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Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma
Author(s) -
Sternberg Christina,
Gruber Wolfgang,
Eberl Markus,
Tesanovic Suzana,
Stadler Manuela,
Elmer Dominik P.,
Schlederer Michaela,
Grund Sandra,
Roos Simone,
Wolff Florian,
Kaur Supreet,
Mangelberger Doris,
Lehrach Hans,
Hache Hendrik,
Wierling Christoph,
Laimer Josef,
Lackner Peter,
Wiederstein Markus,
Kasper Maria,
Risch Angela,
Petzelbauer Peter,
Moriggl Richard,
Kenner Lukas,
Aberger Fritz
Publication year - 2018
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31724
Subject(s) - hedgehog , hedgehog signaling pathway , basal cell carcinoma , signal transduction , cancer research , biology , stat3 , vismodegib , smoothened , cell growth , microbiology and biotechnology , medicine , genetics , basal cell
Persistent activation of hedgehog (HH)/GLI signaling accounts for the development of basal cell carcinoma (BCC), a very frequent nonmelanoma 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.