Project 3
Prof. Dr. Florian Greten
Functional analysis of pathways mediating intestinal stem cell plasticity

In intestinal cancer, Lgr5/Bmi1-expressing intestinal stem cells comprise the cells of origin. Activating mutations in the Wnt pathway have to occur in these cells for a tumor to develop thus underscoring the concept of hierarchical organization of a tumor. We recently obtained evidence that cell plasticity can occur in this hierarchical organization. Enhanced Wnt signaling allows dedifferentiation of post-mitotic epithelial cells and reacquisition of stem cell genes. Once these cells re-express stem cell markers, they are capable of initiating tumorigenesis. Cancer stem like cells (CSLC) are considered essential for tumor maintenance. Moreover, CSLC have been shown to be resistant to chemo- and radiotherapy. Therefore, concepts aiming to eliminate CSLC hold great promise for the therapy of CRC. However, based on our results obtained during tumor initiation and because of the high degree of cell plasticity in an established tumor which is most likely strongly influenced by the tumor microenvironment, we hypothesize that CSLC can be replenished after their elimination by other tumor cells. The aim of this project is to critically examine this concept using genetic models to ablate different subtypes of CSLC. Moreover, we intend to examine whether the inflammatory pathways that have been responsible for de-differentiation during tumor initiation may also be involved in the formation of CSLC.

Publications in the course of this funding:

De Oliveira T, et al.: Loss of Stat6 affects chromatin condensation in intestinal epithelial cells causing diverse outcome in murine models of inflammation-associated and sporadic colon carcinogenesis.
Oncogene. 2018 Oct 23. doi: 10.1038/s41388-018-0551-2. [Epub ahead of print]

Ziegler PK, et al.: Mitophagy in Intestinal Epithelial Cells Triggers Adaptive Immunity during Tumorigenesis.
Cell. 2018 Jun 28;174(1):88-101.e16.

Canli Ö, et al.: Myeloid Cell-Derived Reactive Oxygen Species Induce Epithelial Mutagenesis
Cancer Cell. 2017 Dec 11;32(6):869-883.e5

Varga J, Greten FR: Cell plasticity in epithelial homeostasis and tumorigenesis.
Nat Cell Biol. 2017 Oct;19(10):1133-1141.