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Single-cell RNA-sequencing as a potential approach for studying intratumor heterogeneity in pleural mesothelioma
Ania Alay1, Raúl Marín2, Elisabet Aliagas3
1Doctoral Programme in Medicine and Translational Research, Universitat de Barcelona (UB), Barcelona, Spain; Unit of Bioinformatics for Precision Oncology, Institut Català d'Oncologia, L'Hospitalet de Llobregat, Spain; Preclinical and experimental research in thoracic tumors (PRETT) group, ONCOBELL Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Spain.
Abstract:
Pleural mesothelioma (PM) is a rare and lethal cancer with limited treatment options. Intratumor heterogeneity (ITH) has been postulated as one of the reasons for the poor treatment response observed in most PM patients. In this regard, we aimed to characterize ITH in a multi-site tumor specimen using single-cell RNA-sequencing (scRNA-seq).
Methods:
Tumor cells from three distant biopsies (costal, diaphragmatic, and mediastinal) of an epithelioid PM were analyzed with scRNA-seq.
Results:
Three main cell states were identified in all regions: C1, stem-like; C2, epithelial-like; and C3, mesenchymal-like. C1 state was the most prominent globally, although it was less abundant in the mediastinal biopsy, compared to the other two studied regions. Trajectory analysis was suggestive of an epithelial-mesenchymal plasticity dynamic, including a stem-like intermediate state. Signatures of upregulated genes in each state (SigC1, SigC2, SigC3) were obtained and assessed in a large cohort of PM samples. Patients with tumors enriched in SigC3 were associated with worse survival and with reduced sensitivity to standard of care PM regimens. Additionally, SigC1 appeared to be potentially more sensitive to anti-angiogenic therapies.
Conclusions:
This study highlights that scRNA-seq is useful to capture PM cellular and molecular heterogeneity and identifies gene-expression signatures with potential clinical relevance for future treatment tailoring.
Insights
Single-cell RNA sequencing reveals intratumor heterogeneity in pleural mesothelioma (PM). Gene signatures identified correlate with patient survival and treatment response, offering potential for personalized therapy.
Area of Science:
- Oncology
- Genomics
- Translational Medicine
Background:
- Pleural mesothelioma (PM) is a rare, aggressive cancer with poor treatment outcomes.
- Intratumor heterogeneity (ITH) is a suspected driver of treatment resistance in PM.
- Understanding PM ITH is crucial for developing effective therapies.
Purpose of the Study:
- To characterize ITH in pleural mesothelioma using single-cell RNA sequencing (scRNA-seq).
- To identify distinct cellular states and gene expression signatures within PM tumors.
- To correlate these signatures with clinical outcomes and treatment sensitivity.
Main Methods:
- Analysis of tumor cells from three distinct biopsies of epithelioid PM via scRNA-seq.
- Identification and characterization of cellular states (stem-like, epithelial-like, mesenchymal-like).
- Assessment of gene expression signatures in a large cohort of PM patients.
Main Results:
- Three prevalent cell states (C1-stem-like, C2-epithelial-like, C3-mesenchymal-like) were identified across all tumor regions.
- Trajectory analysis suggested epithelial-mesenchymal plasticity with a stem-like intermediate.
- Enrichment of the C3 signature correlated with poorer survival and reduced sensitivity to standard PM treatments.
- The C1 signature indicated potential sensitivity to anti-angiogenic therapies.
Conclusions:
- scRNA-seq effectively captures cellular and molecular heterogeneity in PM.
- Identified gene expression signatures hold potential clinical relevance for tailoring PM treatments.
- This approach may guide future therapeutic strategies for pleural mesothelioma.
