A total inhibition of the Wnt signalling pathway is not appropriate, given its key role in homeostasis. “Ideally, a more targeted effect on proteins only involved in the constitutive activation of Wnt signaling is required. We think we have identified this protein: it is ELP3”.

For several years now, Pierre Close, a research associate at the FRS-FNRS and head of the Laboratory of Cancer Signalling (GIGA-Research, “Molecular Biology of Diseases” Unit), who published this study with Alain Chariot, has been working on Elongator, a six subunits complex (ELP1-6). He has been working more specifically on ELP3, which is involved in other areas (Read :  Neuron migration ‘under the wing’ of Elongator). Both collaborators have therefore sought to understand its involvement in the development of intestinal cancer cells.

APC and ELP3

When APC is lost, β-catenin stabilises and cells proliferate in an uncontrolled manner. “ Mice lacking APC spontaneously develop tumours due to constitutive Wnt signaling. When the Wnt pathway was constitutively activated, ELP3 expression increased which led us to envision that its inactivation may impact on Wnt-driven tumour initiation. We then looked at mice in which we had inactivated the gene encoding ELP3 in intestinal stem cells. In healthy mice, the architecture of intestinal crypts was unchanged. The stem cells remained functional and we only detected a lower number of Tuft cells upon ELP3 deficiency. But as their exact role is still unclear, it is difficult to know what the implications of such defect. We can, however, conclude from this observation that ELP3 is involved in the production of Tuft cells…”

On the other hand, in mice lacking APC in which intestinal tumours quickly develop, we observed a striking difference between mice expressing ELP3 or not: “Mice lacking APC and ELP3 had a much longer survival rate because they developed much less tumours. Tumour initiation in the intestine was blocked”. In short, when APC is blocked, cancerous stem cells are produced; if APC and ELP3 are absent, the maintenance of cancer cells is limited."

Furthermore, when a healthy mouse has been irradiated, which causes massive cell death in intestinal crypts, we can nevertheless observe cell regeneration in a few crypts thanks to ELP3. This regeneration relies on the Wnt pathway, and consequently on ELP3. Therefore, ELP3 expression is required in pathological situations in which the Wnt pathway is urgently needed (cancer development and intestinal regeneration after irradiation).

A potential target

The tumour has to synthesise several proteins, such as SOX9, for example, to develop and grow: the essential role of ELP3 can be explained by the fact that many proteins, including SOX9, require ELP3 in order to be synthesised. “We are trying to find a specific pharmacological inhibitor for ELP3 to see whether its inhibition leads to tumour regression in circumstances in which Wnt signaling is constitutively activated. ELP3 is an interesting target because it is a Wnt effector and is involved in the development of cancer cells while being dispensable to intestinal homeostasis…”

This inhibitor has yet to be found and some twenty researchers at ULg are actively working on it. However, several years will be needed to isolate some ELP3 inhibitors, to test and to validate them.