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

Abstract

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.

Changes in expression of mesothelial BBS genes in 2D and 3D after lithium chloride and ammonium sulphate induction of primary cilium disturbance: a pilot study

“…In our experiments, the range of PC positive staining ranged from 14 to 18% depending on the cell line. Indeed, our data corroborate findings on the variable occurrence of PC in human pleural biopsies of inflamed and malignant tissue as well as MPM cell lines [ 11 ].…”

“…MPM cells are amongst the most versatile human cells functionally and morphologically, while being heterogeneous at the inter-tumor as well as the intra-tumor level, as established through histological and molecular analyses [ 26 ]. A recent study has identified two distinct epithelioid MPM subtypes regarding gene expression, while the PC status in MPM tissues has demonstrated significant variability [ 11 , 27 ]. Thus, the use of 3D cultures would be ideal given the changes in MPM behavior concerning ECM and tissue architecture [ 16 , 17 ].…”

“…Recently PC was detected in patient biopsies of benign pleura and a fraction of epithelioid and biphasic MPM biopsies as evidenced by the immunostaining of a marker of PC, ADP Ribosylation Factor Like GTPase 13B (ARL13B) [ 11 ]. In MPM the PC is frequently lost without precluding activation of the Hedgehog (Hh) pathway that is regulated through several activators and suppressors residing on it.…”

Recent Advances in Carcinogenesis Transcription Factors: Biomarkers and Targeted Therapies

“…In fact, their results suggest that loss of the PC is a frequent occurrence in aggressive MPM but does not preclude activation of the Hh pathway canonically or noncanonically. These findings highlight the need for innovative approaches for addressing the patient-specific treatment challenges posed by this formidable, highly heterogenetic cancer [28].…”

“…Deregulation of Hh signaling has an important role in the development and progression of cancer, especially MPM. In this Special Issue, researchers investigated the presence of the PC in malignant pleural mesothelioma (MPM) [28], a common cancer of the pleura with a poor prognosis because of limited treatment options. This cancer is extremely heterogenic, which contributes to the lack of available therapies.…”