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
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.
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.
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.