Coevolution of epithelium in colorectal cancer: comprehensive characterization of progress-associated tumor heterogeneity in the colorectal cancer

To understand the characteristics of colorectal cancer (CRC), diverse molecular classifiers have been generated. But these only capture the characteristics of the tumor at a specific stage or in a specific section. CRC has continuously evolving entities, with a complex adenoma-carcinoma sequence and later carcinoma-metastasis sequence, in a continuous coevolutionary crosstalk with the tumor microenvironment. Our past work has shown representative features in the carcinoma, and the current work will elaborate these in detail, integrating different data inputs needed to characterize the dynamic information in these lesions. The adenoma-carcinoma stages of CRC offer a unique opportunity, if exploited well, to understand evolutionary trajectories of the epithelium, the co-evolution of the TME and the possible impact on the targetable immune states. With this project, I will characterize the tumor cells’ sub-characteristics within classified epithelial molecular groups with integration approaches of bulk, single-cell and spatial technologies. In the preliminary data, the heterogeneous pattern within molecular subtypes can clearly be found. Especially, the understudied non adenomatous lesions, non-canonical Wnt driven tumors show very interesting heterogeneity and novel cancer stem cell dynamics. Collectively, signatures combined with bulk-, single-cell RNA sequencing and spatial techniques will identify the optimal stratification for CRC prognosis and therapy.