5 Hedgehog Pathway Questions for Michael T. Lewis

Michael T. Lewis, PhD, runs a research lab at the Baylor College of Medicine in Houston, Texas, focused on understanding the role of hedgehog (Hh) signaling in mammary gland development and breast cancer using the mouse as a model organism. The team’s recently published research indicates that mutations in Hh signaling lead to lesions in mammary tissue that resemble human ductal carcinoma in situ.

What role does hedgehog signaling play in normal cells?

Components of the hedgehog signaling network play roles in virtually every organ and structure in the body, and regulate diverse processes including patterning, differentiation, proliferation, and stem cell behavior. However, much of this activity is limited to embryonic development. Activity in adults is primarily limited to regenerative structures such as the hair follicle, testes, and specialized regions of the brain, as well as in pregnancy where it regulates implantation of the embryo in the uterus. In general, it appears that it is critical to keep signaling “off” in most normal adult cells.

How important is it in cancer development?

For some cancers like basal cell carcinoma and medulloblastoma, the contribution of active hedgehog signaling is very clear. For most others, the relative contribution of hedgehog signaling to tumor growth and behavior is less clear, and even controversial. There’s little argument that inappropriately activated signaling causes problems, but whether these other tumors are actually dependent on activated signaling is still an open question.

Are there any currently available Hh-targeted treatments?

Several pharmaceutical companies now have hedgehog-targeted agents in their pipelines, with a few recently being used in phase I clinical trials. These agents look very promising for tumor types with clear connections to activated signaling. We’ll have to see how well they do against tumors where the hedgehog connections and dependencies are less clear.

Which components of the Hh pathways do they target?

Most of these agents target Smoothened, the main effector of signaling, and prevent it from activating downstream elements of the network. A few target the hedgehog ligands themselves, or the downstream transcription factors Gli1 and Gli2. However, the Smoothened inhibitors are well ahead with respect to translation into the clinic.

What is the future for Hh signaling in cancer research?

There is still a great deal we do not know about how the components of the hedgehog signaling network actually work. In fact, new components are still being identified. We also need to figure out how hedgehog signaling interacts with the other signaling pathways known to influence cancer behavior. While most of our attention has been on trying to inhibit signaling to combat cancer, it may well be that we should explore activation as a potential therapeutic approach in some cases.