PreCODE · Identifying the role of injury-associated cellular reprogramming in the early oncogenic transformation of human colonic epithelium

Colorectal cancer represents a major public health problem being the second leading cause of cancer-related deaths worldwide. The treatment management of the already developed disease is however often time-consuming, expensive and rarely 100% effective. Therefore, the goal should be to start diagnosing and managing the diseased state as early as possible when cancer is still curable. The early cellular transformation events remain poorly understood as cancer-associated mutations have been found to be surprisingly prevalent in seemingly healthy tissues, suggesting the requirement for a potent trigger mechanism. With this project, I aim to study the early colonic transformation via a completely unique hypothesis and approach. My strategy is built on the emerging new “injury-triggered fetal-like state” concept guided by my host lab and the hypothesis that oncogenic mutations require transcriptional reprogramming to a more susceptible fetal-like state to trigger transformation. This hypothesis relies on the fact that the fetal-like state is observed during injury and also in subsets of tumors indicating that cellular reprogramming could play a prominent role in promoting oncogenic transformation. As a primary model system, I will make use of my extensive experience with cancer modeling via 3D human-derived organoids and CRISPR technology, and elevate these techniques by the state-of-the-art expertise available at the host lab and/or institution, such as in vivo orthotopic cell transplantation, epigenetic profiling, advanced CRISPR-screening methodology and clinical collaboration. By bringing together such intelligent methodology, I will be able to effectively investigate the role of injury-induced cellular reprogramming in the transformation of human colonic epithelium. The results of this work will shape the future directions of my own prospective lab, but also cancer research in general, promising major new implications on early cancer detection strategies.