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).

Related articles

  1. Le Guen L, Marchal S, Faure S and de Santa Barbara P. Mesenchymal-epithelial interactions during digstive tract development and epithelial stem cell regeneration. Cell Mol Life Sci. 2015;72(20):3883-96. doi: 10.1007/s00018-015-1975-2. En savoir +
  2. Notarnicola C, Rouleau C, Le Guen L, Virsolvy A, Richard S, Faure S and de Santa Barbara P. The RNA-binding protein RBPMS2 regulates development of gastrointestinal smooth muscle. Gastroenterology. 2012; 143(3):687-697.e9. doi: 10.1053/j.gastro.2012.05.047. En savoir +
  3. Chetaille P, Preuss C, Burkhard S, Côté JM, Houde C, Castilloux J, Piché J, Gosset N, Leclerc S, Wünnemann F, Thibeault M, Gagnon C, Galli A, Tuck E, Hickson GR, El Amine N, Boufaied I, Lemyre E, de Santa Barbara P, Faure S, Jonzon A, Cameron M, Dietz HC, Gallo-McFarlane E, Benson DW, Moreau C, Labuda D; FORGE Canada Consortium, Zhan SH, Shen Y, Jomphe M, Jones SJ, Bakkers J, Andelfinger G. Mutations in SGOL1 cause a novel cohesinopathy affecting heart and gut rhythm. Nat Genet. 2014;46(11):1245-9. doi: 10.1038/ng.3113. En savoir +
  4. Martire D, Garnier S, Sagnol S, Bourret A, Marchal S, Chauvet N, Guérin A, Forgues D, Berrebi D, Chardot C, Bellaiche M, Rendu J, Kalfa N, Faure S and de Santa Barbara P. Phenotypic switch of smooth muscle cells in paediatric chronic intestinal pseudo‐obstruction syndrome. J Cell Mol Med. 2021;00:1–12. doi.org/10.1111/jcmm.16367. En savoir +
  5. Breuker C, Clement F, Mura T, Macioce V, Castet-Nicolas A, Audurier Y, Boegner C, Morcrette E, Jalabert A, Villiet M, Avignon A, Sultan A. Non-achievement of LDL-cholesterol targets in patients with diabetes at very-high cardiovascular risk receiving statin treatment: Incidence and risk factors. Int J Cardiol. 2018;268:195-199. doi: 10.1016/j.ijcard.2018.04.068. En savoir +
  6. Maïmoun L, Mariano-Goulart D, Jaussent A, Lefebvre P, Picot MC, Mahadea K, Boudousq V, Fouillade C, Nocca D, Ben Bouallègue F. The effect of excessive fat tissue on the measure of bone mineral density by dual X-ray absorptiometry: the impact of substantial weight loss following sleeve gastrectomy. Clin Physiol Funct Imaging. 2019;39(5):345-354. doi: 10.1111/cpf.12584. En savoir +
  7. Maïmoun L, Mura T, Avignon A, Mariano-Goulart D, Sultan A. Body Composition in Individuals with Obesity According to Age and Sex: A Cross-Sectional Study. J Clin Med. 2020;9(4):1188. doi: 10.3390/jcm9041188. En savoir +
  8. Hapkova I, Skarda J, Rouleau C, Thys A, Notarnicola C, Janikova M, Bernex F, Rypka M, Vanderwinden JM, Faure S, Vesely J, de Santa Barbara P. High expression of the RNA-binding protein RBPMS2 in gastrointestinal stromal tumors. Exp Mol Pathol. 2013 Apr;94(2):314-21. doi: 10.1016/j.yexmp.2012.12.004. En savoir +
  9. Guérin A, Martire D, Trenquier E, Lesluyes T, Sagnol S, Pratlong M, Lefebvre E, Chibon F, de Santa Barbara P, Faure S. LIX1 regulates YAP activity and controls gastrointestinal cancer cell plasticity. J Cell Mol Med. 2020;24(16):9244-9254. doi: 10.1111/jcmm.15569. En savoir +
  10. Guérin A, Angebault C, Kinet S, Cazevieille C, RojoM, Fauconnier J, Lacampagne A, Mourier A, Taylor N, de Santa Barbara P, Faure S. LIX1-mediated changes in mitochondrial metabolism control the fate of digestive mesenchyme-derived cells. Redox Biology. 2022 Oct;56:102431.doi : 10.1016/j.redox.2022.102431 En savoir +
  11. Boisguérin P, Covinhes A, Gallot L, Barrère C, Vincent A, Busson M, Piot C, Nargeot J, Lebleu B, Barrère-Lemaire S. Cardiovasc Res. A novel therapeutic peptide targeting myocardial reperfusion injury. 2020;116(3):633-644. doi: 10.1093/cvr/cvz145. En savoir +

Collaborations

  1. Rendu, INSERM U1216, CHU de Grenoble
  2. Walther, EA 4278 LAPEC, Avignon
  3. Nocca, CHU de Montpellier
  4. Amblard, IBMM, UMR CNRS 5247, Montpellier
  5. Guichou & G. Labesse, CBS, UMR 5048, INSERM U1054, Montpellier
  6. Chibon, CRT, INSERM U1037, Toulouse
  7. Barthelemy, ARNA, INSERM U1212, UMR CNRS 5320, Bordeaux

Links

Association des POIC : Site web

FIMATHO: Réseau national des maladies rares abdomino-thoracique:  Site web