UNCOVERING HOW TISSUE-SPECIFIC WNT SIGNALING DRIVES COLORECTAL CANCER BEHAVIOUR: A WAY TO DISTINGUISH NORMAL CELLS FROM CANCER CELLS

Wnt signaling is a conserved cell-communication pathway that induces changes in cell behavior during tissue development and homeostasis. Deregulation of this pathway causes several human diseases, in particular colorectal cancer (CRC).

Ca. 90% of CRC cases are caused by loss-of-function of the tumor suppressor gene APC, leading  to uncontrolled activation of Wnt signaling. However, blocking the aberrantly activated Wnt pathway is a difficult task. First, a clear molecular target in the cascade is lacking.

Second, a general inhibition of Wnt signaling is undesirable, as it would impair homeostatic regeneration also of non-malignant cells.

We have previously found that the  in vivo  targeting of the Wnt-related transcriptional activator BCL9 impairs the metastatic traits of CRC without altering intestinal homeostasis. Moreover, we have recently discovered that the limb transcription factor TBX3 assists BCL9 during limb development. Interestingly, while TBX3 is not expressed in normal intestinal epithelium, it becomes overexpressed in CRC.

This generates the impetus to understand if TBX3 is required for BCL9 activity also during CRC progression.

We are determined to understand the mechanism of action of TBX3 in CRC, as this may allow to distinguish CRC from homeostatic cells of the same epithelium.

Finally, we will assess whether the inhibition of the mechanisms uncovered affects metastasis formation, and if they may represent targets for therapeutic interventions to cure CRC.