In Vivo Evidence for Serine Biosynthesis-Defined Sensitivity of Lung Metastasis, but Not of Primary Breast Tumors, to mTORC1 Inhibition

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.

Amino Acid Depletion Therapies: Starving Cancer Cells to Death

“…Hence, it might not come as a surprise that the same tumor cells can show different metabolic and nutrient requirements at their primary or metastatic site. For instance, breast cancer cells were shown to upregulate Ser biosynthesis to support mammalian target of rapamycin complex 1 (mTORC1) growth signaling when metastasized to the lung, but not at their primary location [45], while Cys uptake via the transporter xCT appears to be more important for mammary metastases as compared with the primary tumor [46]. Moreover, the limited availability of Ser and Gly in the brain forces metastasized cells in this tissue to upregulate Ser biosynthesis making these, but not the extracranial growing tumors, sensitive to PHGDH inhibitors [47].…”

Metabolic Reprogramming in Anticancer Drug Resistance: A Focus on Amino Acids

“…In proliferating cells, serine is also essential for redox balance, contributing to NADPH and GSH production [142], and supports the synthesis of sphingolipids, resulting in mitochondrial stability [143]. The SSP can activate mTORC1 signaling pathway through the production of αKG in breast cancer-derived lung metastasis [144]. Moreover, serine catabolism generates glycine, incorporated into the purine ring and GSH structure and provides one-carbon units through its oxidation by the glycine cleavage system [142].…”

A pan-cancer transcriptomic study showing tumor specific alterations in central metabolism

“…Of note, Ser biosynthesis was recently shown to activate mitogenic signaling via mTORC1 in lung metastasis of breast cancer but not in the primary breast tumor. Expression of PHGDH in the lung metastatic tissue was necessary for the sensitivity of mTORC1 to rapamycin 93 ⁠. Cys is conditionally essential because it can be synthesized from Homocysteine and Ser by cystathionine gamma-lyase (CTH).…”