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Preservation of stemness in high-grade serous ovarian cancer organoids requires low Wnt environment

Authors :
Sukanija Thillainadarasan
Tomasz Zemojtel
Hilmar Berger
Hans-Joachim Mollenkopf
Radoslav Chekerov
Elena Iona Braicu
Hagen Kulbe
Karen Hoffmann
Mirjana Kessler
Eliane T Taube
Mandy Mangler
Silvia Darb-Esfahani
Thomas F. Meyer
Jalid Sehouli
Publication Year :
2019
Publisher :
Cold Spring Harbor Laboratory, 2019.

Abstract

SummaryHigh-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 parental tumor mutational profile and phenotype. We found that Wnt pathway activation leads to growth arrest of these cancer organoids. Moreover, active BMP signaling is almost always required for generation of HGSOC organoids, while healthy FT organoids depend on BMP suppression by Noggin. Interestingly, FT organoids modified by stable shRNA knockdown (KD) of p53, PTEN, and Retinoblastoma (RB), also require a low Wnt environment for long-term growth, while FT 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 phenotype of normal and KD organoids confirmed that depletion of tumor suppressors triggers changes in the regulation of stemness and differentiation.

Details

Language :
English
Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....d5dd8a0de53616297dfd417649660c8a
Full Text :
https://doi.org/10.1101/741397