Abstract 4085: Notch1 signaling determines melanoma-regulating role of tumor stromal fibroblasts

Abstract

Abstract Objectives. Tumor stromal fibroblasts are crucial in regulating tumor growth, invasion and metastasis, yet the molecular mechanisms that determine the tumor regulatory role of stromal fibroblasts remains unknown. Here, we uncover the Notch1 signaling pathway as a molecular determinant that controls the tumor regulatory role of tumor stromal fibroblasts in melanoma growth and invasion. Methods. Murine melanoma cells B16-F10, stably transduced with Luciferase 2 (Luc2)/lentivirus, were xenografted on the skin of two new mouse lines: the Gain-Of-Function of Notch1 (GOFNotch1: Fsp1.Cre+/-;ROSALSL-N1IC+/+) and Loss-Of-Function of Notch1 (LOFNotch1: Fsp1.Cre+/-;Notch1LoxP/LoxP+/+), respectively. GOFctrl (FSP1.Cre-/-;ROSALSL-N1IC+/+) and LOFctrl (FSP1.Cre-/-; Notch1LoxP/LoxP+/+) mice were used as control. Tumor growth was measured based on tumor weight and melanoma local invasion were examined by H&E staining of resected tumor tissue. Results. Using a mouse melanoma model in which exogenous melanoma cells were grafted on the skin of two lines of mice where the genetic activation or inactivation of Notch1 signaling specifically occurs in natural host stromal fibroblasts, we demonstrated that Notch1 pathway activity could determine the tumor-promoting or tumor-suppressing phenotype in tumor stromal fibroblasts. Tumor stromal fibroblasts carrying elevated Notch1 activity significantly inhibited melanoma growth and invasion, while those with a null Notch1 promoted melanoma invasion. Conclusions. These findings identify the Notch1 pathway as a molecular determinant that controls the regulatory role of tumor stromal fibroblasts in melanoma skin growth and invasion, unveiling Notch1 signaling as a potential therapeutic target for melanoma and potentially other solid tumors. Citation Format: Hongwei Shao, Ranran Kong, Mecker Moller, Massimiliano L. Ferrari, Leiming Zhang, Freddy Radtke, Anthony J. Capobianco, Zhao-Jun Liu. Notch1 signaling determines melanoma-regulating role of tumor stromal fibroblasts. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4085.