High‐grade serous carcinomas arise in the mouse oviduct via defects linked to the human disease

Zhai, Yali; Wu, Rong; Kuick, Rork; Sessine, Michael; Schulman, Stephanie; Green, Megan; Fearon, Eric R.; Cho, Kathleen R.

doi:10.1002/path.4927

Cited by 81 publications

(108 citation statements)

References 24 publications

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“…Conversely, a mouse model with Pten deletion, Tp53 deletion or mutation, and Brca1/2 deletion driven by the Pax8 promoter, which is expressed selectively in FTE secretory cells (not in OSE) develops STIC-like lesions and eventually, widely metastatic HGSOC (37). Similar results were seen with in mice that express SV40 large T-antigen (TAg) (38) or with simultaneous mutation of Brca1 , Tp53 , Rb1 and Nf1 in Ovgp1 -expressing secretory FTE (39).…”

Section: Introductionsupporting

confidence: 77%

“…2). Thus, while it is clear that HGSOC can arise from mouse FTE, we cannot be certain that FTE secretory cells (as opposed to Pax8- derived, but Pax8- ciliated cells or a specialized Pax8+ progenitor) are the actual/unique cell-of-origin in the FT. Others have found that the Ovgp1 promoter also can drive HGSOC (38,39). This Cre line purportedly is secretory cell-specific (55), but lineage tracing studies have not been reported.…”

Section: Discussionmentioning

confidence: 99%

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Both Fallopian Tube and Ovarian Surface Epithelium Can Act as Cell-of-Origin for High Grade Serous Ovarian Carcinoma

Neel

Zhang

et al. 2018

Preprint

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The cell-of-origin of high grade serous ovarian carcinoma (HGSOC) remains controversial, with fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE) each suggested as candidates. Here, by using genetically engineered mouse models and novel organoid systems, we assessed the tumor-forming capacity and properties of FTE and OSE harboring the same oncogenic abnormalities. Combined RB family inactivation (via T121 expression) and Tp53 mutation in Pax8+ FTE caused transformation to Serous Tubal Intraepithelial Carcinoma (STIC), which rapidly metastasized to the ovarian surface. This mouse model was recapitulated by FTE organoids, which, upon orthotopic injection, generated widely metastatic HGSOC. The same genetic lesions in Lgr5+ OSE cells or organoids also caused metastatic HGSOC, although with longer latency and lower penetrance. Comparative transcriptome analysis was consistent with different human HGSOCs arising from FTE and OSE. Furthermore, FTE- and OSE-derived organoids showed differential sensitivity to HGSOC chemotherapeutics. Our results comport with a dualistic origin for HGSOC and suggest the cell-of-origin could influence therapeutic response. SIGNIFICANCE The cell-of-origin for high grade serous ovarian carcinoma (HGSOC) has been controversial. By generating novel GEMMs and organoid models with the same oncogenic defects, we demonstrate that HGSOC can originate from either fallopian tube epithelium (FTE) or ovarian surface epithelium (OSE). Importantly, FTE- and OSE-derived tumors differ significantly in biologic properties.

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Section: Introductionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Both Fallopian Tube and Ovarian Surface Epithelium Can Act as Cell-of-Origin for High Grade Serous Ovarian Carcinoma

Neel

Zhang

et al. 2018

Preprint

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“…A large number of cancer-driving CNV loci that encode proteins have been successfully identified using high-throughput genome sequencing technologies (5,6). Taking epithelial cancers as an example, integrated cancer genomic analysis and transgenic animal model have confirmed some well-known amplicons induced proto-oncogenic proteins like MYC (7) and PIK3CA (8), as well as deletions induced tumor suppressor-like RB1 (9) and PTEN (10).…”

Section: Introductionmentioning

confidence: 99%

The Circular RNA circPRKCI Promotes Tumor Growth in Lung Adenocarcinoma

et al. 2018

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1Somatic copy-number variations (CNV) may drive cancer progression through both coding and 2 noncoding transcripts. However, noncoding transcripts resulting from CNV are largely unknown, 3 especially for circular RNAs. By integrating bioinformatics analyses of alerted circRNAs and 4 focal CNV in lung adenocarcinoma (LAC), we identify a proto-oncogenic circular RNA 5 (circPRKCI) from the 3q26.2 amplicon, one of the most frequent genomic aberrations in multiple 6 cancers. circPRKCI was overexpressed in LAC tissues, in part due to amplification of the 3q26.2 7 locus, and promoted proliferation and tumorigenesis of LAC. circPRKCI functioned as a sponge 8 for both miR-545 and miR-589 and abrogated their suppression of the pro-tumorigenic 9 transcription factor E2F7. Intra-tumor injection of cholesterol-conjugated siRNA specifically 10 targeting circPRKCI inhibited tumor growth in a patient-derived LAC xenograft model. In 11 summary, circPRKCI is crucial for tumorigenesis and may serve as a potential therapeutic target in 12 LAC patients. 13

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“…In our prior studies aimed at developing various genetically engineered mouse models of ovarian and oviductal carcinomas , we occasionally identified endosalpingiosis‐like lesions in mouse ovaries. The lesions, which we refer to hereafter as endosalpingiosis, are typically characterized by small glands or cysts near the ovarian hilum (Figure A), though occasional glands/cysts are present in the subserosal ovarian cortex distant from the hilum (Figure B).…”

Section: Resultsmentioning

confidence: 99%

Lineage tracing suggests that ovarian endosalpingiosis does not result from escape of oviductal epithelium

Wang

Sessine

Zhai

et al. 2019

The Journal of Pathology

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Most high‐grade serous carcinomas are thought to arise from Fallopian tube epithelium (FTE), but some likely arise outside of the tube, perhaps from ectopic tubal‐type epithelium known as endosalpingiosis. Importantly, the origin of endosalpingiosis is poorly understood. The proximity of the tubal fimbriae to the ovaries has led to the proposal that disruptions in the ovarian surface that occur during ovulation may allow detached FTE to implant in the ovary and form tubal‐type glands and cysts. An alternative model suggests that cells present in ectopic locations outside the Müllerian tract retain the capacity for multi‐lineage differentiation and can form glands with tubal‐type epithelium. We used double transgenic Ovgp1‐iCreERT2;R26RLSL‐eYFP mice, which express an eYFP reporter protein in OVGP1‐positive tissues following transient tamoxifen (TAM) treatment, to track the fate of oviductal epithelial cells. Cohorts of adult mice were given TAM to activate eYFP expression in oviductal epithelium, and ovaries were examined at time points ranging from 2 days to 12 months post‐TAM. To test whether superovulation might increase acquisition of endosalpingiosis, additional cohorts of TAM‐treated mice underwent up to five cycles of superovulation and ovaries were examined at 1, 6, and 12 months post‐TAM. Ovaries were sectioned in their entirety to identify endosalpingiosis. Immunohistochemical staining for PAX8, tubulin, OVGP1, and eYFP was employed to study endosalpingiosis lesions. Ovarian endosalpingiosis was identified in 14.2% of TAM‐treated adult mice. The endosalpingiotic inclusion glands and cysts were lined by secretory and ciliated cells and expressed PAX8, tubulin, OVGP1, and eYFP. Neither age nor superovulation was associated with a significant increase in endosalpingiosis. Endosalpingiosis was also occasionally present in the ovaries of pre‐pubertal mice. The findings imply that ovarian endosalpingiosis in the mouse does not likely arise as a consequence of detachment and implantation of tubal epithelium and other mechanisms may be relevant. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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High‐grade serous carcinomas arise in the mouse oviduct via defects linked to the human disease

Cited by 81 publications

References 24 publications

Both Fallopian Tube and Ovarian Surface Epithelium Can Act as Cell-of-Origin for High Grade Serous Ovarian Carcinoma

Both Fallopian Tube and Ovarian Surface Epithelium Can Act as Cell-of-Origin for High Grade Serous Ovarian Carcinoma

The Circular RNA circPRKCI Promotes Tumor Growth in Lung Adenocarcinoma

Lineage tracing suggests that ovarian endosalpingiosis does not result from escape of oviductal epithelium

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