Research program : Axes

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Digestive mesenchymal Pathologies and innovative therapeutic approaches

P. de Santa Barbara, A. Sultan, P Boisguérin, C. Breuker, E. Vivès, L. Maïmoun,

The smooth muscle cells exhibit the unique ability to dedifferentiate into proliferative progenitors. While this plasticity is essential for maintaining digestive tissue homeostasis during the pediatric period, its deregulation leads to functional alterations and the development of digestive sarcomas (Le Guen et al. 2015).

We are interested in deciphering the mechanisms that govern the plasticity of digestive smooth muscle in different pathologies:

Chronic Intestinal PseudoObstruction Syndrome (CIPO): this syndrome refers to a heterogeneous group of clinical disorders characterized by chronic constipation, without any obvious obstacle. We have shown that the digestive smooth muscle is altered in pediatric POIC patients, and this phenotype is associated with the abnormal expression of smooth muscle immaturity regulators (Notarnicola et al. 2012; Chetaille et al. 2014; Martire et al. 2021).

Obesity: it is a complex chronic disease that often leads to numerous gastrointestinal complications, including an increased risk of gastric emptying and stomach cancers (Breuker et al. 2018; Maimoun et al. 2019; Maimoun et al. 2020). These complications are poorly studied in clinical practice and research. Our preliminary findings argue in favor of a remodeling of the gastric wall in obese patients (team data).

Gastrointestinal stromal tumors (GIST): GISTs are sarcomas arising from interstitial cells of Cajal (ICC) or their mesenchymal progenitors common to ICC and SMC. If the treatment of patients with Imatinib initially increases patient survival, it leads to the appearance of aggressive and resistant secondary GISTs. Our work has shown the abnormally high expression of smooth muscle immaturity markers, an expression associated with a designated prognosis (Hapkova et al. 2013; Guérin et al. 2022). Furthermore, we have shown that the inhibition of the expression of these immaturity markers leads to a differentiation of GIST tumor cells into less proliferative SMCs.

The objectives of the Translational Research Axis are to study the importance of dedifferentiation and immaturity in functional pathologies (pediatric and adult) and sarcomas. We plan to decipher the molecular mechanisms involved in order to develop targeted therapeutic approaches (Boisguérin et al. 2020) to improve smooth muscle differentiation and functionality. This project is based on a multitude of complementary and multidisciplinary approaches (physiopathology and chemical synthesis).