Simple Summary Primary cilium (PC) is a solitary organelle protruding from the cellular membrane of almost all mammalian cells. It transduces signals from external to intracellular compartments regulating many physiological pathways. Dysfunction in PC can lead to a number of pathologic conditions including cancer. Among the pathways transduced by PC, the Hedgehog (Hh) signaling is the focus of recent clinical studies. Malignant pleural mesothelioma (MPM) is a cancer of the membranes covering the lungs with poor prognosis and limited therapeutic options. Although Hh is known to be over-activated in MPM, it responds poorly to smoothened (SMO)/Hh inhibitors. We investigated for the first time the status of PC in MPM tissues, demonstrating intra- and inter-heterogeneity in its expression. We also correlated the presence of PC with activation of the Hh pathway, providing uncovered evidence of the co-existence of a PC-independent regulation of the Hh signaling in MPM. The primary cilium (PC) is a sensory organelle present on the cell surface, modulating the activity of many pathways. Dysfunctions in the PC lead to different pathologic conditions including cancer. Hedgehog signaling (Hh) is regulated by PC and the loss of its control has been observed in many cancers, including mesothelioma. Malignant pleural mesothelioma (MPM) is a fatal cancer of the pleural membranes with poor therapeutic options. Recently, overexpression of the Hh transcriptional activator GL1 has been demonstrated to be associated with poor overall survival (OS) in MPM. However, unlike other cancers, the response to G-protein-coupled receptor smoothened (SMO)/Hh inhibitors is poor, mainly attributable to the lack of markers for patient stratification. For all these reasons, and in particular for the role of PC in the regulation of Hh, we investigated for the first time the status of PC in MPM tissues, demonstrating intra- and inter-heterogeneity in its expression. We also correlated the presence of PC with the activation of the Hh pathway, providing uncovered evidence of a PC-independent regulation of the Hh signaling in MPM. Our study contributes to the understanding MPM heterogeneity, thus helping to identify patients who might benefit from Hh inhibitors.

Analysis of Primary Cilium Expression and Hedgehog Pathway Activation in Mesothelioma Throws Back Its Complex Biology

Bottaro M.;Serio G.
Investigation
;
2022-01-01

Abstract

Simple Summary Primary cilium (PC) is a solitary organelle protruding from the cellular membrane of almost all mammalian cells. It transduces signals from external to intracellular compartments regulating many physiological pathways. Dysfunction in PC can lead to a number of pathologic conditions including cancer. Among the pathways transduced by PC, the Hedgehog (Hh) signaling is the focus of recent clinical studies. Malignant pleural mesothelioma (MPM) is a cancer of the membranes covering the lungs with poor prognosis and limited therapeutic options. Although Hh is known to be over-activated in MPM, it responds poorly to smoothened (SMO)/Hh inhibitors. We investigated for the first time the status of PC in MPM tissues, demonstrating intra- and inter-heterogeneity in its expression. We also correlated the presence of PC with activation of the Hh pathway, providing uncovered evidence of the co-existence of a PC-independent regulation of the Hh signaling in MPM. The primary cilium (PC) is a sensory organelle present on the cell surface, modulating the activity of many pathways. Dysfunctions in the PC lead to different pathologic conditions including cancer. Hedgehog signaling (Hh) is regulated by PC and the loss of its control has been observed in many cancers, including mesothelioma. Malignant pleural mesothelioma (MPM) is a fatal cancer of the pleural membranes with poor therapeutic options. Recently, overexpression of the Hh transcriptional activator GL1 has been demonstrated to be associated with poor overall survival (OS) in MPM. However, unlike other cancers, the response to G-protein-coupled receptor smoothened (SMO)/Hh inhibitors is poor, mainly attributable to the lack of markers for patient stratification. For all these reasons, and in particular for the role of PC in the regulation of Hh, we investigated for the first time the status of PC in MPM tissues, demonstrating intra- and inter-heterogeneity in its expression. We also correlated the presence of PC with the activation of the Hh pathway, providing uncovered evidence of a PC-independent regulation of the Hh signaling in MPM. Our study contributes to the understanding MPM heterogeneity, thus helping to identify patients who might benefit from Hh inhibitors.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11586/496081
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