TY - JOUR
T1 - Assessing the origin of high-grade serous ovarian cancer using CRISPR-modification of mouse organoids
AU - Lõhmussaar, Kadi
AU - Kopper, Oded
AU - Korving, Jeroen
AU - Begthel, Harry
AU - Vreuls, Celien P H
AU - van Es, Johan H
AU - Clevers, Hans
PY - 2020/5/27
Y1 - 2020/5/27
N2 - 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.
AB - 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.
KW - Animals
KW - Antineoplastic Agents/pharmacology
KW - BRCA1 Protein/genetics
KW - CRISPR-Associated Protein 9
KW - CRISPR-Cas Systems/genetics
KW - Epithelium/pathology
KW - Fallopian Tubes/pathology
KW - Female
KW - Gene Editing/methods
KW - Mice
KW - Mutation
KW - Neurofibromatosis 1/genetics
KW - Organ Culture Techniques/methods
KW - Organoids/drug effects
KW - Ovarian Neoplasms/drug therapy
KW - Ovary/pathology
KW - PTEN Phosphohydrolase/genetics
KW - Tumor Suppressor Protein p53/genetics
U2 - 10.1038/s41467-020-16432-0
DO - 10.1038/s41467-020-16432-0
M3 - Article
C2 - 32461556
SN - 2041-1723
VL - 11
SP - 2660
JO - Nature Communications
JF - Nature Communications
IS - 1
ER -