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STARD3 is a sterol transporter located at the interface between the endoplasmic reticulum and endosomes. Interestingly, and as yet unexplained, STARD3 represents a genetic vulnerability for the HER2-type breast cancers+, particularly those resistant to anti-HER2 therapy. In other words, the proliferation of cells that become cancerous following the amplification of HER2 expression is uniquely linked to STARD3 activity. A body of evidence suggests that blocking the transport activity of STARD3 could provide a promising strategy against HER2-type cancers.+. Through approaches in vitro, We aim to select, test, and optimize compounds capable of interfering with STARD3 transport activity in order to identify molecules with anticancer potential and ultimately develop an effective therapeutic strategy centered on STARD3 – in collaboration with Dr. Catherine Tomasseto (IGBMC, Illkirch) and Dr. Jean-Michel Brunel (IJM, Marseille)

Figure 1 – Finding inhibitors against STARD3. (HAS) The STARD3 protein, anchored to the endosome limiting membrane by its MENTAL domain, can associate with VAP receptors residing in the endoplasmic reticulum to form RE-endosome contact sites. STARD3 can via Its StART domain transfers cholesterol from the ER to endosomes. Blocking this sterol transfer could slow the growth of HER2-type tumor cells2+. (B) We have established protocols to reconstitute artificial ER-endosome contact sites with recombinant STARD3 and VAP constructs and lipososomes, and to measure the real-time transfer activity of STARD3 with dehydroergosterol (DHE) by FRET. With these protocols, we can evaluate the inhibitory capacity of numerous anti-STARD3 compounds.

Publications

2020
Di Mattia T, Martinet A, Ikhlef S, McEwen AG, Nominé Y, Wendling C, Poussin-Courmontagne P, Voilquin L, Eberling P, Ruffenach F, Cavarelli J, Slee J, Levine TP, Drin G, Tomasetto C, Alpy F , FFAT motif phosphorylation controls formation and lipid transfer function of inter-organelle contacts. EMBO J 2020 Dec; 39(23): e104369.
2017
Wilhelm LP, Wendling C, Védie B, Kobayashi T, Chenard MP, Tomasetto C, Drin G, Alpy F, STARD3 mediates endoplasmic reticulum-to-endosome cholesterol transport at membrane contact sites. EMBO J 2017 May; 36(10): 1412-1433.