"I was very fortunate to receive The Sontag Foundation Distinguished Scientist Award soon after starting my lab, as I was embarking on a new research direction, in which I had not trained before. The award was critical for allowing us to develop this project, at a time when grant agencies would not have considered funding it. Sontag funding gave me the freedom to pursue a new research direction, which has now become the main focus of our lab."
- Professor, Department of Cell Biology, Harvard Medical School
About DSA-Funded Research
Medulloblastoma is the most frequent brain cancer in children and remains a major cause of pediatric cancer death. Current treatments (surgical excision, chemotherapy and radiation of the brain and spine) are associated with debilitating long-term side effects due to their high toxicity and low specificity. It is thus critical to find novel medulloblastoma therapies that target tumor cells specifically while leaving healthy brain cells intact.
Many medulloblastomas have mutations in a cell-cell communication pathway called the Hedgehog pathway. This pathway controls the proliferation of cerebellar cells from which medulloblastomas arise. Too much Hedgehog pathway activity results in uncontrolled cell growth, which in turn can lead to medulloblastoma. In spite of the critical importance of the Hedgehog pathway, we know little about how it controls cell proliferation and malignant transformation. A detailed understanding of the molecular mechanisms involved in Hedgehog signaling is fundamental to understanding how medulloblastomas appear and to finding powerful and specific new therapies.
This proposal focuses on elucidating a component of Hedgehog signaling called Suppressor of Fused (SuFu) functions. SuFu plays a major role in keeping the Hedgehog pathway off. We will use novel biochemical approaches and experiments in medulloblastoma cells to answer some outstanding questions involving SuFu. We plan to:
- Determine how SuFu keeps the Hedgehog pathway off
- Discover and study other SuFu-interacting proteins
- Elucidate how SuFu itself is regulated
These studies will advance our understanding of Hedgehog signaling, will clarify important steps in medulloblastoma formation and will identify novel therapeutic targets in medulloblastoma.
"Adrian is a very deep thinker, a broad reader of scientific literature, and exceptionally good experimentalist, an adventuresome and creative scientist and an exceptionally dedicated and motivated worker."
Marc W. Kirschner. Ph.D.
Harvard Medical School
"Dr. Salic is creative, technically brilliant, and wonderfully interactive. He is at the outset of an outstanding academic career. There is no doubt that a grant from The Sontag Foundation will be invaluable in helping him launch his research program."
Joan S. Brugge, Ph.D
Harvard Medical School
- Tukachinsky H, Lopez L and Salic A – 2010 A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes, J Cell Biol, 191(2), 415-28.
- Chen X, Tukachinsky H, Huang CH, Jao C, Chu YR, Tang HY, Mueller B, Schulman S, Rapoport TA and Salic A – 2011 Processing and turnover of the Hedgehog protein in the endoplasmic reticulum, J Cell Biol, 192(5), 825-38.
- Tukachinsky H, Kuzmickas RP, Jao CY, Liu J and Salic A – 2012 Dispatched and Scube mediate the efficient secretion of the cholesterol-modified Hedgehog ligand, Cell Rep, 2(2), 308-20.
- Nedelcu D, Liu J, Xu Y, Jao C and Salic A – 2013 Oxysterol binding to the extracellular domain of Smoothened is required for vertebrate Hedgehog signaling, Nat Chem Biol, 9, 557-564.
- Jao C, Nedelcu D, Lopez L, Samarakoon T, Welti R and Salic A – 2015 Biooorthogonal probes for imaging sterols in cells, Chembiochem. in press.