Mechanisms of WNT-related tumour suppressor mutations in colorectal cancer progression

Abstract

In my PhD thesis, I explore how cancer cells hijack processes meant for healthy tissue growth. Healthy regeneration of our intestine relies on special cells called stem cells. Stem cells get instructions from nearby cells called niche cells that use signals like WNT to tell the stem cells to replenish the damaged tissue by making new cells. In the stem cells there are tumor suppressor genes that make sure the cells do not grow uncontrollably.

However, in colorectal cancers, these tumor suppressor genes are often mutated (damaged). I focused on the tumor suppressor gene RNF43 that is often mutated in an aggressive form of colorectal cancer. To study this, we grew tumor cells from patients into 3D mini-tumors (organoids) in the lab. In contrast to organoids from healthy intestinal stem cells, these mini-tumors could grow without the normally needed supplementation of signals, such as WNT. When we repaired the mutated RNF43 gene using advanced techniques (CRISPR), the mini-tumors needed the signals again and lost their ability to spread when transplanted into mice.

By looking closely at the cells in our mini-tumors, we discovered that the mutated RNF43 gene creates special cells within the tumor that fulfill a supporting role. These "tumor intrinsic niche cells" independently produce growth signals that allow the tumor to grow and spread aggressively. This research helps us understand how colorectal cancer spreads, and opens the door to potential new treatments.