Hedgehog and EGFR Signaling in Basal Cell Carcinoma

Signaling via the Hedgehog (HH)/GLI pathway is a key regulatory mechanism in vertebrate embryogenesis and tissue homeostasis by controlling a multitude of cellular processes such as differentiation, proliferation, survival and stem cell renewal. More recently, Hedgehog/GLI signaling has also become of considerable interest to cancer biologists as uncontrolled pathway activation has been implicated in the development and growth of various malignancies such as tumors of the skin, brain, lung, digestive tract, breast and prostate. Our understanding of how aberrant HH/GLI signaling drives tumorigenesis and how HH/GLI activation is integrated into complex oncogenic signaling networks is only poorly defined. In previous work we have focused on cross-talk signaling between the Epidermal Growth Factor Receptor (EGFR) and HH/GLI pathway in epidermal cells. We have shown that EGFR signaling selectively modulates the expression profile of HH/GLI target genes, and that parallel EGFR activation is required for the proliferative activity of oncogenic HH/GLI signaling. Based on these findings we hypothesize that integration of EGFR and HH/GLI signaling is a crucial event in HH/GLI-driven cancers such as Basal Cell Carcinoma (BCC), the most common cancer in the caucasian population. In this project we will address the in vivo role of cross-talk between EGFR and HH/GLI signaling in BCC, using mice engineered to allow rapid tumor development in response to conditional activation of HH/GLI signaling. The results of these studies will shed light on the pathophysiological role of signal integration of the HH/GLI and EGFR pathway and will also provide a basis for possible novel therapeutic strategies in human cancers.

In this project we analyzed the synergistic interactions of the Hedgehog and EGFR signaling pathway in the development of basal cell carcinoma, a very frequent form of non-melanoma skin cancer. Basal cell carcinoma arises in response to uncontrolled activation of Hedgehog signaling and targeted inhibition of the Hedgehog pathway has a remarkable therapeutic benefit for patients. However, cancer recurrence after drug withdrawal and severe side effects of Hedgehog inhibitor drugs pose major challenges for improved medical treatments of Hedgehog-dependent cancer entities. Using mouse models of Hedgehog-induced basal cell carcinoma we could show that targeted inhibition of EGFR signaling prevents the development and growth of invasive tumors. In addition, we identified EGFR-mediated activation of the MEK/ERK/JUN signaling cascade as the key intracellular effector branch required for synergistic oncogenic transformation in combination with simultaneous Hedgehog signaling. The results of these studies explain the molecular details of Hedgehog-EGFR signal cooperation in cancer, demonstrate the in vivo relevance of signal cooperation in basal cell carcinoma and provide a rationale for the development of novel combination therapies relying on combined targeting of Hedgehog and EGFR signaling.