The 2022 ICCNS AWARD

The 2022 ICCNS award was presented to Professor Lester Lau for his significant contributions to the field of CCN biology. It was a mark of our willingness to renew with traditions that suffered from the COVID-19 pandemy.

Professor Lau, one of the founding members of the ICCNS, was a strong supporter for the adoption of a new unified nomenclature that would advantageously substitute for the misleading original names given to the CCN proteins (Perbal et al. 2018). His scientific recognition goes beyond the CCN field in which his work led to the description of critical interactions between CCN proteins and integrins. Lester recently shared with Annick and myself his conviction that indeed, future studies should not only address the interactions of CCN proteins with themselves, but also with their ligands at a spatiotemporal scale via emerging technologies.

On this occasion, Professor Lau gave a talk in which he presented the role of CCN1 in wound healing and tissue regeneration which is summarized in the upcoming scientific report of the 11th workshop on the CCN family of genes that was held last October in Nice, France.

Time for spatial transcriptomics and genome wide association studies

Even though CCN proteins have been studied for almost 35 years, they have not yet revealed all of their hidden biological properties.

In my introduction to the workshop, entitled “From Molecular to Functional: A wide angle Approach to Cellular Communication Networks Factors” I presented a review focusing on a few CCN3 features that could help the field to significantly expand should they be considered with a wider angle.

The goal to reach requires a shift from considering the CCN proteins as independent members of a small family of signaling regulators and addressing questions regarding only the physical and biological interactions of CCN proteins with themselves, to going a step beyond and focus, above all, on their connections within the realm of other « CCN» factors that belong to other superfamilies (manuscript in preparation). Among the questions that are still pending, I pointed out a few features of CCN3 which should be reconsidered with a wider angle.

One of them addressed pieces of evidence suggesting that CCN proteins might be part of moonlighting proteins (Perbal B, in Brigstock et al. 2005).

CCN3 behaves both as a transforming factor ex vivo, and as an antiproliferative and tumor suppressor factor both in vitro and ex vivo (Joliot et al. 1992; Scholz et al. 1996; Gupta et al. 2001; Benini et al. 2005). The reasons for this dual activity remained a puzzle until it was shown that, while CCN3 is interfering with cell differentiation in various animal models, it is acting as a break in the normal cell cycle, resulting in an accumulation of cells in the S phase (Bleau et al. 2007).

A nuclear CCN3 species, which was not detected in resting cells, was selectively expressed both in normal proliferative undifferentiated cells and cancer cells, suggesting that CCN3 might have different functions in distinct cell compartments (Perbal 1999).

Whereas the N-terminal signal peptide drives CCN3 outside of the cells, the addressing of CCN3 directed by a nuclear localization sequence localized in its C-terminal module, CCN3 physically interacts with a few nuclear factors such the rpb7 subunit of the RNA polymerase III. Other CCN proteins showed a dual localization pattern but no studies addressed the biological functions of these nuclear proteins.

Based on the tetramodular structure of the CCN proteins I originally proposed that “the different modules correspond to functional domains that can interact either sequentially or simultaneously with other partners, and that the final biological properties of the CCN proteins might be dependent upon different combinatorial effects” (Perbal 2001). During my introduction, I presented a more elaborate version of the spatiotemporal combinatorial model that I originally proposed to account for the complex regulatory processes governing the wide array of CCN proteins biological activities (Perbal 2018 and Fig. 1).

Fig. 1
figure 1

The spatiotemporal combinatorial interactions model. The model is based on the CCN proteins (panel B) and partners (panel A) bioavailability, as a function of time and biological space

Full size image

In this model, the bioactivities of the CCN proteins depend upon the bioavailability of both the CCN proteins and their partners in various tissues at different developmental stages. The wide array of flexible combinations made possible by the time-and space- dependent expression of the CCN proteins and their partners translates into the vast variety of biological activities shown by the CCN proteins and their isoforms.

The biological power of these combinatorial events is directly dependent upon the complexity of the CCN partner pools and is amplified by the presence of the four CCN modules that were reported to bind independently several different ligands and regulatory factors.

I concluded that future research directions in the fields of CCN communication and signaling should aim at new technologies which recently proved to be effective in personalized molecular medicine. For example, understanding the various interconnected aspects of this spatiotemporal regulatory model requires the identification of all partners, their temporal localization and their expression levels, through global approaches such as Genome Wide Association Studies and Spatial transcriptomics which proved very powerful in the past few years (see my Commentary in this issue). Studying the circadian control of both the CCN proteins and their various partners, might also turn out to be a productive approach since anti-apoptotic roles of the master clock regulators BMAL1 and CLOCK were recently involved in promoting proliferation of liver cancer cells (Qu et al. 2023).

Since then, the recent report of a Drosophila CCN protein lacking the amino-proximal module (Garett et al. 2023), raised very exciting questions regarding the importance of the CCN 3D structural state influencing their biological properties in the nervous system through various interactions with their partners as previously suggested (Perbal 2004). The dCCN (drosophila CCN protein) might be a good system, among others, in which to assess the spatiotemporal combinatorial model proposed earlier to be a key step in controling the multifunctional biological properties assigned to CCN proteins.