PRIMARY CILIUM LOSS IN ADVANCED MESOTHELIOMA CORRELATES WITH CONSTITUTIVE GLI1 OVEREXPRESSION

Malignant mesothelioma is an aggressive cancer of the membranes covering the lung and chest cavity (pleura), or the abdomen (peritoneum), mainly linked to asbestos exposure. It is characterized by high intrinsic heterogeneity, diagnosis in the late stages and a high immunosuppressive microenvironment. In the past years many agents have been evaluated for use in mesothelioma but with modest results so that the prognosis remains poor. Recently, in light of the promising results achieved in other cancers, the targeting of the Hedgehog-GLI (HH-GLI) pathway has been investigated as possible new therapy for MPM cure. The HH-GLI pathway starts at Primary Cilium (PC), an organelle protruding from the extracellular membrane of the cells that expresses specific receptors for the Hedgehog ligands. In cells lacking PC, the HH-GLI pathway can also be activated by intracellular signaling that make cells resistant to HH-GLI ligand-dependent pathway inhibitors. In MPM the HH-GLI signaling is active but response to targeting agents is poor. Activating mutations in the core components of the pathway that in other cancers lead to drug resistance in MPM are rare. Here we studied the presence of PC in mesothelioma and its correlation with HH-GLI pathway activation. We found an heterogeneous presence of PC in MPM and, in the cells loosing PC, GLI1 was overexpressed. Our preliminary results suggested that PI3K/AKT pathway can be, at least in some cells, responsible for the activation of HH-GLI1 pathway. In summary, we have documented for the first time the loss of PC in mesothelioma and the activation of a non-canonical HH-GLI pathways in this cancer.