Hedgehog/Interleukin-6 signaling in basal cell carcinoma

Cancer is leading cause of death worldwide with increasing incidence. The disease arises as a result of an accumulation of genetic and epigenetic alterations that endow the cells with malignant properties including uncontrolled proliferation and metastasis. Cooperation of oncogenic signals activated by cancer mutations and/or epigenetic changes in oncogenes and tumor suppressor genes are key etiologic events in cancer. The identification and detailed molecular understanding of signal interactions in cancer, particularly of those amenable to drug targeting, is pivotal to the establishment of rationale-based combination treatments to overcome or at least ameliorate major problems in oncology such as limited therapeutic efficacy, development of drug resistance, severe side effects and disease relapse. In this proposal, we will investigate a novel synergistic oncogenic signal interaction recently discovered in our lab involving cooperation of the Hedgehog and Interleukin-6 pathway. Using a combination of genetic mouse models, cell biology and molecular approaches, we will address the therapeutic relevance of HH-IL6 signal cooperation in basal cell carcinoma (BCC), a very frequent non-melanoma skin cancer caused by aberrant activation of Hh/Gli signaling. In addition, we will decipher the molecular details of HH-IL6 signal integration and identify the critical HH-IL6 targets responsible for the determination of the malignant phenotype induced by synergistic Hh-Il6 signaling. The detailed analysis of HH-IL6 signal cooperation proposed in this application will provide new insights into the intricate regulatory mechanisms of oncogenic HH/GLI signaling and shed light on the molecular effectors controlled by HH-IL6 cooperation. This will eventually help defining novel rational combination treatments relying on combined inhibition of HH-IL6 signaling and critical downstream effectors.

The immune system plays a central role in cancer development and growth. On the one hand, chronic inflammatory processes can promote cancer growth; on the other hand, immunological processes play an essential role in the recognition and destruction of malignant cells, which is of utmost importance for modern immunotherapeutic treatment approaches. The aim of this project was to investigate the role of the inflammation-promoting Interleukin-6 (IL6) signaling pathway in the development of Hedgehog (HH)/GLI-induced basal cell carcinoma, a very common non-melanoma skin cancer, and to propose new combination treatments based on the findings. Using cellular in vitro and genetic in vivo models, it was shown that the simultaneous activation of oncogenic HH/GLI and IL6 signaling cascades has a synergistic, i.e. more than additive effect on cancer growth. The molecular mechanism responsible for this involves the simultaneous activation of GLI and STAT3 transcription factors, which bind jointly and cooperatively to selected HH-IL6 target genes with cancer-promoting effects and activate their expression. The integration of HH-IL6 signal activation in the context of skin cancer development enhances the proliferation of cancer cells and suppresses the defense and destruction of malignant cells by the anti-tumoral immune response. The latter mechanism is controlled by a change in the amino acid metabolism within the microenvironment of cancer cells, thereby suppressing the activation and proliferation of so-called cytotoxic T cells, which play a central role in the immune attack and destruction of malignant cells. The results of the project suggest that the simultaneous inhibition of HH/GLI and IL6/STAT3 signal transduction in combination with immunotherapeutic agents supporting the anti- tumoral immune response represents an effective and sustained treatment for patients with advanced basal cell carcinoma.