Effect of asparagine depletion on Rspo3 fusion positive colorectal cancer cell organoid transcriptomes. Effect of asparagine depletion on Rspo3 fusion positive colorectal cancer cell organoid transcriptomes

Amino acid availability is a crucial factor for survivability of cancer cells. Colorectal cancer cells have been shown to resist asparagine depletion by utilizing GSK3-dependent proteasomal degradation, termed Wnt-dependent stabilization of proteins (Wnt/STOP), to replenish their amino acid pool. Inhibition of GSK3a halts the sourcing of amino acids, which subsequently leads to cancer cell vulnerability towards asparaginase therapy. Leveraging RNA sequencing we show that GSK3a inhibition leads to a significant enrichment of ribosomal transcripts amongst transcripts that are differentially downregulated in asparaginase treated Rspo3 fusion positive colorectal cancer cell organoids. Overall design: The effect of asparagine depletion on gene expression in Rspo3 fusion positive colorectal cancer cell organoids was investigated. Transcriptomes of vehicle and asparaginase treated organoids were sequenced and gene expression levels compaired.

氨基酸的可获得性是癌细胞存活的关键因素。已有研究证实，结直肠癌细胞可通过依赖于糖原合成激酶3（GSK3）的蛋白酶体降解途径——即Wnt依赖性蛋白质稳定（Wnt/STOP）——补充自身氨基酸池，以此抵抗天冬酰胺耗竭。抑制GSK3α可阻断氨基酸的补给通路，进而使癌细胞对天冬酰胺酶治疗产生敏感性。本研究通过RNA测序（RNA sequencing）分析证实，在经天冬酰胺酶处理的Rspo3融合阳性结直肠癌细胞类器官中，经GSK3α抑制处理后，其差异下调的转录本内核糖体转录本的富集程度显著升高。
整体实验设计：本研究考察了天冬酰胺耗竭对Rspo3融合阳性结直肠癌细胞类器官基因表达的影响。对溶剂对照与天冬酰胺酶处理的类器官进行转录组测序，并比较两组的基因表达水平。