Host autophagy mediates organ wasting and nutrient mobilization for tumor growth.
Host autophagy mediates organ wasting and nutrient mobilization for tumor growth.
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DOI：
10.15252/embj.2020107336
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发表时间：
2021-09-15
期刊：
影响因子：
--
通讯作者：
Rusten TE
中科院分区：
文献类型：
--
作者：
Khezri R;Holland P;Schoborg TA;Abramovich I;Takáts S;Dillard C;Jain A;O'Farrell F;Schultz SW;Hagopian WM;Quintana EM;Ng R;Katheder NS;Rahman MM;Teles Reis JG;Brech A;Jasper H;Rusan NM;Jahren AH;Gottlieb E;Rusten TE
在肿瘤生长过程中，当营养和合成代谢需求很高时，自噬通过溶酶体细胞器周转和营养循环支持肿瘤代谢和生长。Ras驱动的肿瘤还在微环境中引发非自主性自噬以支持肿瘤生长，部分通过转移氨基酸。在这里，我们发现了自噬在介导全身器官浪费和营养动员肿瘤生长中的第三个关键作用，使用了一个特征良好的恶性肿瘤模型在果蝇中。微型计算机X射线断层扫描和代谢分析显示，RasV 12; scrib −/−肿瘤体积增长10倍，而全身器官萎缩表现为进行性肌肉萎缩、体重减轻、运动能力下降、进食减少，最终死亡。组织消耗被发现是由自噬介导的，并导致氨基酸和糖进入循环的宿主动员。天然丰度碳13示踪表明，随着消耗的进展，肿瘤生物量越来越多地来源于宿主组织作为营养源。我们的结论是，宿主自噬介导的器官浪费和营养动员，是用于肿瘤生长。X射线断层扫描、代谢组学和碳示踪显示，自噬介导的远端组织消耗提供了增加果蝇眼肿瘤生物量的氨基酸和糖。
During tumor growth—when nutrient and anabolic demands are high—autophagy supports tumor metabolism and growth through lysosomal organelle turnover and nutrient recycling. Ras‐driven tumors additionally invoke non‐autonomous autophagy in the microenvironment to support tumor growth, in part through transfer of amino acids. Here we uncover a third critical role of autophagy in mediating systemic organ wasting and nutrient mobilization for tumor growth using a well‐characterized malignant tumor model in Drosophila melanogaster. Micro‐computed X‐ray tomography and metabolic profiling reveal that RasV12; scrib −/− tumors grow 10‐fold in volume, while systemic organ wasting unfolds with progressive muscle atrophy, loss of body mass, ‐motility, ‐feeding, and eventually death. Tissue wasting is found to be mediated by autophagy and results in host mobilization of amino acids and sugars into circulation. Natural abundance Carbon 13 tracing demonstrates that tumor biomass is increasingly derived from host tissues as a nutrient source as wasting progresses. We conclude that host autophagy mediates organ wasting and nutrient mobilization that is utilized for tumor growth. X‐ray tomography, metabolomics and carbon tracing reveal that autophagy‐mediated wasting of distal tissues provides amino acids and sugars that increase eye tumor biomass in Drosophila melanogaster.
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影响因子：
29
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