Thesis defense Kadi Lõhmussaar: Organoid technology as an emerging tool for gynecological oncology research

There are various types of gynecological cancers that affect different parts of the female reproductive system, such as the ovaries, fallopian tubes, uterus and cervix. The previous methods to model these cancers had many limitations. Researchers often used 2D cell lines, which were not able to fully recapitulate the tumors. Another method involves the use of mouse models, but differences in reproductive biology make it difficult to directly translate the results from mice to humans. The aim of Lõhmussaar and her colleagues was therefore to develop new organoid-based model systems for gynecological cancers. They started with modeling the most common and aggressive form of ovarian cancer.

The origin lies in the tubes, not the ovaries

The origin for this type of ovarian cancer has long been under debate. As the name implies, it was historically believed to arise from the ovarian epithelium, which is the tissue that lines the outer surface of the ovaries. However, more recent evidence suggests that the epithelium of the fallopian tubes, and not the ovaries, might be the main origin for this type of cancer. Lõhmussaar and her colleagues turned to organoid technology to shed light on the ongoing debate. Organoid technology allows the cultivation of mini organs in the lab. These organoids are about half a millimeter in size and closely mimic the function of actual organs. Organoids can be grown from the tissue of various types of animals, including mice and snakes, but also from healthy or sick tissue of humans.

Lõhmussaar derived organoids from the fallopian tube epithelium and the ovarian epithelium of mice. Consequently, she used a gene editing technique called CRISPR-Cas9 to remove a similar set of genes from both models and induce the growth of tumors. When transplanted into mice, the organoids derived from the fallopian tubes rapidly developed tumors, whereas the ovarian organoids did not. This implies that the origin of the most common type of ovarian cancer lies in the fallopian tubes and not the ovaries – at least in mice.

New model system

Researchers can also establish organoids from the sick tissue of humans. Many successful patient-derived cancer organoid models have been established previously, for example from the colon, pancreas and liver. However, until now, a long-term organoid model for ovarian cancer was lacking.

In her thesis, Lõhmussaar provides a protocol for the development of organoids from the tissue of patients with various subtypes of ovarian cancer. With this, she and her colleagues present the first long-term model system in the field of ovarian cancer. Now that Lõhmussaar and her colleagues have optimized organoid technology for the modelling of ovarian cancer, the protocol can be modified and applied to cultivate organoids from the tissue of other types of gynecological cancers. This way, Lõhmussaar brings organoid technology to the field of gynecological oncology and provides a valuable tool for further research.

Alternative defense

The ceremony of Lõhmussaar’s thesis defense was different than usual. “No guests were allowed at the Academy Hall, not even my opponents. It was just me, my paranymphs, my promotor and the chairman. The opponents were present virtually and my guests could follow the event via a live stream. This way, my family – who could not come over from Estonia due to the current pandemic – was still able to see my defense, albeit in an alternative way”, she says. Now that Lõhmussaar obtained her doctorate, she is going to start a postdoc in Copenhagen, hopefully in January. When asked about this next step in her career, she explains: “The past years in the Clevers’ lab made me a more independent researcher and gave me the confidence that I can do a postdoc.” However, her time in the Clevers’ lab has felt anything but isolated.  “The Clevers group is a real community. You can always ask anyone for help and we really complement each other. And that actually applies to the whole Hubrecht: I have always felt very welcome and I love all the connections I made during my time here.”