Assessing the origin of high-grade serous ovarian cancer using CRISPR-modification of mouse organoids

Kadi Lõhmussaar, Oded Kopper, Jeroen Korving, Harry Begthel, Celien P. H. Vreuls, Johan H. Es and Hans Clevers ()
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Kadi Lõhmussaar: Royal Netherlands Academy of Arts and Sciences and UMC Utrecht
Oded Kopper: Royal Netherlands Academy of Arts and Sciences and UMC Utrecht
Jeroen Korving: Royal Netherlands Academy of Arts and Sciences and UMC Utrecht
Harry Begthel: Royal Netherlands Academy of Arts and Sciences and UMC Utrecht
Celien P. H. Vreuls: UMC Utrecht
Johan H. Es: Royal Netherlands Academy of Arts and Sciences and UMC Utrecht
Hans Clevers: Royal Netherlands Academy of Arts and Sciences and UMC Utrecht

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract High-grade serous ovarian cancer (HG-SOC)—often referred to as a “silent killer”—is the most lethal gynecological malignancy. The fallopian tube (murine oviduct) and ovarian surface epithelium (OSE) are considered the main candidate tissues of origin of this cancer. However, the relative contribution of each tissue to HG-SOC is not yet clear. Here, we establish organoid-based tumor progression models of HG-SOC from murine oviductal and OSE tissues. We use CRISPR-Cas9 genome editing to introduce mutations into genes commonly found mutated in HG-SOC, such as Trp53, Brca1, Nf1 and Pten. Our results support the dual origin hypothesis of HG-SOC, as we demonstrate that both epithelia can give rise to ovarian tumors with high-grade pathology. However, the mutated oviductal organoids expand much faster in vitro and more readily form malignant tumors upon transplantation. Furthermore, in vitro drug testing reveals distinct lineage-dependent sensitivities to the common drugs used to treat HG-SOC in patients.

Date: 2020
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DOI: 10.1038/s41467-020-16432-0

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