Barbarino Marcella, Bottaro Maria, Spagnoletti Laura, de Santi Maria Margherita, Guazzo Raffaella, Defraia Chiara, Custoza Cosimo, Serio Gabriella, Iannelli Francesco, Pesetti Matilde, Aiello Raffaele, Rosati Diletta, Zanfrini Edoardo, Luzzi Luca, Bellan Cristiana, Giordano Antonio
Department of Medical Biotechnologies, Siena University, 53100 Siena, Italy.
Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA.
Cancers (Basel). 2022 Oct 25;14(21):5216. doi: 10.3390/cancers14215216.
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.
初级纤毛（PC）是一种存在于细胞表面的感觉细胞器，可调节许多信号通路的活性。PC功能障碍会导致包括癌症在内的不同病理状况。刺猬信号通路（Hh）受PC调控，在包括间皮瘤在内的许多癌症中都观察到其调控缺失。恶性胸膜间皮瘤（MPM）是一种致命的胸膜癌症，治疗选择有限。最近，已证明Hh转录激活因子GL1的过表达与MPM患者的总生存期（OS）较差有关。然而，与其他癌症不同，MPM对G蛋白偶联受体平滑蛋白（SMO）/Hh抑制剂的反应较差，这主要归因于缺乏用于患者分层的标志物。基于所有这些原因，特别是考虑到PC在Hh调控中的作用，我们首次研究了MPM组织中PC的状态，证实其表达存在内部和之间的异质性。我们还将PC的存在与Hh信号通路的激活相关联，提供了MPM中Hh信号通路存在不依赖PC调控的新证据。我们的研究有助于理解MPM的异质性，从而有助于识别可能从Hh抑制剂中获益的患者。
