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

Kadi Lõhmussaar,Harry Begthel,Hans Clevers,Jeroen Korving,Celien P H Vreuls,Oded Kopper,Johan H Van Es

doi:10.1038/s41467-020-16432-0

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.

Highlights

High-grade serous ovarian cancer (HG-SOC)—often referred to as a “silent killer”—is the most lethal gynecological malignancy
It was believed that HG-SOC originates from the ovarian surface epithelium (OSE), which actively participates in the cyclical ovulatory rupture and repair processes[2]
It was previously shown that Lgr[5], a key player in the WNT signaling pathway, marks stem cells of the murine OSE23,24, and that estrogen plays a stimulatory effect on OSE growth and proliferation[25]

Summary

Introduction

High-grade serous ovarian cancer (HG-SOC)—often referred to as a “silent killer”—is the most lethal gynecological malignancy. One of the first indications that suggested the FT as a possible origin of ovarian cancer were the lesions that were identified in the FT of high-risk patients carrying BRCA1/2 germline mutations[4,5,6]. These lesions, that are referred to as serous tubal intraepithelial carcinomas (STICs), were found to carry mutations in the TP53 gene, as present in almost all cases of HG-SOC (96%)[7,8]. Understanding the early stages of HG-SOC development and its tissue of origin is crucial for the design of early diagnosis and preventive strategies, especially for high-risk individuals such as women with BRCA1 and BRAC2 germline mutations

Methods

Results

Conclusion