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Evolution of the earliest stages of ovarian cancer from mutant fallopian tube epithelial cells

ABSTRACT: Ovarian cancer is also known as a silent killer as women are usually diagnosed in advanced stages when the disease has already spread to vital peritoneal organs leading to poor survival. Therefore, improving outcomes for this disease would require a greater understanding of the earliest stages, where the disease can be cured with current treatments. Fallopian tubes (FTs) are a site of origin of ovarian cancer. Here, by combining gene sequencing, proteomics, organoids, mouse genetics, lineage tracing, and quantitative modeling, we showed that mutant Pax8+ FT progenitor cells gain clonal growth advantage over their wild-type neighbors and expand over time, colonizing large areas of FT epithelium, resulting in the formation of pre-cancerous lesions. The growth of these precursor lesions is modulated by ovarian hormones, where estrogen promotes and progesterone suppresses their growth. Collectively, this study provides insight into how a single mutant FT epithelial cell leads to early ovarian cancer evolution.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Muhammad Fairuz Jamaluddin Dr Pradeep Tanwar

PROVIDER: MSV000093831 | MassIVE | Wed Jan 10 16:51:00 GMT 2024

SECONDARY ACCESSION(S): PXD048419

REPOSITORIES: MassIVE

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Project description:Recent evidence suggests that ovarian high-grade serous carcinoma (HGSC) originates from the epithelium of the fallopian tube. However, most mouse models are based on the previous prevailing view that ovarian cancer develops from the transformation of the ovarian surface epithelium. Here, we report the extensive histological and molecular characterization of the mogp-TAg transgenic mouse, which expresses the SV40 large T-antigen (TAg) under the control of the mouse müllerian-specific Ovgp-1 promoter. Histologic analysis of the fallopian tubes of mogp-TAg mice identified a variety of neoplastic lesions analogous to those described as precursors to ovarian HGSC. We identified areas of normal appearing p53-positive epithelium that are similar to “p53 signatures” in the human fallopian tube. More advanced proliferative lesions with nuclear atypia and epithelial stratification were also identified that were morphologically and immunohistochemically reminiscent of human serous tubal intraepithelial carcinoma (STIC), a potential precursor of ovarian HGSC. Beside these noninvasive precursor lesions, we also identified invasive adenocarcinoma in the ovary of 56% of the mice. Microarray analysis revealed several genes differentially expressed between the fallopian tube of mogp-TAg and WT C57BL/6. One of these genes, Top2a, which encodes topoisomerase II-alpha, was shown by immunohistochemistry to be concurrently expressed with elevated p53 and specifically elevated in mouse STICs, but not in surrounding tissues. TOP2A protein was also found elevated in human STICs, low-grade, and high-grade serous carcinoma. The mouse model reported here displays a progression from normal tubal epithelium to invasive HGSC in the ovary, and therefore closely simulates the current emerging model of human ovarian HGSC pathogenesis. This mouse therefore has the potential to be a very useful new model for elucidating the mechanisms of serous ovarian tumorigenesis, as well as for developing novel approaches for the prevention, diagnosis, and therapy of this disease. Keywords: transgenic mouse model, ovarian cancer, fallopian tube, intraepithelial carcinoma 6 mouse fallopian tubes (FT) were analyzed with experimental repeats; 3 wildtype C57BL6 mice (FT) and 3 transgenic mogp-TAg (FT), with one set of each at 7, 8 and 9 weeks of age.

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Evolution of the earliest stages of ovarian cancer from mutant fallopian tube epithelial cells

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