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TP53 loss initiates chromosomal instability in fallopian tube epithelial cells.

ABSTRACT: High-grade serous ovarian cancer (HGSOC) originates in the fallopian tube epithelium and is characterized by ubiquitous TP53 mutation and extensive chromosomal instability (CIN). However, direct causes of CIN, such as mutations in DNA replication and mitosis genes, are rare in HGSOC. We therefore asked whether oncogenic mutations that are common in HGSOC can indirectly drive CIN in non-transformed human fallopian tube epithelial cells. To model homologous recombination deficient HGSOC, we sequentially mutated TP53 and BRCA1 then overexpressed MYC. Loss of p53 function alone was sufficient to drive the emergence of subclonal karyotype alterations. TP53 mutation also led to global gene expression changes, influencing modules involved in cell cycle commitment, DNA replication, G2/M checkpoint control and mitotic spindle function. Both transcriptional deregulation and karyotype diversity were exacerbated by loss of BRCA1 function, with whole-genome doubling events observed in independent p53/BRCA1-deficient lineages. Thus, our observations indicate that loss of the key tumour suppressor TP53 is sufficient to deregulate multiple cell cycle control networks and thereby initiate CIN in pre-malignant fallopian tube epithelial cells. This article has an associated First Person interview with the first author of the paper.

SUBMITTER: Bronder D

PROVIDER: S-EPMC8649171 | biostudies-literature |

REPOSITORIES: biostudies-literature

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TP53 loss initiates chromosomal instability in fallopian tube epithelial cells

Project description:High-grade serous ovarian cancer originates in the fallopian tube and is characterized by ubiquitous mutations in TP53. Here, we generated TP53 single-, TP53/BRCA1 and TP53/MYC double- and TP53/BRCA1/MYC triple-mutant subclones of the fallopian tube-derived cell line FNE1 using CRISPR/Cas9. These mutant subclones were subsequently subjected to RNA sequencing to determine the impact of these oncogenic mutations on signaling pathways.

2021-09-28 | GSE182487 | GEO

TP53 loss initiates chromosomal instability in fallopian tube epithelial cells

Project description:TP53 loss initiates chromosomal instability in fallopian tube epithelial cells

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In vitro three-dimensional modeling of fallopian tube secretory epithelial cells.

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YAP induces high-grade serous carcinoma in fallopian tube secretory epithelial cells.

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Molecular requirements for transformation of fallopian tube epithelial cells into serous carcinoma.

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Mucinous adenocarcinoma developed from human fallopian tube epithelial cells through defined genetic modifications.

Project description:Recent studies have suggested that some ovarian and pelvic serous carcinomas could originate from the fimbriated end of the distal fallopian tube. To test this hypothesis, we immortalized a normal human fallopian tube epithelial (FTE) cell line by using retrovirus-mediated overexpression of the early region of the SV40 T/t antigens and the human telomerase reverse transcriptase subunit (hTERT). These immortalized FTEs were then transformed by ectopic expression of oncogenic human HRAS (V12) . Tumorigenicity of the immortalized and/or transformed cells was subsequently tested by anchorage-independence growth assay and inoculation into nude mice via subcutaneous and intraperitoneal injection. As expected, the HRAS (V12) -transformed FTEs produced tumors through both subcutaneous and intraperitoneal injections, whereas no tumor growth was observed in immortalized FTEs. Unexpectedly, histopathological examination of tumors resulting from subcutaneous as well as intraperitoneal injections revealed largely poorly differentiated mucinous adenocarcinoma mixed with undifferentiated carcinoma. The tumor implants invaded extensively to the liver, colon, spleen, omentum, adrenal gland and renal capsule. Immunohistochemical staining of tumor cells showed positive staining for the epithelial cell markers cytokeratin AE1/AE3 and Müllerian lineage marker PAX8. Our study demonstrates that FTEs can generate poorly differentiated mucinous adenocarcinoma mixed with undifferentiated carcinoma through genetic modifications. Thus, we provide the first experimental evidence that fimbrial epithelial cells of the fallopian tube could be a potential source of ovarian mucinous adenocarcinoma.

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