Assessing the origin of high-grade serous ovarian cancer using CRISPR-modification of mouse organoids
| Autor: | Harry Begthel, Johan H. van Es, Hans Clevers, Oded Kopper, Celien P.H. Vreuls, Kadi Lõhmussaar, Jeroen Korving |
|---|---|
| Přispěvatelé: | Hubrecht Institute for Developmental Biology and Stem Cell Research |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
endocrine system diseases General Physics and Astronomy Organ Culture Techniques/methods Epithelium Mice 0302 clinical medicine CRISPR-Associated Protein 9 lcsh:Science Gene Editing/methods Gene Editing Ovarian Neoplasms Multidisciplinary biology BRCA1 Protein Fallopian Tubes/pathology CRISPR-Cas Systems/genetics Ovarian Neoplasms/drug therapy PTEN Phosphohydrolase/genetics female genital diseases and pregnancy complications Organoids medicine.anatomical_structure 030220 oncology & carcinogenesis Oviduct Tumor Suppressor Protein p53/genetics Female Antineoplastic Agents/pharmacology Epithelium/pathology Organoids/drug effects endocrine system Neurofibromatosis 1 Science Antineoplastic Agents General Biochemistry Genetics and Molecular Biology Neurofibromatosis 1/genetics Article 03 medical and health sciences Organ Culture Techniques Ovarian cancer medicine Organoid PTEN Animals Cancer models Fallopian Tubes Ovary PTEN Phosphohydrolase Cancer General Chemistry medicine.disease Transplantation 030104 developmental biology Tumor progression Mutation Genetic engineering biology.protein Cancer research BRCA1 Protein/genetics lcsh:Q Ovary/pathology CRISPR-Cas Systems Tumor Suppressor Protein p53 Fallopian tube |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-14 (2020) Nature Communications Nature Communications, 11(1). Nature Publishing Group |
| ISSN: | 2041-1723 |
| Popis: | 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. The relative contribution of fallopian tube (FT) or ovarian surface epithelium (OSE) to high-grade serous ovarian cancer (HG-SOC) development is unclear. Here, the authors establish organoid models from murine oviductal and OSE tissues that allow cancer modeling via CRISPR-Cas9 genome editing, and report a dual origin of murine HG-SOC. |
| Databáze: | OpenAIRE |
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