Synergistic Cross‐Talk of Hedgehog and Interleukin‐6 Signaling Drives Growth of Basal Cell Carcinoma
Christina  Sternberg, Wolfgang  Gruber, Markus  Eberl, Suzana  Tesanovic, Manuela Stadler, Dominik P. Elmer, Michaela Schlederer, Sandra Grund, Simone Roos, Florian Wolff, Supreet  Kaur, Doris  Mangelberger, Hans  Lehrach, Hendrik  Hache, Christoph Wierling,  Josef Laimer,  Peter Lackner, Markus Wiederstein, Maria Kasper, Angela Risch, Peter Petzelbauer, Richard Moriggl, Lukas Kenner and Fritz Aberger


Abstract:

Persistent activation of Hedgehog (HH)/GLI signaling accounts for the development of basal cell carcinoma (BCC), a very frequent non‐melanoma skin cancer with rising incidence. Targeting HH/GLI signaling by approved pathway inhibitors can provide significant therapeutic benefit to BCC patients. However, limited response rates, development of drug resistance and severe side effects of HH pathway inhibitors call for improved treatment strategies such as rational combination therapies simultaneously inhibiting HH/GLI and cooperative signals promoting the oncogenic activity of HH/GLI.
In this study, we identified the Interleukin‐6 (IL6) pathway as a novel synergistic signal promoting oncogenic HH/GLI via STAT3 activation. Mechanistically, we provide evidence that signal integration of IL6 and HH/GLI occurs at the level of cis‐regulatory sequences by co‐binding of GLI and STAT3 to common HH‐IL6 target gene promoters. Genetic inactivation of Il6 signaling in a mouse model of BCC significantly reduced in vivo tumor growth by interfering with HH/GLI‐driven BCC proliferation. Our genetic and pharmacologic data suggest that combinatorial HH‐IL6 pathway blockade is a promising approach to efficiently arrest cancer growth in BCC patients. This article is protected by copyright. All rights reserved.

The open access article can be found  here.

Reviewed by Stefan Dötterl