Abstract 1636: Altering the function of cancer-associated fibroblasts via activation of Notch signaling to inhibit tumor growth.

Abstract

Abstract Objectives. Cancer-associated fibroblasts (CAF) play critical roles in determining tumor growth, invasion, metastasis, drug response and tumor angiogenesis. We have previously demonstrated that activation of the Notch1 pathway confers normal human dermal fibroblasts a suppressive phenotype to melanoma growth. Here, we further investigated whether manipulation of Notch signaling in melanoma-associated fibroblasts (MAF) alter their regulatory phenotype by which affects melanoma growth. Methods. MAF were isolated from human metastatic melanoma and characterized. Notch pathway activity in MAF versus normal human dermal fibroblasts was examined using Notch pathway RT2-PCRArray and immunoblotting. Enforced activation of Notch pathway was achieved by transducing MAF with lentiviral vector encoding active form of Notch1 (NIC). The effect of active Notch1-engineered MAF on melanoma growth was tested by in vitro co-culture and in vivo co-xenografting animal model. Results. Isolated MAF are α-smooth muscle actin (α-SMA) and fibroblast activation protein (FAP) positive. MAF exhibited a relatively lower Notch activity compared to normal human dermal fibroblasts. Enforced activation of Notch1 pathway suppressed cellular activities of MAF. Active Notch1-engineered MAF significantly inhibited melanoma cell growth in vitro and retarded xenografted human melanoma cell growth on mouse skin. Conclusions. Notch pathway activity is lower in MAF. Constitutive activation of Notch pathway confers MAF to a suppressive phenotype in regulating melanoma growth. Our study demonstrated that Notch signaling functions as a critical molecular switch in determining the regulatory role of tumor stromal fibroblasts and provided a novel approach to target tumor microenvironment through modulating stromal fibroblasts by manipulation of Notch signaling. Citation Format: Hongwei Shao, Mecker G. Moller, Omaida C. Velazquez, Zhao-Jun Liu. Altering the function of cancer-associated fibroblasts via activation of Notch signaling to inhibit tumor growth. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1636. doi:10.1158/1538-7445.AM2013-1636