PhD, University of Buenos Aires
At A Glance
- The main focus of the laboratory is to uncover cell signaling mechanisms that play a role in inherited disorders, and cancer.
- We use a combination of approaches including cellular biology, biochemistry, molecular biology, and genetics. We work with cultured cells and mouse models.
- We are particularly interested in the signaling pathways triggered by Wnts, Hedgehogs, bone morphogenetic proteins, and fibroblasts growth factors, and in the role that the glypican family of proteoglycans plays in these signaling pathways.
After finishing postdoctoral training at the Princess Margaret Hospital Cancer Centre, Dr. Filmus worked as a Scientist at Connaught Laboratories in Toronto. In 1991 he started his own laboratory at the Sunnybrook Research Institute, and was appointed Assistant professor at the Dept. of Medical Biophysics, Univ. of Toronto. One of the main discoveries made by Dr. Filmus has been the identification of Glypican-3 as a marker and a therapeutic target in hepatocellular carcinoma.
OCI-5/GPC3, a glypican encoded by a gene which is mutated in the Simpson Dysmorphia Syndrome, induces apoptosis in a cell-specific manner. J. Cell Biol. 141: 1407-1414 (1998). Loss-of-function mutations of GPC3 are the cause of the Simpson-Golabi-Behmel syndrome (SGBS). This syndrome is characterized by overgrowth, and a series of developmental abnormalities. Some of these abnormalities suggested that GPC3 can trigger apoptosis in specific tissues during development. In this paper we provided experimental evidence showing that indeed GPC3 can induce apoptosis in specific types of cultured cells. In addition, we showed that a non-glycanated GPC3 can also induce apoptosis, although the heparan sulfate chains are required for optimal activity. Finally, we showed that GPC3-induced cell death requires the attachment of this glypican to the cell surface.
Glypican-3-deficient mice exhibit developmental overgrowth and some of the abnormalities typical of Simpson-Golabi-Behmel syndrome. J. Cell Biol. 146:255-264 (1999). In this paper we reported the generation of GPC3-null mice. Because these mice display the overgrowth and other developmental abnormalities typical of SGBS, this paper confirmed that loss-of-function mutations of GPC3 are the cause of SGBS. In addition, the generation of GPC3-null mice has provided the scientific community with an animal model to study SGBS.
Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma. Gastroenterology 125:89-97 (2003). In this paper we reported the generation of monoclonal antibodies against GPC3, and we used these antibodies to show that GPC3 is expressed in ~ 75 % of hepatocellular carcinomas (HCCs), but that it is not detectable in normal liver and benign liver disease. We proposed that GPC3 can be used as a marker for the early diagnosis of HCC. We have patented and licensed our discovery to a Company that is now selling our GPC3 antibodies, which are being used by clinical pathologists around the world to confirm HCC diagnosis in difficult cases. The American Association for the Study of Liver Diseases, and the European Association for the Study of the Liver currently recommend immunostaining for GPC3 as one of the tests to be used by clinical pathologists to confirm HCC diagnosis. Currently, anti-GPC3 antibodies are being tested by Roche in Phase II clinical trials for HCC therapy.
Glypican-3 inhibits Hedgehog signaling by competing with Patched for Hedgehog binding. Dev.Cell. 14:700-711 (2008). The involvement of GPC3 in SGBS has been reported 15 years ago (Pilia et al., Nature Genet, 1996). In that report the authors proposed that GPC3 inhibits embryonic growth by blocking insulin-like growth factor activity. Although we showed a year later that this was not correct, the mechanism of action of GPC3 remained unknown. In this paper we reported that GPC3 regulates embryonic growth by acting as a negative regulator of Hedgehog (Hh) signaling. We showed that GPC3 binds to Hh at the cell surface and induces its endocytosis and degradation. This discovery clearly represents a breakthrough in this area of research, and led us to propose that the overgrowth observed in SGBS patients and GPC3-null mice, is, at least in part, the consequence of hyperactivation of the Hh signaling pathways.
Li,F., Shi,W., Capurro,M., and Filmus,J. Glypican-5 stimulates rhabdomyosarcoma cell proliferation by activating hedgehog signaling. J.Cell Biol. 192:691-704 (2011).. In this paper we showed that GPC5 stimulates Hh signaling by increasing the binding of Hh to its signaling receptor Patched-1. Furthermore,we demonstrated that, unlike GPC3, GPC5 binds to Patched-1. The binding is mediated by the heparan sulfate chains of GPC5. In addition, we showed that GPC5 is located at cilia. This paper provides a new target for rhabdomyosarcoma therapy.
- Processing by convertases is required for glypican-3-induced inhibition of Hedgehog signaling. Capurro M, Shi W, Izumikawa T, Kitagawa H, Filmus J. J Biol Chem. 2015 Mar 20;290(12):7576-85. doi: 10.1074/jbc.M114.612705. Epub 2015 Feb 4. PMID: 25653284
- Glypican-3 binds to Frizzled and plays a direct role in the stimulation of canonical Wnt signaling. Capurro M, Martin T, Shi W, Filmus J. J Cell Sci. 2014 Apr 1;127(Pt 7):1565-75. doi: 10.1242/jcs.140871. Epub 2014 Feb 4. PMID:24496449
- LRP1 mediates Hedgehog-induced endocytosis of the GPC3-Hedgehog complex. Capurro MI, Shi W, Filmus J. J Cell Sci. 2012 Jul 15;125(Pt 14):3380-9. doi: 10.1242/jcs.098889. Epub 2012 Mar 30.PMID:22467855
- Glypican-5 stimulates rhabdomyosarcoma cell proliferation by activating Hedgehog signaling. Li F, Shi W, Capurro M, Filmus J. J Cell Biol. 2011 Feb 21;192(4):691-704. doi: 10.1083/jcb.201008087. PMID:21339334
- Soluble glypican 3 inhibits the growth of hepatocellular carcinoma in vitro and in vivo. Zittermann SI, Capurro MI, Shi W, Filmus J. Int J Cancer. 2010 Mar 15;126(6):1291-301. doi: 10.1002/ijc.24941. PMID:19816934
- Overgrowth of a mouse model of Simpson-Golabi-Behmel syndrome is partly mediated by Indian hedgehog. Capurro MI, Li F, Filmus J. EMBO Rep. 2009 Aug;10(8):901-7. doi: 10.1038/embor.2009.98. Epub 2009 Jul 10.PMID:19590577
- Glypicans. Filmus J, Capurro M, Rast J. Genome Biol. 2008;9(5):224. doi: 10.1186/gb-2008-9-5-224. Epub 2008 May 22. Review. PMID:18505598
- Glypican-3 inhibits Hedgehog signaling during development by competing with patched for Hedgehog binding. Capurro MI, Xu P, Shi W, Li F, Jia A, Filmus J. Dev Cell. 2008 May;14(5):700-11. doi: 10.1016/j.devcel.2008.03.006. PMID:18477453