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功能基因组筛选揭示天冬酰胺依赖性是肉瘤中的一种代谢脆弱性。

Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma.

作者信息

Hettmer Simone, Schinzel Anna C, Tchessalova Daria, Schneider Michaela, Parker Christina L, Bronson Roderick T, Richards Nigel Gj, Hahn William C, Wagers Amy J

机构信息

Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, United States.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, United States.

出版信息

Elife. 2015 Oct 24;4:e09436. doi: 10.7554/eLife.09436.

DOI:10.7554/eLife.09436
PMID:26499495
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4695385/
Abstract

Current therapies for sarcomas are often inadequate. This study sought to identify actionable gene targets by selective targeting of the molecular networks that support sarcoma cell proliferation. Silencing of asparagine synthetase (ASNS), an amidotransferase that converts aspartate into asparagine, produced the strongest inhibitory effect on sarcoma growth in a functional genomic screen of mouse sarcomas generated by oncogenic Kras and disruption of Cdkn2a. ASNS silencing in mouse and human sarcoma cell lines reduced the percentage of S phase cells and impeded new polypeptide synthesis. These effects of ASNS silencing were reversed by exogenous supplementation with asparagine. Also, asparagine depletion via the ASNS inhibitor amino sulfoximine 5 (AS5) or asparaginase inhibited mouse and human sarcoma growth in vitro, and genetic silencing of ASNS in mouse sarcoma cells combined with depletion of plasma asparagine inhibited tumor growth in vivo. Asparagine reliance of sarcoma cells may represent a metabolic vulnerability with potential anti-sarcoma therapeutic value.

摘要

目前针对肉瘤的治疗方法往往并不充分。本研究旨在通过选择性靶向支持肉瘤细胞增殖的分子网络来确定可操作的基因靶点。天冬酰胺合成酶（ASNS）是一种将天冬氨酸转化为天冬酰胺的酰胺转移酶，在由致癌性Kras和Cdkn2a破坏产生的小鼠肉瘤功能基因组筛选中，ASNS的沉默对肉瘤生长产生了最强的抑制作用。在小鼠和人类肉瘤细胞系中沉默ASNS可降低S期细胞的百分比并阻碍新多肽的合成。通过外源补充天冬酰胺可逆转ASNS沉默的这些作用。此外，通过ASNS抑制剂氨基磺胺肟5（AS5）或天冬酰胺酶消耗天冬酰胺可在体外抑制小鼠和人类肉瘤的生长，在小鼠肉瘤细胞中ASNS的基因沉默与血浆天冬酰胺的消耗相结合可在体内抑制肿瘤生长。肉瘤细胞对天冬酰胺的依赖可能代表一种具有潜在抗肉瘤治疗价值的代谢弱点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6c0/4695385/93609f6150ca/elife-09436-fig5-figsupp1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6c0/4695385/3ab462a0c378/elife-09436-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6c0/4695385/21686ed6d8e2/elife-09436-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6c0/4695385/8a379b5f1c34/elife-09436-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6c0/4695385/2c221fe0cce0/elife-09436-fig2-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6c0/4695385/c5a9fe95051d/elife-09436-fig2-figsupp3.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6c0/4695385/0cca3f51f00f/elife-09436-fig4-figsupp1.jpg
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