Abstract
Abstract Melanoma initiation is known to involve specific genetic changes as well as the disruption of both cell-cell and cell-microenvironment interactions. However, the mechanisms by which dysregulated cell-cell interactions lead to melanoma development remain elusive. To better understand melanoma initiation and progression we have developed a hybrid multiscale mathematical model of normal skin (virtual skin). The model focuses on key cellular and microenvironmental variables that regulate normal homeostatic skin function, and is constructed to recapitulate how keratinocytes and fibroblasts regulate melanocyte proliferation, migration and death. Experimentally, we have shown that as fibroblasts age and become senescent their behavior changes significantly, leading to the expression of multiple growth factors, matrix proteins and proteases. We also showed, using 2D/3D culture, that interactions with senescent fibroblasts can aid melanoma initiation. Using our virtual skin model, we systematically investigated the effects of disrupting interactions between melanocytes, keratinocytes, fibroblasts and the microenvironment in driving melanoma initiation. The resulting virtual skin pathology readily recapitulates a spectrum of aberrant clinical pathology. Direct comparison between these pathologies allowed us to find the key perturbations leading to melanoma initiation and progression. To better understand the role of aging we also integrated senescent fibroblasts into our virtual skin model. Our primary finding is that melanoma initiation can be directly facilitated by fibroblast senescence. However, successful initiation requires the existence of preexisting mutations within the melanocyte population allowing them to exploit the stromal activation. These findings provide additional evidence demonstrating the importance of therapeutically targeting the stroma. We believe that any effective therapy will need to not only eradicate the melanoma population but also restore normal homeostatic stromal function. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 505. doi:10.1158/1538-7445.AM2011-505
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