Hedgehog (Hh) signaling is implicated not only in the development of basal cell carcinoma (BCC), but also in epithelial-mesenchymal interactions critical to hair follicle development and cycling, However, the more distal downstream effectors of Hh signaling remain to be elucidated. Hair follicle development is profoundly affected by a variety of natural and engineered mutations affecting ErbB signaling, and our preliminary data demonstrate that increased and qualitatively altered expression of ErbB proteins is a characteristic feature of BCCs. These findings suggest the hypothesis that ErbB signaling is an important distal effector of Hh signaling in BCC and follicular development. BCC tumors are highly invasive. Matrix metalloproteinases (MMPs) are strongly implicated in tumor invasiveness, and ErbB signaling is in turn strongly implicated in the control of MMP activity in the skin. BCC and early anagen hair follicles display high levels of MMP-1, MMP-2, and MMP-9 expression and activity, whereas in normal skin, the same MMPs are present but inactive. Our preliminary data indicate that secretion and activation of MMP- I and MMP-9 are markedly reduced in response to pharmacologic blockade of ErbB signaling in short-term organ cultures of BCC. However, we do not know whether the MMPs we are observing derive from BCC tumor cells, from the surrounding stroma, or from reactive normal epithelium, and we do not know which ErbB species are responsible for the observed MMP activities. Due to its simplicity and flexibility, organ culture offers significant opportunities to probe distal signaling pathways downstream of Hh signaling in BCC. However, prior efforts to maintain BCC for extended periods in organ culture have been unsuccessful. We have previously developed conditions for successful long-term maintenance of normal skin in organ culture (up to 30 days). We also have IRB-approved access to an abundant supply of clinically well-characterized, fresh BCC tumors. Here we propose to use these resources: (i) to determine whether specific blockade of ErbB signaling specifically reduces tyrosine phosphorylation and the activation of MMPs in BCC tumor cells, and (ii) to define optimal conditions for the long-term organ culture of BCC.
| Rittie, Laure; Kansra, Sanjay; Stoll, Stefan W et al. (2007) Differential ErbB1 signaling in squamous cell versus basal cell carcinoma of the skin. Am J Pathol 170:2089-99 |
| Kansra, Sanjay; Stoll, Stefan W; Johnson, Jessica L et al. (2005) Src family kinase inhibitors block amphiregulin-mediated autocrine ErbB signaling in normal human keratinocytes. Mol Pharmacol 67:1145-57 |
| Kansra, Sanjay; Stoll, Stefan W; Johnson, Jessica L et al. (2004) Autocrine extracellular signal-regulated kinase (ERK) activation in normal human keratinocytes: metalloproteinase-mediated release of amphiregulin triggers signaling from ErbB1 to ERK. Mol Biol Cell 15:4299-309 |
| Stoll, Stefan W; Kansra, Sanjay; Elder, James T (2002) Metalloproteinases stimulate ErbB-dependent ERK signaling in human skin organ culture. J Biol Chem 277:26839-45 |
