Abstract
The cell-of-origin of high grade serous ovarian carcinoma (HGSOC) remains controversial, with fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE) both considered candidates. Here, by using genetically engineered mouse models and organoids, we assessed the tumor-forming properties of FTE and OSE harboring the same oncogenic abnormalities. Combined RB family inactivation and Tp53 mutation in Pax8 + FTE caused Serous Tubal Intraepithelial Carcinoma (STIC), which metastasized rapidly to the ovarian surface. These events were recapitulated by orthotopic injection of mutant FTE organoids. Engineering the same genetic lesions into Lgr5 + OSE or OSE-derived organoids also caused metastatic HGSOC, although with longer latency and lower penetrance. FTE- and OSE-derived tumors had distinct transcriptomes, and comparative transcriptomics and genomics suggest that human HGSOC arises from both cell types. Finally, FTE- and OSE-derived organoids exhibited differential chemosensitivity. Our results comport with a dualistic origin for HGSOC and suggest that the cell-of-origin might influence therapeutic response.
Highlights
The cell-of-origin of high grade serous ovarian carcinoma (HGSOC) remains controversial, with fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE) both considered candidates
Previous mouse models showed that FTE can be the cell-of-origin of HGSOC, but a similar role for OSE had neither been excluded, nor demonstrated convincingly
By introducing the same genetic abnormalities into FTE or OSE in GEMMs and organoids, we establish that HGSOC can originate from either cell type (Supplementary Fig. 13)
Summary
The cell-of-origin of high grade serous ovarian carcinoma (HGSOC) remains controversial, with fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE) both considered candidates. Combined RB family inactivation and Tp53 mutation in Pax8 + FTE caused Serous Tubal Intraepithelial Carcinoma (STIC), which metastasized rapidly to the ovarian surface. These events were recapitulated by orthotopic injection of mutant FTE organoids. Attention turned to the fallopian tube epithelium (FTE) as the likely cell-of-origin after serous tubular intra-epithelial carcinomas (STICs), defined as in situ neoplasms with increased proliferative capacity, TP53 mutation, and other characteristic markers, were reported in the fallopian tube fimbria of women with BRCA1/2 mutations undergoing risk-reducing salpingoophorectomy[10,11,12]. Some genomic studies have found that HGSOCs can metastasize to the FT and mimic STICs25,26, consistent with a non-FTE origin, whereas metastases from other sites (e.g., uterine serous carcinoma) can apparently mimic STICs26–29
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