LAUSR

BP180, also known as type 17 collagen, is a transmembrane glycoprotein located in the hemidesmosome of epidermal basal keratinocytes. BP180 is a critical cell/matrix adhesion molecule in dermal-epidermal junction of the skin. Various clinical reports indicated that the altered expression of hemidesmosomal protein BP180 is associated with melanoma progression. However, it is unclear whether BP180 is directly involved in melanoma progression. To investigate the role of BP180 in melanoma progression, we generated novel mouse strains lacking BP180 functions in whole body (by crossing floxed mice with germline Cre), in the local skin (tamoxifen-inducible Cre), or in basal keratinocytes (K14-driven Cre). These BP180 functional knockout mice showed dermal-epidermal junction separation in the skin, indicating that the cell/cell matrix adhesion mediated by BP180 is impaired. Loss of BP180 function also lead to a proinflammatory microenvironment in skin accompanied with an influx of immune cells including mast cells, neutrophils and T cells. When tested in B16 mouse melanoma model BP180 functional deficient mice (globally, in the local skin, or in basal keratinocytes) showed significantly increased melanoma progression. These results demonstrated that BP180 deficiency limited in local skin microenvironment or basal keratinocyte is sufficient to promote melanoma progression. To determine whether increased neutrophil or mast cells are required for the accelerated melanoma progression in BP180 functional deficient mice, we injected B16 melanoma cells into mice lacking both mast cells and BP180 function. Mast cell deficiency drastically reduced the inflammation, neutrophil influx into skin and melanoma progression caused by loss of BP180 function. These findings provide the first evidence suggesting that BP180, as a hemidesmosomal cell-cell matrix adhesion protein, plays a vital role in host defense against melanoma progression through modulating basal keratinocytes, neutrophil and mast cells in local tumor microenvironment. Citation Format: Bin-Jin Hwang, Bin Peng, Yang Zhang, Jaime Marie Brozowski, Lin Lin, Scott E. Williams, Ning Li, Zhen Liu, Maureen Su, Nancy E. Thomas, Luis A. Diaz, Zhi Liu. The loss function of BP180 (Collagen type XVII) in skin, leads to a mast cell dependent pro-inflammatory microenvironment which promotes melanoma progression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B07.