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

Our plain-English summary of Analysis of Primary Cilium Expression and Hedgehog Pathway Activation in Mesothelioma Throws Back Its Complex Biology, by M. Barbarino, M. Bottaro, L. Spagnoletti, et al (Cancers, 2022).

The study

• Authors: M. Barbarino, M. Bottaro, L. Spagnoletti, M.M. de Santi, R. Guazzo, C. Defraia, C. Custoza, G. Serio, F. Iannelli, M. Pesetti, R. Aiello, D. Rosati, E. Zanfrini, L. Luzzi, C. Bellan, A. Giordano
• Journal: Cancers
• Published: 2022;14(21)
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study from Siena, Italy, examined the primary cilium (a small antenna-like structure on the cell surface) and the Hedgehog signaling pathway in malignant pleural mesothelioma. The article does not discuss asbestos exposure. The authors stained 28 pleural tissue samples: 24 mesothelioma and 4 non-cancer. In the mesothelioma samples, the cilium was present in 7 (29.1%), lost in 13 (54.2%) and mixed within the tumor in 4 (16.7%). All biphasic and desmoplastic tumors had lost it, while all non-cancer samples kept it. The link between cilium status and tumor type was statistically significant (p = 0.020). Among patient-derived cell lines, four of eight mesothelioma lines lacked cilia. Nuclear GLI1, a marker of Hedgehog activity, was found in 12 of 19 tumors tested (63.2%). Its link to cilium status was not statistically significant (p = 0.373). The authors concluded that cilium loss occurs frequently in mesothelioma and does not prevent Hedgehog activation. They called the work a pilot study and said its sample size does not allow robust conclusions about prognosis.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Pilot laboratory study of tumor tissue specimens, patient-derived and commercial cell lines, and a public gene-expression database (TCGA)
• Who was studied: 28 formalin-fixed pleural tissues (24 mesothelioma, 4 non-oncological: 2 pleuritis, 2 reactive mesothelial hyperplasia) from Siena University Hospital, Italy. Also 8 patient-derived mesothelioma cell lines established between 2016 and 2022, 3 non-tumoral mesothelial cell lines, the commercial LP-9 line, the MSTO-211H and NCI-H2052 lines, and 19 TCGA samples (10 epithelial, 9 biphasic; male, stage 3).
• Main results:
  • Of the 24 mesothelioma tissues, 7 (29.1%) had the primary cilium, 13 (54.2%) had lost it, and 4 (16.7%) showed mixed expression within the tumor
  • All biphasic (n = 4) and desmoplastic (n = 1) mesotheliomas had lost the cilium. The correlation between cilium expression and histology was statistically significant (p = 0.020).
  • All four non-cancer tissues retained the cilium
  • Among the 8 patient-derived mesothelioma cell lines, 4 (MMP1, MMP4, MMP14, MMP43) lacked the cilium and 4 (MMP18, MMP21, MMP23, MMP32) retained it
  • Cilium-negative mesothelioma cells showed increased activity of the Hedgehog target genes GLI1, PTCH1 and c-MYC, although GLI1 in MMP1 did not reach statistical significance
  • Regardless of cilium status, all mesothelioma cell lines showed GLI1 in the nucleus, except MMP21
  • Nuclear GLI1 was found in 12 of 19 mesothelioma tissues (63.2%), 3 of them cilium-positive and 9 cilium-negative. The correlation between GLI1 score and cilium expression was not significant (p = 0.373).
  • In the 19 TCGA samples, GLI1 was not significantly differentially expressed between epithelial and biphasic tissue (padj = 0.81). In the authors' tissues, nuclear GLI1 was not significantly correlated with histology (p = 0.845).
• The authors' conclusion: The authors concluded that loss of the primary cilium occurs frequently in pleural mesothelioma and does not prevent activation of the Hedgehog pathway. They proposed analyzing cilium presence together with nuclear GLI1 as a predictive marker of response to SMO inhibitors.
• Limitations the authors state:
  • The sample size does not allow robust conclusions about the prognostic significance of cilium frequency in mesothelioma
  • The findings need to be confirmed in a larger cohort
  • The non-canonical pathways that drive Hedgehog/GLI1 activation in cilium-negative mesothelioma remain to be identified
  • It is unclear whether the one change in cilium status seen after chemotherapy reflects different responses of cilium-positive and cilium-negative cells

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Overall Survival.

Related studies

• 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 — E. Rouka, R.M. Jagirdar, et al. (2023)
• TAZ activation by Hippo pathway dysregulation induces cytokine gene expression and promotes mesothelial cell transformation — A. Matsushita, T. Sato, et al. (2019)
• Aberrant expression of NPPB through YAP1 and TAZ activation in mesothelioma with Hippo pathway gene alterations — T. Sato, K. Akao, et al. (2023)
• Targeting of the Hedgehog signal transduction pathway suppresses survival of malignant pleural mesothelioma cells in vitro — M. You, J. Varona-Santos, et al. (2014)
• Mutational analysis of hedgehog signaling pathway genes in human malignant mesothelioma — C.B. Lim, C.M. Prêle, et al. (2013)
• Antagonizing the Hedgehog Pathway with Vismodegib Impairs Malignant Pleural Mesothelioma Growth In Vivo by Affecting Stroma — M. Meerang, K. Bérard, et al. (2016)

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