SUMMARY Basal cell carcinoma (BCC) is characterized by frequent loss of PTCH1, leading to constitutive activation of the Hedgehog pathway. Although the requirement for Hedgehog in BCC is well-established, the identity of disease-initiating cells and the compartments in which they reside remain controversial. By using several inducible Cre drivers to delete Ptch1 in different cell compartments in mice, we show here that multiple hair follicle stem cell populations readily develop BCC-like tumors. In contrast, stem cells within the interfollicular epidermis do not efficiently form tumors. Notably, we observed that innervated Gli1-expressing progenitors within mechanosensory touch dome epithelia are highly tumorigenic. Sensory nerves activate Hedgehog signaling in normal touch domes, while denervation attenuates touch dome-derived tumors. Together, our studies identify varying tumor susceptibilities among different stem cell populations in the skin, highlight touch dome epithelia as “hot spots” for tumor formation, and implicate cutaneous nerves as mediators of tumorigenesis.

Persistent activation of the Hedgehog (HH)/GLI signaling pathway has been implicated in the development of a number of human cancers. The GLI zinc finger transcription factors act at the end of the HH signaling cascade to control gene expression, and recent studies have shown that the activity of GLI proteins can be additionally modified by integration of distinct signals, such as the MEK/extracellular signal-regulated kinase (ERK) and phosphinositide-3 kinase (PI3K)/AKT pathway. However, little is known about the identity of the upstream activators of these HH/GLI interacting signaling pathways in cancer. Here, we provide evidence that integration of the HH/GLI and epidermal growth factor receptor (EGFR) pathway synergistically induces oncogenic transformation, which depends on EGFR-mediated activation of the RAS/RAF/MEK/ERK but not of the PI3K/AKT pathway. EGFR/ MEK/ERK signaling induces JUN/activator protein 1 activation, which is essential for oncogenic transformation, in combination with the GLI activator forms GLI1 and GLI2. Furthermore, pharmacologic inhibition of EGFR and HH/GLI efficiently reduces growth of basal cell carcinoma (BCC) cell lines derived from mice with activated HH/GLI signaling. The results identify the synergistic integration of GLI activator function and EGFR signaling as a critical step in oncogenic transformation and provide a molecular basis for therapeutic opportunities relying on combined inhibition of the HH/GLI and EGFR/MEK/ERK/JUN pathway in BCC. [Cancer Res 2009;69(4):1284-92]

Inhibition of Hedgehog (HH)/GLI signaling in cancer is a promising therapeutic approach. Interactions between HH/GLI and other oncogenic pathways affect the strength and tumorigenicity of HH/GLI. Cooperation of HH/GLI with Epidermal Growth Factor Receptor (EGFR) signaling promotes transformation and cancer cell proliferation in vitro. However, the in vivo relevance of HH-EGFR signal integration and the critical downstream mediators are largely undefined. In this report we show that genetic and pharmacologic inhibition of EGFR signaling reduces tumor growth in mouse models of HH/GLI driven basal cell carcinoma (BCC). We describe HH-EGFR cooperation response genes including SOX2, SOX9, JUN, CXCR4 and FGF19 that are synergistically activated by HH-EGFR signal integration and required for in vivo growth of BCC cells and tumor-initiating pancreatic cancer cells. The data validate EGFR signaling as drug target in HH/GLI driven cancers and shed light on the molecular processes controlled by HH-EGFR signal cooperation, providing new therapeutic strategies based on combined targeting of HH-EGFR signaling and selected downstream target genes.

PurposeTheory has made many assumptions about the consequences of a “good” corporate reputation. The aim of this paper is to provide evidence of the effect of a positive corporate reputation on the firm's future financial performance by means of a more differentiated concept of reputation than the one commonly used in literature.Design/methodology/approachIn contrast to prior research, reputation is conceptualised by means of a two‐dimensional approach. Therefore, two distinct reputational components are hypothesised as affecting financial performance differently. A large‐scale representative survey of 30 of the largest German firms is conducted to gain reputational evaluations of these firms. The overall assessment of reputation is differentiated into a part that is explained by past financial performance and an idiosyncratic part to control for the effect of past performance on today's reputation. Finally, the idiosyncratic effect of reputation on future performance is assessed with an econometric model.FindingsBoth the cognitive and the affective reputational dimension significantly influence future financial performance after controlling for past performance. Furthermore, the results suggest that the decompositional model outperforms a non‐decompositional approach in terms of goodness of fit.Research limitations/implicationsThere is only a limited possibility to generalise the results to all firms.Practical implicationsThe results imply a need for differentiated reputation management, since the cognitive and affective components of corporate reputation drive financial performance differently.Originality/valueThe two‐dimensional reputational approach broadens prior research with a focus on the differences in performance – the effects of both the reputational components.

Summary Primary cilia are required for Smoothened to transduce vertebrate Hedgehog signals, but how Smoothened accumulates in cilia and is activated is incompletely understood. Here, we identify cilia-associated oxysterols that promote Smoothened accumulation in cilia and activate the Hedgehog pathway. Our data reveal that cilia-associated oxysterols bind to two distinct Smoothened domains to modulate Smoothened accumulation in cilia and tune the intensity of Hedgehog pathway activation. We find that the oxysterol synthase HSD11β2 participates in the production of Smoothened-activating oxysterols and promotes Hedgehog pathway activity. Inhibiting oxysterol biosynthesis impedes oncogenic Hedgehog pathway activation and attenuates the growth of Hedgehog pathway-associated medulloblastoma, suggesting that targeted inhibition of Smoothened activating oxysterol production may be therapeutically useful for patients with Hedgehog-associated cancers.