TGTC : TGFβ signaling, Glutathione homeostasis & Innovative therapies in Cancer

TGTC entête3

Team leaders:

Cédric Coulouarn (CR1 Inserm) & Pascal Loyer (CR1 Inserm)

 

The Team TGTC gathers basic researchers and hospital practitioners with a common interest and complementary expertise in hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma and pancreatic ductal adenocarcinoma (PDAC). These are aggressive cancers with rising incidence, poor prognosis and limited therapeutic options. Tumor onset and progression are associated with drastic changes in the tumor microenvironment modulating key signaling pathways which contribute to carcinogenesis, and high intracellular glutathione (GSH) content promoting cancer cell survival and proliferation.

 The general objective of the team is to better understand changes in the tumor microenvironment and their impact on tumor cell biology to provide new therapeutic orientations in cancer. We explore this issue by using two paradigms, namely the TGFβ signaling and GSH homeostasis. In this context we aim at better characterizing the contextual determinants that shape the TGFβ pathway in normal and cancer cells to provide a rationale for efficient targeted therapies using TGFβ inhibitors. Notably, we explore the role of long non coding RNA as novel effectors and regulators of the TGFβ pathway in cancer. We also address the contribution of the cystine/glutamate xCT antiporter in the intracellular levels of cysteine, the main limiting factor in GSH biosynthesis, in normal liver and HCC and the role of the GSH homeostasis in tumor cell survival and growth.

 

At the translational and clinical level, our objectives include: i) the identification of non-invasive companion biomarkers for targeted therapies and prognosis biomarkers (e.g. exosome content, cytokine production), ii) the evaluation of new clinical approaches to prevent tumor recurrence (e.g. administration of local anesthetics during surgery) and iii) the development of synthetic nanovectors for tumor drug delivery, in collaboration with the National School of Chemistry in Rennes, and metabolic radiotherapy.

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Research themes:

  1. TGFβ signaling: mechanisms of action during tumor progression & clinical relevance in liver and pancreatic cancers
  • Genomics in the tumor microenvironment of PDAC
  • Contextualization and regulation of the TGFβ pathway in cancer cells
  • TGFβ signaling & personalized biotherapies in cancer
  • Local anesthetics & tumor recurrence prevention
  1. Glutathione homeostasis during tumor growth
  1. Vectorization and radiotherapy in HCC
  • Nanoparticles of poly(malic acid) for drug delivery
  • Metabolic radiotherapy and radioembolisation

 

Representative publications:

  • Coulouarn C (2015) Modulating the activation of hepatic stellate cells: a cunning way for metastatic cells to create a permissive soil for seeding in the liver? Hepatology, 61:37-40.
  • Barouti G, Jarnouen K, Cammas-Marion S*, Loyer P*, Guillaume S* (2015) Polyhydroxylakanoate-based diblock copolymers: potential biocompatible nanovectors. Polym Chem, 6: 5414-5429. *Co-corresponding authors.
  • Garin E, Rolland Y, Edeline J, Icard N, Lenoir L, Laffont S, Mesbah H, Breton M, Sulpice L, Boudjema K, Rohou T, Raoul JL, Clément B, Boucher E. (2015) Personalized dosimetry with intensification using 90Y-loaded glass microsphere radioembolization induces prolonged overall survival in hepatocellular carcinoma patients with portal vein thrombosis. J Nucl Med. 3:339-46.
  • Sulpice L, Rayar M, Desille M, Turlin B, Fautrel A, Boucher E, Llamas-Gutierrez F, Meunier B, Boudjema K, Clément B, Coulouarn C (2013) Molecular profiling of stroma identifies osteopontin as an independent predictor of poor prognosis in intrahepatic cholangiocarcinoma. Hepatology, 6:1992-2000.
  • Loyer P, Busson A, Trembley JH, Hyle J, Grenet JA, Zhao W, Ribault C, Montier T, Kidd VJ, Lahti JM (2011) The RNA binding motif protein 15B (RBM15B/OTT3) is a functional competitor of serine-arginine (SR) proteins and antagonizes the positive effects of the CDK11p110-cyclin L2alpha complex on splicing. J Biol Chem, 286:147-159.

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