Hopital Saint-Antoine - Bâtiment Kourilsky - 4ème étage - 184, rue du Faubourg Saint-Antoine, 75012 Paris, France
Transforming Growth Factor beta (TGF-B) is a multifunctional cytokine that plays key roles in metazoan biology from the early stages of embryogenesis to regeneration of mature tissues. TGF-B maintains tissue homeostasis by a multitude of processes, such as regulation of pluripotency and differentiation of stem cells as well as suppression of the oncogenic capability of premalignant cells. Paradoxically, TGF-B can also exert pro-metastatic functions to support migration and invasion at late stages of carcinogenesis. How TGF-B elicits these dual functions remains a subject of intense investigation. In this context, our research projects point at elucidating the interplays among key components of the TGF-B pathway with particular emphasis on their roles in cancer progression and cell plasticity.
Aim 1: One of the ongoing projects is dedicated to understanding the mechanisms by which ubiquitination and ubiquitination-like modification affect TGF-B signaling in the context of cancer development and progression. Specifically, we characterized several E3 ubiquitin ligases (Arkadia, PHRF1 and WWP1) deregulated in cancer that modulate TGF-B signaling. We are currently pursuing the molecular characterization of these E3 ubiquitin ligases, seeking to identify the mechanisms by which they influence tumor formation and metastasis, mainly through the discovery of new substrates for these E3 ubiquitin ligases.
Aim 2: Another research project is dedicated to the homeodomain protein TGIF. We identified novel mechanisms by which TGIF restricts TGF-B signaling during cancer progression. We are currently pursuing the characterization of TGIF through dissecting its role in pluripotency, cellular reprogramming, and how its deregulation can contribute to epithelial cancer pathogenesis, in particular to pancreatic cancer.
Aim 3: We extend our analysis of TGF-B signaling during late tumoral progression by investigating the functions of the nucleotide metabolism enzyme/metastasis suppressor NM23-H1/NME and the molecular motor kinesin KIF20A/MKlp2, two new players in cell invasion. We aim at understanding how NM23-H1/NME interferes with local invasion process/basement membrane transmigration in vivo in human cancer and we propose a thorough study of the role of the MKlp2/KIF20A kinesin in cell-cell and cell-matrix adhesion, in TGF-B-induced cell invasion.
We believe that completion of these complementary research projects will provide valuable information on cancer signaling and cell plasticity that would allow for a better rational drug design