Computational Oncology: Exploring the origin of Colon Cancer

22. July 2021

Colon cancer is one of the most common cancers in men and women worldwide. Due to the microscopic size of the morphological units in the colon from which cancer originates, the processes during cancer initiation remain clinically obscure. Researchers from Heidelberg and Leipzig have used computer simulations to model biological processes behind the initial steps of colon cancer development to unravel the otherwise invisible cancer formation process. Their research has now been published in the Special Issue “Frontiers in quantitative cancer modeling” of the journal “Computational and Systems Oncology”.

The human colon consists of several million cells which, like other highly proliferating cells in our body, divide rapidly. During this replication process, mutations can occur that may alter the behavior of the cell. Certain types of mutations enable the mutated cell to divide more frequently than its neighboring cells without this mutation. After some time, the mutated cells overgrow the non-mutated cells in the colon because of their rapidly increasing number. The mutated cells might even take over an entire colonic crypt (also referred to as intestinal gland), which is a collection of a few thousand cells in the colon wall. Those single mutated crypts might then develop into a polyp or adenoma (precancerous tissue formations that are looked for in colonoscopy) or even a manifest cancer.

Current research suggests that specific mutated crypts are the origin of colon cancer. Therefore, analyzing these mutational processes within a crypt is key for understanding early cancer development and may have significant implications for cancer prevention. However, as the colonic crypts are too small and too numerous, scientists cannot directly observe these processes in humans.

A team of scientists from Heidelberg and Leipzig has now built a computational model to simulate these mutational processes within a crypt on a computer. These computer simulations allow to analyze if and how fast different so-called driver mutations which play a key role in cancer formation take over a crypt. The scientists focused in their work on the Lynch syndrome, a genetic condition which leads to an increased risk of developing colon cancer during lifetime. The research was conducted in the framework of the “Mathematics in Oncology” initiative including scientists from HITS, Heidelberg University, and the University Hospital Heidelberg. The paper of their work has now been published in the Special Issue “Frontiers in quantitative cancer modeling” of the journal Computational and Systems Oncology. The mathematicians Saskia Haupt and Vincent Heuveline (DMQ Group at HITS and EMCL Group at Heidelberg University) have also presented those results at the online SMB Meeting , the annual meeting of the Society for Mathematical Biology, in June 2021.

Cancer research: A computational approach

Building on existing approaches which are already used for simulating healthy colon tissue, the researchers incorporated recent biomedical data and clinical observations into their model to make the computer simulations for the crypts as realistic as possible. In their paper, the researchers quantified each mutation’s potential to take over entire crypts for different types of mutations and investigated how the mutation spread is influenced by the cell location within the crypt or the stem cell dynamics.

The now conducted simulations show that simulated driver mutations in an active stem cell almost always take over the entire crypt within a few weeks. Depending on the location of the mutated cell, there are different possibilities to spread throughout the crypt, either in a top-down or in a bottom-up process (see video). The researchers showed in their simulations that both scenarios are theoretically possible.

Bottom-up process of a driver mutation spread throughout a crypt.
The crypt is populated by a stem cell at the bottom of the crypt. The cells in the lower region of the crypt replicate leading to an upward movement of the cells to the top of the crypt. After some time, a first driver mutation (light grey) occurs at the bottom of the crypt which is followed by a further mutation in the same gene (dark grey). Subsequently, this mutation spreads throughout the crypt quite fast from the bottom to the top of the crypt. This entire process is known as bottom-up morphogenesis.

Current studies indicate that there is always one active stem cell populating a crypt which is, after some time, replaced by a neighboring stem cell. In simulations, the researchers observed the following scenario: If a mutated stem cell is replaced by a non-mutated stem cell, it is possible that the previous mutation does not take over the crypt or at least that the time of spread is prolonged. This means that stem cell exchange can restore the integrity of crypts and contribute to the elimination of specific mutations which are of particular importance for individuals with Lynch syndrome. In other words, a stem cell exchange might explain why some mutated crypts do not progress further to cancer and support the hypothesis of spontaneous regression of precancerous lesions in Lynch syndrome.

In general, the predictions of the time span required for taking over a crypt carrying certain mutations provide the basis for future studies. In particular, the researchers will address the time required for a mutated crypt to become an endoscopically visible lesion. Further, they will analyze how long it usually takes until a mutation occurs in a cell of a crypt. This is essential to obtain estimates for the duration of the whole cancer formation process. With these findings, the researchers want to support tailored treatment approaches for Lynch syndrome cancer patients and prevention strategies for cancer-free Lynch syndrome carriers.

Original Publication:

A computational model for investigating the evolution of colonic crypts during Lynch syndrome carcinogenesis, Comput Syst Oncol. 2021; DOI: 10.1002/cso2.1020

About HITS

The Heidelberg Institute for Theoretical Studies (HITS) was established in 2010 by the physicist and SAP co-founder Klaus Tschira (1940-2015) and the Klaus Tschira Foundation as a private, non-profit research institute. HITS conducts basic research in the natural sciences, mathematics and computer science, with a focus on the processing, structuring, and analyzing of large amounts of complex data and the development of computational methods and software. The research fields range from molecular biology to astrophysics. The shareholders of HITS are the HITS-Stiftung, which is a subsidiary of the Klaus Tschira Foundation, Heidelberg University and the Karlsruhe Institute of Technology (KIT). HITS also cooperates with other universities and research institutes and with industrial partners. The base funding of HITS is provided by the HITS Stiftung with funds received from the Klaus Tschira Foundation. The primary external funding agencies are the Federal Ministry of Education and Research (BMBF), the German Research Foundation (DFG), and the European Union.

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