PO-237 Neutralising extracellular morgana impairs breast tumour growth and migration

ABSTRACT Introduction Morgana is a ubiquitously expressed protein with chaperone activity per se and HSP90 co-chaperone function. High Morgana expression correlates with high tumour grade, mitosis number, and lymph node positivity in different breast cancer subtypes. Several chaperones are overexpressed in a wide range of human cancers and are implicated in tumour progression. Moreover, it has become evident that also from the extracellular compartment, where surprisingly chaperones and co-chaperones are actively released by cancer and immune cells, they favour tumour progression. If, the cytoplasmic role of Morgana has been well characterised in tumorigenesis and metastasis formation of Triple-Negative Breast Cancer (TNBC), nothing is known about extracellular Morgana (eMorgana). Material and methods Conditioned medium from human and murine TNBCs cell lines were analysed for Morgana presence. To address the role of eMorgana, a Maltose Binding Protein (MBP) fused recombinant protein was produced in ClearColi BL21 and used to evaluate eMorgana role in migration, treating MDA-231 and BT-549. The identification of Morgana receptor was performed indirectly, through the inhibition of Toll-like 2 and Toll-like 4 receptors (TLR2, TLR4). The activity of extracellular Morgana was inhibited, in mice injected with the syngenic cancer cell line E0771, using the homemade blocking antibody 5B11. Results and discussions Morgana is secreted by TNBC cell lines and as for other chaperones and co-chaperones, Morgana reaches the outside with an unconventional mechanism. From the extracellular compartment Morgana is able to induce cell migration, through theTLR2 and TLR4. Blocking of eMorgana with 5B11 inhibits migration in vitro and proliferation in vivo. Different efforts are needed to understand if Morgana binds to TLRs alone or through HSP90 and the consequently downstream signalling pathway. Moreover since TLR are prevalently expressed by immune cells it is important to address the role of eMorgana in this context and the possible crosstalk between the tumour and microenvironment. Conclusion Since TNBCs have an high rate of recurrence and poor prognosis, the identification of innovative treatments is an urgent need. In this view, although many other studies are required, eMorgana in serum patients could represent a new biomarker and its targeting a possible clinical approach in breast cancers.