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Molecular Subtype Specific Stem Cell Dynamics in Developing and Established Colorectal Cancers

Periodic Reporting for period 4 - CRCStemCellDynamics (Molecular Subtype Specific Stem Cell Dynamics in Developing and Established Colorectal Cancers)

Reporting period: 2019-10-01 to 2021-03-31

Colon cancer is a very common malignancy with a high burden of disease and mortality. Unfortunately, improvements in the outcome of disease have been limited in the last decades. A major contributing factor to this fact is that colon cancer is a highly heterogeneous disease. Both the variation in characteristics of colon cancers between individual patients is very large, and also within one colon tumor the cells can be widely distinct. These two aspects make it difficult to devise new therapies that effectively target all tumors, and all cells within the cancers. Therefore, personalized strategies are required to classify patients in subgroups with similar characteristics, and that in the future might guide treatment decisions. In addition, the variation in cell types within individual cancers needs to be understood better to make sure that we can effectively kill as many tumor cells as possible and not only specific populations.

The questions raised above are of major importance for society as annually 1.2 million cases of colorectal cancer are seen worldwide, and approximately 50% of these patients die as a result of this disease. Clearly, developments of novel more effective treatment strategies are therefore required. In order to achieve this more, fundamental insights in the biology of colon cancers and the origins of heterogeneity are pivotal.

The project CRCStemCellDynamics aims to understand how stem cells contribute to the heterogeneity of colon cancers both between patients and within individual cancers. We investigate how the specific cell of origin impacts on the properties of the resulting cancer. In addition we study how stem cell-like cells within established colon cancer tissue are responsible for the observation that within individual cancers some cells do respond to therapy and other do not, allowing for relapse of the disease. We study this by using state of the art biomolecular cancer models in combination with bioinformatic- and mathematical analyses.
Within the first phase of the project we were able to reach a consensus with a large team of international researchers on how to best describe colon cancer heterogeneity. We reported that four major colon cancer subtypes can be described based on gene expression data. All these four subtypes have unique molecular and clinical properties and now form the foundation of a large amount of follow-up work both in my team and worldwide.

Studying the origins of the variation between the subtypes we have investigated how the exact cell of origin is related to the gene expression program of the pre-malignant cells that derive from them upon induction of a oncogenic DNA change (mutation). We found that indeed the cell of origin has a major influence and that the differences between cell types is in fact enhanced by accumulation of mutations. These findings directly support a major hypothesis of the program that the cell of origin is pivotal for the phenotype and clinical properties of the malignancy.
Another focus has been intestinal stem cell competition underlying cancer development and growth. Here we use established quantitative frameworks of clonal dynamics following cancer-initiating mutations, such as Apc inactivation, the most common mutation in CRC. My laboratory recently uncovered the mechanism by which Apc-mutant clones outcompete their wild type neighbors through cell competition. We demonstrated that Apc-loss leads to a supercompetitor phenotype involving the secretion of Wnt antagonists that actively suppress the fitness of neighboring wild type cells by inducing differentiation. 

With respect to the heterogeneity of cells within individual cancers, and the role of stem cells in this matter we have made important progress. We have established a model system in which we can analyze the behavior of cells within colon cancer tissue. This model systems allows us to describe the ability of cells to contribute to tumor expansion in detail. The single most striking finding we have obtained so far is that the heterogeneity in the ability to drive tumor growth and relapse after therapy is for a large part dictated by the environment. This is in contrast to many earlier studies that suggest that also cell intrinsic properties, for example the degree of differentiation, define this. This is very valuable information as it enforces the idea that for effective therapy we should disrupt the interaction between the cancer cells and the cells in the microenvironment.
This project resulted in new and relevant scientific insights. We have established a very valuable model system that allows us to study the dynamics of cells within colon cancer tissue that can be exploited to test new treatment regimens in a more effective fashion. Using this model system we identified that that stem cells in cancers are not intrinsically distinct but rather represent a temporary cell state dependent on environmental input.
Furthermore, my laboratory, supported by the ERC starting grant, has made an important contribution to the consensus classification of colon cancer that is now widely adopted and forms the foundation of clinical studies and personalized drug development initiatives. In the coming years it will be established if these promising contributions to fundamental and translational colon cancer research will be converted into clinical benefit as well.
Fig 1 Consensus molecular subtypes (CMS) in colon cancer.
Fig 2 3D image of lineage tracing in human colon cancer tissue.