Spatiotemporal regulation of clonogenicity in colorectal cancer xenografts
Menée à l'aide de xénogreffes de cancer colorectal humain sur un modèle murin et à l'aide d'une modélisation, cette étude analyse l'évolution de la forme et de la disposition spatiale de clones de cellules cancéreuses durant le développement d'une tumeur
Colorectal cancer (CRC) is a heterogeneous disease, with significant variation in genotype and phenotype within each individual tumor. This intratumor heterogeneity emerges during tumor development due to clonal evolution and in part can explain therapy resistance in CRC. However, a detailed understanding of the spatiotemporal development of tumors underlying cancer evolution and intratumor heterogeneity remains absent. Here, we use lineage-tracing experiments of human CRC cells transplanted into immunocompromised mice, in combination with computational modeling, to study the growth mode of CRC. We found that the clonal position is crucial for clonal outgrowth. This demonstrates that, in addition to the genetic composition, the environment and the geometry of tumor growth play a significant role in shaping tumor evolution.Cancer evolution is predominantly studied by focusing on differences in the genetic characteristics of malignant cells within tumors. However, the spatiotemporal dynamics of clonal outgrowth that underlie evolutionary trajectories remain largely unresolved. Here, we sought to unravel the clonal dynamics of colorectal cancer (CRC) expansion in space and time by using a color-based clonal tracing method. This method involves lentiviral red-green-blue (RGB) marking of cell populations, which enabled us to track individual cells and their clonal outgrowth during tumor initiation and growth in a xenograft model. We found that clonal expansion largely depends on the location of a clone, as small clones reside in the center and large clones mostly drive tumor growth at the border. These dynamics are recapitulated in a computational model, which confirms that the clone position within a tumor rather than cell-intrinsic features, is crucial for clonal outgrowth. We also found that no significant clonal loss occurs during tumor growth and clonal dispersal is limited in most models. Our results imply that, in addition to molecular features of clones such as (epi-)genetic differences between cells, clone location and the geometry of tumor growth are crucial for clonal expansion. Our findings suggest that either microenvironmental signals on the tumor border or differences in physical properties within the tumor, are major contributors to explain heterogeneous clonal expansion. Thus, this study provides further insights into the dynamics of solid tumor growth and progression, as well as the origins of tumor cell heterogeneity in a relevant model system.