A comprehensive study of alternative splicing in malignant pleural mesothelioma identifies potential therapeutic targets in a new cluster with poor survival

Our plain-English summary of A comprehensive study of alternative splicing in malignant pleural mesothelioma identifies potential therapeutic targets in a new cluster with poor survival, by M.M. Shao, X. Qiao, Q.Y. Chen, et al (Thoracic Cancer, 2022).

The study

• Authors: M.M. Shao, X. Qiao, Q.Y. Chen, F.S. Yi
• Journal: Thoracic Cancer
• Published: 2022;13(16):2318-2330
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is one of the most aggressive tumors with few effective treatments worldwide. It has been suggested that alternative splicing at the transcriptome level plays an indispensable role in MPM.

Methods: We analyzed the splicing profile of 84 MPM patients from the TCGA cohort by using seven typical splicing types. We classified MPM patients based on their splicing status and conducted a comprehensive analysis of the correlation between the splicing classification and clinical characteristics, genetic variation, pathway changes, immune heterogeneity, and potential therapeutic targets.

Results: The expression of the alternative splicing regulator SRPK1 is significantly higher in MPM tissues than in normal tissues, and correlates with poor survival. SRPK1 deficiency promotes MPM cell apoptosis and inhibits cell migration in vitro. We divided the MPM patients into four clusters based on their splicing profile and identified two clusters associated with the shortest (cluster 3) and longest (cluster 4) survival time. We present the different gene signatures of each cluster that are related to survival and splicing. Comprehensive analysis of data from the GDSC and TCGA databases revealed that cluster 3 MPM patients could respond well to the small-molecule inhibitor CHIR-99021, a small-molecule inhibitor of GSK-3.

Conclusion: We performed unsupervised clustering of alternative splicing data from 84 MPM patients from the TCGA database and identified a cluster associated with the worst prognosis that was sensitive to a GSK-3 inhibitor.

© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

In plain English

This laboratory and computer-based study looked at alternative splicing, the process by which cells make different versions of a gene's message, in malignant pleural mesothelioma. It did not study asbestos exposure. The authors analysed genetic data from 84 tumors in the Cancer Genome Atlas. Separately, they reduced a splicing regulator, SRPK1, in one mesothelioma cell line, and matched 21 pleural mesothelioma cell lines with drug-response records to their tumor groups. Patients with higher SRPK1 levels had worse survival. Lowering SRPK1 in the cell line increased cell death and reduced cell movement. Grouping the tumors by splicing pattern gave four clusters of 26, 17, 29 and 12 patients, and survival differed significantly between them. Cluster 3 had the worst survival. Cluster 4, all epithelioid, had the best. Of 16 cell lines resembling cluster 3, 50% were sensitive to the drug CHIR-99021, a GSK-3 inhibitor. All five other lines were resistant. The authors concluded that CHIR-99021 could be a candidate treatment for cluster 3 patients. These drug findings came from cell lines, which the authors noted do not mimic tumors in the body.

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: Analysis of public genetic databases (tumor RNA sequencing and splicing data, plus cell-line drug-response data) combined with laboratory experiments in one mesothelioma cell line
• Who was studied: 84 malignant pleural mesothelioma tumor tissues from the Cancer Genome Atlas (TCGA). Also used: 40 mesothelioma tumors and 8 normal pleura tissues from a GEO dataset, the NCI-H2452 mesothelioma cell line, and 21 pleural mesothelioma cell lines in the GDSC database. The article gives no locations or dates for the patients.
• Exposure: No asbestos or other exposure was studied. Asbestos is mentioned only as background in the introduction.
• Main results:
  • SRPK1 expression was higher in tumor tissue from MPM patients than in healthy tissue.
  • MPM patients with higher SRPK1 expression had a worse prognosis than those with lower levels (p less than 0.01).
  • In the H2452 cell line, reducing SRPK1 increased cell death (apoptosis) and reduced cell migration compared with controls.
  • The 84 TCGA patients were divided into four splicing clusters.
  • Survival differed significantly across the four clusters (p less than 0.001).
  • After adjusting for histology and CDKN2A mutation status, the survival differences remained significant (p less than 0.01).
  • Cluster 3 had worse overall survival than the other clusters.
  • All cluster 4 patients and 55% of cluster 3 patients had the epithelioid type.
  • Cluster 3 tumors showed enrichment of epithelial-to-mesenchymal transition and DNA replication pathways.
  • Cluster 4 tumors showed enrichment of type I interferon immune signals.
  • A score reflecting immune-cell killing activity (the cytolytic score) was highest in cluster 4 and lowest in cluster 3 (p = 0.014).
  • The authors built a 3-to-6-gene marker signature for each cluster. Tested on the TCGA patients, its sensitivity was 88.5, 82.4, 89.7 and 91.7% and its specificity was 84.5, 94.0, 85.5 and 94.4% for clusters 1 to 4.
  • The 21 GDSC pleural mesothelioma cell lines were grouped with the TCGA patients using the marker signature. 16 resembled cluster 3 (labelled GDSC-1) and 5 did not (labelled GDSC-2).
  • 50% of GDSC-1 cell lines were sensitive to CHIR-99021, while all GDSC-2 cell lines were resistant.
• The authors' conclusion: The authors concluded that the splicing-based classification has prognostic value. They also concluded that CHIR-99021 showed a good therapeutic effect only in cluster 3 and could be a candidate for personalized MPM treatment. This drug conclusion rests on cell-line data, not on treated patients.
• Limitations the authors state:
  • The drug sensitivity tests were done in cell lines outside the body, which do not reproduce the tumor environment in patients.
  • Classifying patients by their full splicing profile is not feasible in practice. This is why the authors built the smaller gene marker signature.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Apoptosis, Prognosis.

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