KWF grants for research on tumor vesicles and uterine cancer

The role of CTCF in uterine cancer

In different types of cancer, particularly cancers in organs that are very hormone-sensitive (prostate cancer, ovarian cancer, breast cancer and uterine cancer) a copy of the CTCF gene is often inactive. This gene produces the CTCF protein, which forms loops in our DNA and thereby acts as a kind of border guard that separates the long DNA molecules in segments.

How genes are turned on and off is determined for a large part by genetic on and off switches – enhancers. Such enhancers literally contact a gene it regulates to activate it. CTCF border guards can prevent an enhancer from contacting genes on the other side of the border, thereby preventing that the enhancer activates on unwanted genes.

Roel Neijts and Wouter de Laat will use their KWF-grant to investigate whether these borders are less strong when one of the two copies of the CTCF gene is turned off, as is the case in uterine cancer. In cells that have weaker borders enhancers can maybe contact and activate genes that should not be activated. These genes, so-called proto-oncogenes, can induce unwanted cell divisions which can result in uninhibited growth and tumor formation.

Together with the research groups of Hans Clevers and Alexander van Oudenaarden, Neijts and De Laat will use endometrium organoids, mini-organs of the endometrium, of multiple donors to investigate whether the boundaries on the DNA are indeed weakened when there is less CTCF protein in a cell. Subsequently, they will investigate which proto-oncogenes are activated as a result and whether this leads to more cell divisions. This will provide tehm with insights into how gene regulation may derail in cancers in which the CTCF gene is affected, which on and off switches are responsible for this, and what this means for genes that should not have been activated.

The role of exosomes in colorectal cancer

Frederik Verweij will use his Young Investigator Grant to study two essential steps during metastasis of colorectal cancer. The first step is the development of blood vessels to the tumor, called tumor angiogenesis; the second step is the attachment of circulating tumor cells – tumor cells that have escaped the primary tumor and have ended up in the circulation – at the site of the metastasis. Small vesicles that are secreted by the tumor, called exosomes, seem to be involved in both processes. These vesicles are so small, around 50-150 nanometers in diameter, that in practice, they can only be studied indirectly. This makes research into these vesicles more difficult.

During his PhD and postdoc, Verweij developed cellular and in vivo models to study these vesicles with video-microscopy in zebrafish. He will use these techniques at the Hubrecht Institute in collaboration with the research groups of Jeroen Bakkers and Hans Clevers, to study the two essential steps in colorectal cancer metastasis.

He will use the zebrafish model to study how exosomes behave and which role they exactly play. In addition, he will use colorectal cancer organoids, mini-organs of colorectal cancer tumors, to study what the vesicles exactly contain that causes them to play this role in colorectal cancer metastasis.

New insights into these processes may lead to more specific therapies that can inhibit metastasis of a tumor in the future.