Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York 10021, USA.
Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, New York 10021, USA.
Nat Commun. 2017 Jul 11;8:15945. doi: 10.1038/ncomms15945.
Defining the genetic drivers of cancer progression is a key in understanding disease biology and developing effective targeted therapies. Chromosome rearrangements are a common feature of human malignancies, but whether they represent bona fide cancer drivers and therapeutically actionable targets, requires functional testing. Here, we describe the generation of transgenic, inducible CRISPR-based mouse systems to engineer and study recurrent colon cancer-associated EIF3E-RSPO2 and PTPRK-RSPO3 chromosome rearrangements in vivo. We show that both Rspo2 and Rspo3 fusion events are sufficient to initiate hyperplasia and tumour development in vivo, without additional cooperating genetic events. Rspo-fusion tumours are entirely Wnt-dependent, as treatment with an inhibitor of Wnt secretion, LGK974, drives rapid tumour clearance from the intestinal mucosa without effects on normal intestinal crypts. Altogether, our study provides direct evidence that endogenous Rspo2 and Rspo3 chromosome rearrangements can initiate and maintain tumour development, and indicate a viable therapeutic window for LGK974 treatment of RSPO-fusion cancers.
明确癌症进展的遗传驱动因素是理解疾病生物学和开发有效靶向治疗的关键。染色体重排是人类恶性肿瘤的一个常见特征，但它们是否代表真正的癌症驱动因素和治疗上可操作的靶点，需要进行功能测试。在这里，我们描述了转基因、诱导型 CRISPR 基于的小鼠系统的生成，用于在体内设计和研究复发性结肠癌相关的 EIF3E-RSPO2 和 PTPRK-RSPO3 染色体重排。我们表明，Rspo2 和 Rspo3 融合事件都足以在体内引发增生和肿瘤发展，而不需要额外的合作遗传事件。Rspo-融合肿瘤完全依赖于 Wnt，因为用 Wnt 分泌抑制剂 LGK974 治疗可迅速清除肠道黏膜中的肿瘤，而对正常肠隐窝没有影响。总之，我们的研究提供了直接证据，表明内源性 Rspo2 和 Rspo3 染色体重排可以启动和维持肿瘤的发展，并表明 LGK974 治疗 RSPO 融合癌症的治疗窗口是可行的。
