Abstract 1903: Tenascin C affects tumor associated macrophage phenotype and tumor invasion in breast cancer

Abstract

Abstract Breast cancer metastasis is one of the major causes of cancer deaths among women. Tumor associated macrophages (TAMs) play a role in metastasis by inducing angiogenesis and remodeling the tumor matrix, as well as providing chemotactic, survival and proliferative signals to the tumour cells. Conventional classification of TAMs has been revised due to their complex phenotypic and functional variability dependent on cancer type and location. Therefore the temporal and spatial microenvironment within tumours is crucial to define macrophage subtypes and their effect on the tumor. In our studies we show that the expression pattern of the extracellular matrix glycoprotein tenascin-C (TNC) correlates with the invasion sites of the tumor and affects the TAM phenotype in breast cancer. TNC is known to promote metastatic seeding and correlates with poor prognosis, however only a few studies have investigated how the tumor and immune cells interact with this matrix. We determined the spatial distribution of TNC using whole slide imaging of mouse breast cancer sections. In a mouse model of breast cancer caused by the mammary restricted expression of the Polyoma Middle T oncoprotein (MMTV-PyMT) we showed that TNC expression is located at the peri-tumor and peri-vascular sites in late stages of disease and is also correlated with angiogenic regions of human breast cancer. We analyzed MMTV-PyMT breast peri-tumor (high tenascin-C and angiogenesis) and intra-tumor (low tenascin-C and angiogenesis) regions separately and found that macrophages at peri-tumor site express more TAM markers associated with pro-tumoural functions such as CD206, CD204, CD11b and CD49d (integrin alpha-4). To better understand how this matrix affects macrophage function, we polarized bone-marrow derived mouse macrophages using the E0771 mammary cancer cell line conditioned medium on collagen, fibronectin and tenascin C coated 2D surfaces. We found that tenascin C significantly increased CD11b, CD49d and CX3CR-1 expression in macrophages. CD49d functions as a co-receptor of CX3CR-1 and its ligand VCAM-1 on E0771 also increases with TNC in macrophage-conditioned medium. It was previously shown that VCAM-1 expression and binding to CD49d promotes breast cancer progression and metastasis. We also show that a 3D matrix with TNC increases transwell migration and spheroid invasion of E0771 cells, suggesting that TNC expression at the invasion site could directly affect breast cancer invasion. Consequently we suggest that TNC not only has prognostic value but could also be crucial to predict invasion sites within breast tumors due its effect on macrophage-tumor interaction and metastasis. Citation Format: Esra Guc, Gabriella Sammut DeMarco, Giulia Pieracci, Jeffrey W. Pollard. Tenascin C affects tumor associated macrophage phenotype and tumor invasion in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1903.