New organoid model to study the origin of colorectal cancer

Colorectal cancer is caused by the accumulation of mutations in different genes, for instance, genes involved in cell growth. One commonly mutated gene is the MLH1 gene. This gene normally prevents errors during DNA replication, thereby reducing the risk of mutations occurring in the DNA. Patients with an inherited MLH1 mutation have a condition called Lynch’s syndrome, in which the gene is inactive. Due to the malfunctioning of the MLH1 gene, these patients are at higher risk of developing colorectal cancer at an early age because mutations accumulate in their DNA faster than in that of healthy people.

Uncovering the sequence using colon organoids

Patients with Lynch syndrome often develop tumors that are different from those occurring in spontaneous colorectal cancer cases. These tumors happen at an earlier age, are caused by a different kind of mutations, and are referred to as Microsatellite Instability High (MSI-H) tumors. It is unclear in what sequence these mutations occur and therefore the early stages of colorectal MSI-H cancer formation are difficult to understand. Tomohiro Mizutani, co-first author on the paper, says: “This process of tumor formation is difficult to study because it is challenging to identify the individual mutations as they happen and to obtain a clear picture of the sequence in which mutations accumulate.” The researchers decided to investigate the sequential order of mutation accumulation by using colon organoids, to model the transition from a normal cell to a cancer cell. Colon organoids or mini-intestines are 3D structures that closely recapitulate the biology of the colon in our body and therefore allow the researchers to study health and disease in great detail.

Miniaturized model

To mimic the tumors occurring in Lynch syndrome patients, the researchers started with a single human colon cell, genetically modified to have a mutation in the MLH1 gene. This single cell was grown into organoids that spontaneously developed multiple critical mutations across several key genes. Matteo Boretto, co-first author on the paper, explains: “This allowed us to investigate each mutational step as it happened and generate a model of spontaneous tumor formation.” This closely mimicked the progression of a normal cell into a cancerous one seen in patients with MSI-H tumors. Surprisingly, the study found that certain mutations occurred in a different order than expected, which could influence the genetics of the colon cancer cell. This in turn, could affect the further development of the tumor and have consequences for treatment.

Future prospects

These findings provide valuable insights into the initial stages of tumor development in MSI-H colorectal cancers. They enable researchers to observe how mutations spread through individual cells and how these altered cells manage to grow unchecked by normal cellular controls. This research marks a further step in our understanding of how colorectal cancer begins and progresses.

Publication:

Recapitulating the adenoma-carcinoma sequence by selection of four spontaneous oncogenic mutations in mismatch repair-deficient human colon organoid. Tomohiro Mizutani*, Matteo Boretto*, Sangho Lim, Jarno Drost, Diego Montiel González, Rurika Oka, Maarten H. Geurts, Harry Begthel, Jeroen Korving, Johan H. van Es, Ruben van Boxtel and Hans Clevers. Nature Cancer, 2024.
*These authors contributed equally.