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.

中文翻译：

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高档浆液性卵巢癌类器官的稳定扩张需要低Wnt环境。

高度浆液性卵巢癌（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，它们与亲本肿瘤的突变谱和表型紧密匹配。我们发现Wnt途径激活导致这些癌症类器官的生长停滞。此外，几乎总是需要活跃的BMP信号产生HGSOC类器官，而健康的输卵管类器官则依赖于Noggin抑制BMP。通过稳定的p53，PTEN和视网膜母细胞瘤蛋白（shRNA）的shRNA敲除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会触发生长停滞。因此，需要干细胞生态位环境的早期改变来支持这些遗传改变的细胞的生长。