Description

Role of Tenascin-C in modulating the immune microenvironment of breast cancer

Devadarssen Murdamoothoo¹, Zhen Sun¹, Ines Velazquez-Quesada¹, Claire Deligne², Kim Midwood² and Gertraud Orend¹

¹University of Strasbourg, INSERM U1109 –Strasbourg France

²University of Oxford, Kennedy Institute of Rheumatology – Oxford, UK

High expression of the extracellular matrix molecule tenascin-C (TNC) correlates with worsened survival of breast cancer patients (Midwood et al., 2016, JCS in press). TNC promotes tumor cell survival, proliferation and invasion as well as angiogenesis and metastasis (Saupe et al., 2013, Cell Reports 5). The immune system plays an important role in cancer progression and anti-cancer therapies. Despite some evidence for a role of TNC on immunity in chronic inflammation, there is poor mechanistic insight how TNC impacts on immunity in breast cancer due to the lack of relevant immune competent models.

Here, we used the stochastic MMTV-NeuNT breast cancer model (expressing activated ErbB2) with abundant and no TNC and investigated tumor onset and lung metastasis. We also established the NT193 cell line from an MMTV-NeuNT tumor (Arpel et al., 2014, Cell Reports 8) that upon orthotopic syngeneic grafting recapitulates important aspects of the genetic disease (Sun, Murdamoothoo et al., in preparation). We observed that in the absence of TNC, tumour latency and lung metastasis were reduced. A gene expression analysis by mRNA profiling revealed a role of TNC in regulating the expression of immunity-related genes that will be presented here.

The NT193 grafting model further revealed a dual role of TNC in breast cancer. Despite high metastasis TNC induced tumor cell rejection. This was not seen when either the host or the tumor cells lacked TNC expression. As in other tumors (Spenlé et al., 2015, Cell Adh Migr 9) TNC is organised into tracks together with laminin and fibronectin that delineate the tumor nests. Whereas T cells were predominantly present in the TNC containing matrix tracks, they were more abundant inside the tumor nests in the absence of TNC. These results support an immune-suppressive role of TNC in breast cancer that will be further shown here.