Neural Promotion of Hedgehog-Driven Skin Cancer

[摘要] Basal cell carcinoma (BCC) is the most common form of skin cancer. It is caused by de- regulated Hedgehog (HH) signaling, most often due to loss-of-function mutations in the HH receptor Patched1 (PTCH1). Ptch1 deletion in mice yields BCC-like tumors that mimic human disease. Using this model, I identified several epidermal populations that are susceptible to Ptch1-driven BCC formation. These populations include the hair follicle (HF) isthmus and bulge regions, as well as the mechanosensory touch dome (TD). In contrast, the interfollicular epidermis (IFE) is resistant to BCC initiation. One striking difference in the micro-environment of the HF/TD versus the IFE is the presence or absence of innervation. The HF/TD niches contain sensory nerves which secrete HH ligand to activate signaling, while the IFE lacks innervation. Based on this observation, I chose to investigate the contribution of nerves to BCC tumorigenesis. First, I found that surgical denervation reduces TD-derived tumor growth, which highlights a promoting role for nerves in BCC. In addition, my preliminary data suggest hyper- innervation via expression of nerve growth factor Neurotrophin-3 (NT-3) may enhance BCC initiation in the HF and TD compartments. Despite the apparent promoting role for nerves in HF/TD BCC, ectopic innervation of the IFE via NT-3 expression is not sufficient to impart BCC susceptibility. This suggests that additional mutations are required to overcome the IFE’s resistance to BCC formation. Several in vitro and in vivo studies suggest that in the absence of Ptch1, HH signaling is mediated by its homologue Patched 2 (Ptch2). However, I found that additional loss of Ptch2 does not affect BCC tumorigenesis or the level of HH activation.Together, this data highlight a novel role for sensory innervation in promoting BCC tumorigenesis, and uncovers a new potential therapeutic target for BCC treatment.

[发布机构] University of Michigan

[效力级别] hedgehog signaling

[关键词] skin cancer;hedgehog signaling;Molecular;Cellular and Developmental Biology;Science;Cellular & Molecular Biology