Abstract 2071: Disruption of TGFβ-mediated tumor suppression in a Tpl2 model of cutaneous squamous cell carcinoma

Skin cancer is the most common form of cancer in the United States, with an estimated two million cases diagnosed annually, and incidence continues to increase. Tpl2 (Map3k8) is a serine threonine protein kinase in the mitogen-activated protein kinase (MAPK) signal transduction cascade. Previous studies have shown that Tpl2-/- mice develop significantly more skin tumors than matched wildtype controls and keratinocytes harvested from Tpl2-/- mice display multiple biomarkers for cutaneous squamous cell carcinoma (cSCC.) We have previously established that crosstalk between Tpl2-/- keratinocytes and dermal fibroblasts contributes to the transformative potential of our model, and we hypothesized that one of the possible mechanisms driving this transformation was dysregulation of the TGFβ pathway, which plays multiple roles in carcinogenesis but is known to have an anti-proliferative function in noncancerous cells. Using various techniques, including real-time polymerase chain reaction, matrix-metalloproteinase zymography, in vitro angiogenesis assays, and immunoblotting, we saw that both Tpl2-/- keratinocytes and dermal fibroblasts secreted less TGFβ and displayed significant dysregulation of multiple components of the TGFβ pathway. In summary, our studies demonstrate that loss of Tpl2 results in disruption of TGFβ-mediated tumor suppression, and that disruption is in part caused by abnormal signalling from fibroblasts in the tumor microenvironment. Citation Format: Lauren Falkenberg, J. Curtis Gwilliam, Katie L. Decicco-Skinner. Disruption of TGFβ-mediated tumor suppression in a Tpl2 model of cutaneous squamous cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2071. doi:10.1158/1538-7445.AM2015-2071