| dc.description.abstract | Summary:
Cells are the building blocks of all life and different types of cells combine to make up tissues and organs. Epithelial cells line the inside of the large intestine that includes the colon and the rectum. Each cell is programmed by a genetic code that gives instructions on every decision that the cell has to make, including division, growth, movement and death. These cellular processes are accomplished by genes that are being expressed according to the genetic code. When genes are expressed, proteins are produced that make up different parts of cells. The cells divide to give rise to new cells with the same characteristics as the mother cell. If there is a mistake in the genetic code also called a mutation, the cells could divide uncontrollably resulting in a massive formation referred to as a tumour. If the cells within the tumour accumulate more mutations, this could lead to some cells detaching and migrating to a different tissue in the body to form more tumours called metastases. Forming tumours and developing metastasis are part of the cancer disease, and cancer with metastases is called metastatic. The originating tissue of cancer gives it its name. When the cancer develops from the epithelium of the colon or rectum, it is referred to as colorectal cancer (CRC). CRC can be classified by specific mutations that often co-occur together. An aggressive and deadly type of metastatic CRC is highly associated with a mutation in the BRAF gene, that is abbreviated V600E, that forms a mutant BRAF protein. The V600E mutation is correlated with other genes, namely FOSL1. FOSL1 is known to be dysregulated in metastatic cancers, but the mechanism is poorly understood. The aim of this report is to understand how FOSL1 and its gene product called FRA1 are involved in metastatic CRC that has the V600E mutation in the BRAF gene. To address this aim we used small 3D spherical models of cancer that are referred to as organoids. The organoids were generated from patient-derived colorectal tumours positive for the BRAF-V600E mutation. The BRAF-V600E cancerous organoids were used in this study along with organoids that were corrected for the V600E mutation and produced a normal BRAF protein. We used anti-cancer drugs called chemotherapy to block the mutated BRAF protein and identified that FRA1 was also blocked. We mimicked the metastatic process and found out that the BRAF-V600E mutation causes the spherical organoids to change shape and to form sprouts protruding from the spheres. The shape of cells and organoids is called morphology. The sprouting morphology was reversed to spherical or normal when BRAF was blocked with chemotherapy. From that we concluded that the V600E mutation causes the change in shape possibly in combination with FRA1. We performed further experiments to understand how FRA1 interacts with other genes involved in metastasis, but we did not find a connection. | |
