Stable expansion of high‐grade serous ovarian cancer organoids requires a low‐Wnt environment

• Karen Hoffmann ^[3] ; Hilmar Berger ^[1] ; Hagen Kulbe ^[4] ; Sukanija Thillainadarasan ^[1] ; Hans‐Joachim Mollenkopf ^[1] ; Tomasz Zemojtel ^[5] ; Eliane Taube ^[2] ; Silvia Darb‐Esfahani ^[2] ; Mandy Mangler ^[6] ; Jalid Sehouli ^[4] ; Radoslav Chekerov ^[4] ; Elena I Braicu ^[4] ; Thomas F Meyer ^[1] ; Mirjana Kessler ^[3]
  1. [1] Max Planck Institute for Infection Biology

     Max Planck Institute for Infection Biology

     Berlin, Stadt, Alemania

     
  2. [2] Charité

     Charité

     Berlin, Stadt, Alemania

     
  3. [3] 1 Department of Molecular Biology Max Planck Institute for Infection Biology Berlin Germany; 6Present address: Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine Charité University Medicine Berlin Germany
  4. [4] 2 Department of Gynecology Charité University Medicine, Campus Virchow‐Klinikum Berlin Germany
  5. [5] 3 BIH Genomics Core Unit Charité University Medicine, Campus Virchow‐Klinikum Berlin Germany
  6. [6] 5 Department of Gynecology Vivantes Auguste‐Viktoria‐Klinikum Berlin Germany

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 39, Nº. 6, 2020
• Idioma: inglés
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  • 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.