Periodic Reporting for period 4 - COLGENES (Defining novel mechanisms critical for colorectal tumourigenesis)
Período documentado: 2022-02-01 hasta 2023-01-31
The sequencing of cancer genomes has led to a paradigm shift in our understanding of how tumours form and spread. These projects have identified thousands of genetic alterations that broadly segregate into two groups, a small number of frequently mutated genes and a much larger number of infrequently mutated genes. The causative role of frequently mutated genes is often clear and are the focus of concerted therapeutic development efforts. The role of those infrequently mutated is often unclear and can be difficult to separate from ‘mutational noise’. Determining the relevance of low frequency mutations is important for providing a full understanding of processes driving tumourigenesis and if functionally relevant may have broader implications on the applicability of targeted therapies. The aim of this project is to determine whether infrequently mutated genes contribute to the colorectal tumourigenesis. Using a combination of CRISPR genetic disruption in state-of-the-art 3D mouse and human organoid cultures and advanced mouse models I will characterise the importance of the entire spectrum of mutations in CRC. This will open new avenues of research into the function of these genes and more broadly, has the potential to make a profound impact on how we think about tumourigenic mechanisms and cancer therapeutics.
We have developed and utilised a new method for identifying genes that when mutated drive colorectal tumourigenisis. This has led us to identify numerous new cancer driver genes several of which we have investigated in more detail. These genes are mutated at low frequency in colorectal cancer suggesting that infrequently mutated genes can contribute to tumour development. The function of these genes is interesting. One of them appears to function in a similar way to other, well known cancer driver genes and is therefore likely to represent an alternative pathway for tumour initiation via this route. Another has a much different function. When mutated it leads to a reprogramming of adult intestinal tissue to a state reminiscent of the developing, fetal intestine. This reprogramming is also observed during intestinal regeneration suggesting that mutations in this gene drive cancer initiation via a different path, with similarities to tissue regeneration. A third, controls a process called cell plasticity, and, when mutated, leads to cancer progression. Together, the main results of our project support our original hypothesis that infrequently mutated genes contribute to cancer. In addition to this, by investigating in more detail, the function of these genes we are gaining a better understanding of the different ways tumours can form and spread. We believe that these findings will have important implications on our understanding of cancer driving mutations.
We have also begun developing a beyond the state of the art method for inducing genetic mutations in adult mouse colon using gene editing technologies. The purpose of this technique is to enable rapid validation of potential tumour driving mutations in an animal model. Now that we have identified a number of new cancer driving mutations we are well placed to develop this technology to test them. If successful, this will provide an extremely useful tool for the field to use for identifying cancer driver genes. We expect this technique to be in place in the next year.
In addition to this, due to the progress made during our project, we expect to be able to investigate the function of a number of additional novel cancer driver genes, thus increasing our understanding of tumour driving mechanisms. We think the results of this project will inform future work to determine the implications our findings have on anti cancer therapy resistance mechanisms.
In addition to this, due to the progress made during our project, we expect to be able to investigate the function of a number of additional novel cancer driver genes, thus increasing our understanding of tumour driving mechanisms. We think the results of this project will inform future work to determine the implications our findings have on anti cancer therapy resistance mechanisms.