生长中的肿瘤细胞总是很“饥饿”，近日刊登在国际著名杂志Nature上的研究论文中，来自荷兰癌症研究所（Netherlands Cancer Institute）的科学家们设计了一种新方法，其可以帮助揭示那些氨基酸非常受限制但又急需用来维持肿瘤生长的单一肿瘤，而微分化的核糖体密码子阅读器就可以通过剥除特殊的氨基酸来帮助饿死肿瘤。
人类细胞会利用大多数能量来进行细胞分裂和生存，但通常其会耗尽一种或者少有的几种氨基酸，并且将其限定在一定水平下，阐明肿瘤中受限的氨基酸或许就可以帮助开发特殊疗法来限制肿瘤生长，然而目前研究人员很难发现哪种氨基酸最应该受到限制。
研究者Reuven Agami说道，氨基酸的脆弱性具有肿瘤特异性及病人特异性，但如今我们几乎可以在每一种肿瘤中测定受限制的氨基酸，这项研究中研究者对肿瘤组织和正常组织中的RNA核糖体复合物进行了分析研究，RNA核糖体复合物可以产生蛋白，而RNA是一种包含蛋白质翻译指令的分子，而核糖体则可以阅读RNA上的这些指令，从而携带着RNA同氨基酸进行连接，再将氨基酸进行合适的排序。文章中研究者对肿瘤组织和正常组织中蛋白质的合成产生进行了两次快照分析，第一次和第二次快照之间的差异表明，核糖体会在用作合成氨基酸的RNA指令位置上积累，而这些氨基酸是最受限制的。
一旦肿瘤中受限制氨基酸已知，未来对氨基酸供给的限制就会以特殊的方式来影响肿瘤的发育，而这或许可以通过添加可以关闭氨基酸合成过程的物质来完成或者通过关闭产生特殊氨基酸的基因来完成。而通过注射破碎氨基酸的酶类就可以将氨基酸维持在一个较低的循环水平上。
研究者Agami表示，我们利用遗传工具阐明了乳腺癌细胞中受限氨基酸所遵循的一种原则，的确关闭受限制氨基酸的产生就可以降低动物模型中肿瘤的生长。本文研究对于揭示癌症发生发展的机制提供了一定线索，也为开发癌症的个体化靶向疗法带来了希望。
doi:10.1038/nature16982
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Tumour-specific proline vulnerability uncovered by differential ribosome codon reading
Fabricio Loayza-Puch, Koos Rooijers, Levi C. M. Buil, Jelle Zijlstra, Joachim F. Oude Vrielink, Rui Lopes, Alejandro Pineiro Ugalde, Pieter van Breugel, Ingrid Hofland, Jelle Wesseling, Olaf van Tellingen, Axel Bex &Reuven Agami
Tumour growth and metabolic adaptation may restrict the availability of certain amino acids for protein synthesis. It has recently been shown that certain types of cancer cells depend on glycine, glutamine, leucine and serine metabolism to proliferate and survive1, 2, 3, 4. In addition, successful therapies using L-asparaginase-induced asparagine deprivation have been developed for acute lymphoblastic leukaemia5. However, a tailored detection system for measuring restrictive amino acids in each tumour is currently not available. Here we harness ribosome profiling6 for sensing restrictive amino acids, and develop diricore, a procedure for differential ribosome measurements of codon reading. We first demonstrate the functionality and constraints of diricore using metabolic inhibitors and nutrient deprivation assays. Notably, treatment with L-asparaginase elicited both specific diricore signals at asparagine codons and high levels of asparagine synthetase (ASNS). We then applied diricore to kidney cancer and discover signals indicating restrictive proline. As for asparagine, this observation was linked to high levels of PYCR1, a key enzyme in proline production7, suggesting a compensatory mechanism allowing tumour expansion. Indeed, PYCR1 is induced by shortage of proline precursors, and its suppression attenuated kidney cancer cell proliferation when proline was limiting. High PYCR1 is frequently observed in invasive breast carcinoma. In an in vivo model system of this tumour, we also uncover signals indicating restrictive proline. We further show that CRISPR-mediated knockout of PYCR1 impedes tumorigenic growth in this system. Thus, diricore has the potential to reveal unknown amino acid deficiencies, vulnerabilities that can be used to target key metabolic pathways for cancer treatment.
