Stable expansion of high-grade serous ovarian cancer organoids requires a low-Wnt environment
Stable expansion of high-grade serous ovarian cancer organoids requires a low-Wnt environment
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DOI：
10.15252/embj.2019104013
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发表时间：
2020-02-03
期刊：
影响因子：
11.4
通讯作者：
Kessler, Mirjana
中科院分区：
文献类型：
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作者：
Hoffmann, Karen;Berger, Hilmar;Kessler, Mirjana
高级别浆液性卵巢癌（HGSOC）可能起源于输卵管（FT）上皮。在这里，我们从HGSOC原发性肿瘤沉积物中建立了15个类器官系，这些细胞系与亲本肿瘤的突变谱和表型密切匹配。我们发现Wnt通路激活导致这些癌症类器官的生长停滞。此外，HGSOC类器官的产生几乎总是需要活性BMP信号传导，而健康的输卵管类器官依赖于Noggin对BMP的抑制。通过稳定的p53、PTEN和视网膜母细胞瘤蛋白（RB）的shRNA敲低修饰的输卵管类器官也需要低Wnt环境才能长期生长，而输卵管类器官培养基则会触发生长停滞。因此，需要干细胞生态位环境的早期变化来支持这些遗传改变的细胞的生长。事实上，对正常与功能丧失类器官的基因表达模式和表型的比较分析证实，肿瘤抑制因子的耗竭引发了干性和分化调节的变化。
High-grade serous ovarian cancer (HGSOC) likely originates from the fallopian tube (FT) epithelium. Here, we established 15 organoid lines from HGSOC primary tumor deposits that closely match the mutational profile and phenotype of the parental tumor. We found that Wnt pathway activation leads to growth arrest of these cancer organoids. Moreover, active BMP signaling is almost always required for the generation of HGSOC organoids, while healthy fallopian tube organoids depend on BMP suppression by Noggin. Fallopian tube organoids modified by stable shRNA knockdown of p53, PTEN, and retinoblastoma protein (RB) also require a low-Wnt environment for long-term growth, while fallopian tube organoid medium triggers growth arrest. Thus, early changes in the stem cell niche environment are needed to support outgrowth of these genetically altered cells. Indeed, comparative analysis of gene expression pattern and phenotypes of normal vs. loss-of-function organoids confirmed that depletion of tumor suppressors triggers changes in the regulation of stemness and differentiation.