogenasa
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Diana Mecanicista del Complejo 1 de la Rapamicina
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Neoplasias Pulmonares
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Neoplasias Mamarias Experimentales
Tipo de estudio:
Diagnostic_studies
Idioma:
En
Revista:
Mol Cell
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2021
Tipo del documento:
Article