In Vivo Evidence for Serine Biosynthesis-Defined Sensitivity of Lung Metastasis, but Not of Primary Breast Tumors, to mTORC1 Inhibition.
In Vivo Evidence for Serine Biosynthesis-Defined Sensitivity of Lung Metastasis, but Not of Primary Breast Tumors, to mTORC1 Inhibition.
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DOI：
10.1016/j.molcel.2020.11.027
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发表时间：
2021-01-21
期刊：
影响因子：
16
通讯作者：
Fendt, Sarah-Maria
中科院分区：
文献类型：
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作者：
Rinaldi, Gianmarco;Pranzini, Erica;Van Elsen, Joke;Broekaert, Dorien;Funk, Cornelius M.;Planque, Melanie;Doglioni, Ginevra;Altea-Manzano, Patricia;Rossi, Matteo;Geldhof, Vincent;Teoh, Shao Thing;Ross, Christina;Hunter, Kent W.;Lunt, Sophia Y.;Gruenewald, Thomas G. P.;Fendt, Sarah-Maria
在肿瘤中，营养物质的可用性和代谢被认为是生长信号的重要调节剂。然而，在转移性微环境中生长的癌细胞是否依赖与原发肿瘤内的癌细胞相同的营养和代谢途径来激活生长信号传导仍然难以捉摸。我们发现乳腺癌来源的肺转移瘤（而非相应的原发性乳腺肿瘤）使用丝氨酸生物合成途径来支持 mTORC1 生长信号传导。从机制上讲，通过 Mct2 摄取丙酮酸通过促进乳腺癌肺转移中丝氨酸生物合成衍生的 α-酮戊二酸的产生来支持 mTORC1 信号传导。因此，在乳腺癌衍生的肺肿瘤中，丝氨酸生物合成酶 PHGDH 的表达是对 mTORC1 抑制剂雷帕霉素敏感性所必需的，但在原发性乳腺肿瘤中则不然。总之，我们提供的体内证据表明，激活生长信号传导的代谢和营养需求在肺转移微环境和原发性乳腺癌部位之间是不同的。
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.
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影响因子：
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作者：
Clasquin, Michelle F;Melamud, Eugene;Rabinowitz, Joshua D
通讯作者：
Rabinowitz, Joshua D
影响因子：
64.8
作者：
Hosseini H;Obradović MMS;Hoffmann M;Harper KL;Sosa MS;Werner-Klein M;Nanduri LK;Werno C;Ehrl C;Maneck M;Patwary N;Haunschild G;Gužvić M;Reimelt C;Grauvogl M;Eichner N;Weber F;Hartkopf AD;Taran FA;Brucker SY;Fehm T;Rack B;Buchholz S;Spang R;Meister G;Aguirre-Ghiso JA;Klein CA
通讯作者：
Klein CA
影响因子：
64.8
作者：
Harper KL;Sosa MS;Entenberg D;Hosseini H;Cheung JF;Nobre R;Avivar-Valderas A;Nagi C;Girnius N;Davis RJ;Farias EF;Condeelis J;Klein CA;Aguirre-Ghiso JA
通讯作者：
Aguirre-Ghiso JA
影响因子：
4.8
作者：
Bernfeld, Elyssa;Menon, Deepak;Foster, David A.
通讯作者：
Foster, David A.
DOI：
10.1007/978-1-0716-0159-4_6
发表时间：
2020-01-01
期刊：
METABOLIC FLUX ANALYSIS IN EUKARYOTIC CELLS: METHODS AND PROTOCOLS
影响因子：
--
作者：
Altea-Manzano, Patricia;Broekaert, Dorien;Fendt, Sarah-Maria
通讯作者：
Fendt, Sarah-Maria