Team identifies cause of deadly ovarian cancer

Researchers have identified the origin of ovarian cancer that develops in the fallopian tube, opening the door to the discovery of new methods of diagnosing the disease and potential therapies.

This cancer, called high-grade serous carcinoma, is the primary and most aggressive form of ovarian cancer, the sixth leading cause of cancer death in women, with most patients dying within five years of detection. There are no symptoms and no diagnostic tools exist for early detection.

Scientists knew little about its origins, but a study published in Natural communications identifies a transitional cell in the fallopian tube, called pre-ciliated tubal epithelial cells, as being particularly prone to cancer.

Pre-hair cells develop from stem cells and are intermediates in the lineage between the stem cells and their final state, called hair cells, which allow the movement of fluids and eggs through the fallopian tube.

“We not only identified the cells that cause cancer, but we also identified mechanisms that can potentially be used for new treatments and new diagnostic tools,” said Dr. Alexander Nikitin, professor of pathology at the Department of Biomedical Sciences of the College of Veterinary Medicine. and the main author of the paper.

The study was carried out on mice. The fallopian tube in humans is called the oviduct in mice, so researchers called it the uterine tube to refer to the same structure in both species. A high-grade serous carcinoma develops in both the ovary and part of the fallopian tube. While previous work by Nikitin and colleagues identified the origins of this cancer in the ovary, this is the first time they have identified cancer-prone cells in the fallopian tube.

The first stage of the study characterized all cell types found in the fallopian tube, which were not previously known. “The question was to what extent all cells contribute to ovarian cancer,” Nikitin said.

Nikitin and his colleagues also knew that in high-grade human serous carcinomas, a gene called TP53 (Trp53 in mice) is mutated in more than 96% of cases, while different components of a pathway controlled by another gene called retinoblastoma 1 (RB1 in humans, Rb1 in mice) are altered in more than 60% of cases. Both genes suppress tumors when functioning properly.

In previous research on high-grade serous carcinoma of the ovary, stem cells were one of the main culprits in cancer development after inactivation of Trp53 and Rb1. In the section of the fallopian tube that this study focused on, called the distal tubal epithelium, stem cells differentiate to become secretory or hair cells.

Researchers found no cancer, even a year after treatment, when Trp53 and Rb1 were silenced in engineered mouse stem cells, revealing that these cells themselves were not causing the cancer . Instead, they found that stem cells died after inactivating Trp53 alone or with Rb1.

“They just can’t live without Trp53, so instead of transforming the cells, you eliminate them,” Nikitin said.

The researchers noticed that high-grade serous carcinomas formed in a modified mouse after knockout of Trp53 and Rb1 in cells expressing a gene called Pax8. Using computational analysis based on single-cell sequencing data, they looked for cells that were not stem cells but expressed Pax8.

“We found that there is a population of cells that actually fit these criteria,” Nikitin said. “And the cells turn out to be premature ciliogenesis cells, or pre-ciliated transitional cells.”

Pre-hair cells are characterized by the expression of several very specific genes at different stages of their own development. One of these genes, Krt5, is specific to these pre-ciliated transitional cells. In another engineered mouse line, the researchers knocked out Trp53 and Rb1 in Krt5 pre-ciliated cells and found that the mice efficiently formed high-grade serous carcinomas.

Ciliogenesis, or the formation of cilia, is well studied, Nikitin said, which will make it easier to find potential diagnostic and therapeutic targets.