Frederic de Sauvage

I came to Genentech in 1990 thinking I would be here only for a few years. I loved the work and the culture so much that I've been here ever since.

Over the years I have had many collaborations across the company. Recently, my lab's interest was mostly focused on the characterization of the hedgehog signaling pathway and the development of pathway antagonists for the treatment of various cancer. This project has evolved into a multidisciplinary project that involves many departments across the organization, which has given me the opportunity to interact with fantastic people.

The Hedgehog (Hh) pathway is a signaling cascade that directs patterning in most animals and is crucial for proper development. At the molecular level, Hh ligands drive cell proliferation in some cell types while causing others to undergo differentiation. Hh signaling is most active during embryogenesis and aberrant reactivation of the pathway in adult tissue can lead to the development of cancer.

Mutations in the Hh receptor components, Patched (PTCH1) or Smoothened (SMOH), result in constitutive pathway activation and have been identified in tumors such as basal cell carcinoma and medulloblastoma. The lab is interested in (i) understanding the contribution of Hh signaling in cancer by using genetic mouse models of cancer, (ii) uncovering signaling mechanisms by which the Hh signal is transduced into a cell and how novel therapeutic agents that target the Hedgehog pathway work for the treatment of cancer and finally (iii) understand the mechanism of resistance to hedgehog pathway inhibitors.

More recently my lab has become interested in the role of intestinal stem cells in homeostasis and in tumor development. While developing agents to target stem cells in the gut we have uncovered mechanism(s) of compensations that allows the GI track to tolerate depletion of the stem cell compartment during homeostasis but not under various challenge situations. However this mechanism probably also reflects a great deal of plasticity in tumors as well and we are studying the signaling mechanisms that underlie this phenomenon as well as various approaches to target stem cells in cancer.