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In Vivo Evidence for Serine Biosynthesis-Defined Sensitivity of Lung Metastasis, but Not of Primary Breast Tumors, to mTORC1 Inhibition
- Source :
- Molecular Cell
- Publication Year :
- 2021
- Publisher :
- Elsevier (Cell Press), 2021.
-
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. ispartof: Molecular Cell vol:81 issue:2 ispartof: location:United States status: Published online
- Subjects :
- Monocarboxylic Acid Transporters
Lung Neoplasms
Mice, Nude
Breast Neoplasms
mTORC1
Mechanistic Target of Rapamycin Complex 1
Biology
Serine
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Breast cancer
Biosynthesis
Cell Movement
Cell Line, Tumor
Pyruvic Acid
medicine
Animals
Humans
Phosphoglycerate dehydrogenase
RNA, Small Interfering
Molecular Biology
Phosphoglycerate Dehydrogenase
Cell Proliferation
030304 developmental biology
Sirolimus
Mice, Inbred BALB C
0303 health sciences
Antibiotics, Antineoplastic
Mammary Neoplasms, Experimental
Cell Biology
medicine.disease
Primary tumor
3. Good health
Gene Expression Regulation, Neoplastic
Metabolic pathway
chemistry
Drug Resistance, Neoplasm
Cancer cell
Cancer research
Ketoglutaric Acids
Female
030217 neurology & neurosurgery
Signal Transduction
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Molecular Cell
- Accession number :
- edsair.doi.dedup.....11e92bb2194df7c798c8f13787643b7e