Premium
Stable expansion of high‐grade serous ovarian cancer organoids requires a low‐Wnt environment
Author(s) -
Hoffmann Karen,
Berger Hilmar,
Kulbe Hagen,
Thillainadarasan Sukanija,
Mollenkopf HansJoachim,
Zemojtel Tomasz,
Taube Eliane,
DarbEsfahani Silvia,
Mangler Mandy,
Sehouli Jalid,
Chekerov Radoslav,
Braicu Elena I,
Meyer Thomas F,
Kessler Mirjana
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019104013
Subject(s) - biology , organoid , serous ovarian cancer , ovarian cancer , serous fluid , wnt signaling pathway , cancer research , cancer , genetics , gene , biochemistry
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 sh RNA 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.