BONEMETTNC · Analysis of Tenascin C function in breast cancer metastasis to bone

Analysis of Tenascin C function in breast cancer metastasis to bone

Metastasis is the spread and outgrowth of cancer cells in secondary organs and is frequently associated with resistance to therapeutic intervention (Lambert et al 2017). Today, metastatic cancer is essentially incurable, thus there is urgent need to develop novel treatment options. A corrupted microenvironment in tumors is recognized to play a key role in cancer progression and metastasis (Oskarsson et al 2014). This includes local fibroblasts and endothelial cells that have acquired a wound healing phenotype as well as recruited bone marrow derived immune and non-immune cells (Quail and Joyce 2013). Moreover, growing evidence indicates that the extracellular matrix (ECM), the non-cellular network of the microenvironment, can have a major effect on cancer progression. Within the tumor ECM network, a striking increase is observed in specific ECM proteins. These are for example, matricellular proteins, a heterogenous subgroup of ECM proteins that are commonly expressed during embryonic development and in response to wounding. Interestingly, whereas healthy adult tissues largely do not express matricellular proteins, these proteins are found expressed in specific locations such as stem cell niches (Insua-Rodriguez and Oskarsson 2016). We have previously identified the ECM protein tenascin C (TNC) as an essential component of the metastatic niche in breast cancer (Oskarsson et al 2011). TNC is one of the founding members of the group of matricellular proteins and follows their common expression pattern (Midwood et al 2016). TNC is expressed in stem cell niches such as the subventricular zone of the brain, hair follicle bulge region and the hematopoietic stem cell niche in the bone marrow (Chiquet-Ehrismann et al 2014). This suggests that TNC may have a role in regulating stem cells characteristics that are known to be important for tumor initiation, particularly at distant sites. Indeed, we have demonstrated a link between TNC and stem cell properties in lung metastasis. We showed that TNC is essential for metastatic colonization of the lung and bone in mouse models (Oskarsson et al 2011). In the lung, TNC engages stem cell signaling such as the Notch and Wnt pathways to promote fitness of metastasis initiating cells. The objective of this study was to dissect the functional and molecular role of TNC within the metastatic niche and to identify the cellular receptor(s) that mediate TNC function in metastasis. Moreover, we aimed to determine whether inhibition of TNC can sensitize breast cancer metastasis to therapeutic intervention. We addressed this by using 3D culture systems of breast cancer cells, RNA interference, transcriptomic screens and xenograft mouse models of cancer progression and metastasis. The studies have contributed to increase our understanding of TNC function in breast cancer. We have dissected the clinical relevance of TNC in breast cancer subtypes and identified receptors that mediate TNC function in lung metastasis. Furthermore, we provide new evidence for TNC association to mammary stem cells, of which several properties are hijacked by metastatic breast cancer cells. Finally, our study provides insight into the role of TNC in therapy resistance. Overall, the findings may have significant societal impact. Increasing evidence suggests that proteins of the ECM support the fitness of disseminated cancer cells at distant sites, facilitating metastatic outgrowth. Notably, our work shows that cancer cells may bring their own ECM niche components to secondary organs for this purpose. Targeting these components or their receptors may provide the means to impair the competence of disseminated cancer cells and prevent metastatic relapse. References Chiquet-Ehrismann R, Orend G, Chiquet M, Tucker RP, Midwood KS. (2014) Tenascins in stem cell niches. Matrix Biol. 37:112-23. Insua-Rodríguez J, Oskarsson T. (2016) The extracellular matrix in breast cancer. Adv Drug Deliv Rev. 97:41-55. Lambert, A. W., Pattabiraman, D. R., and Weinberg, R. A. (2017). Emerging Biological Principles of Metastasis. Cell 168, 670-691. Midwood KS, Chiquet M, Tucker RP, Orend G. (2016) Tenascin-C at a glance. J Cell Sci. 129:4321-4327. Oskarsson T, Batlle E, Massagué J. (2014) Metastatic Stem Cells: Sources, Niches, and Vital Pathways. Cell Stem Cell. Mar 6;14(3):306-321. Oskarsson T, Acharyya S, Zhang X H.-F, Vanharanta S, Tavazoie SF, Morris PG, Downey RJ, Manova-Todorova K, Brogi E and Massagué J. (2011) Breast cancer cells produce tenascin-C as a metastatic niche component to colonize the lungs. Nature Medicine. 17:867-74. Quail DF, Joyce JA. (2013) Microenvironmental regulation of tumor progression and metastasis. Nat Med.19:1423-37.

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