Fibroblast-like cells in mesothelioma can derive from tumor cells

Our plain-English summary of Fibroblast-like cells in mesothelioma can derive from tumor cells, by J.M. Garcia-Manteiga, E. Rrapaj, F. Caprioglio, et al (Cell Death and Differentiation, 2026).

The study

• Authors: J.M. Garcia-Manteiga, E. Rrapaj, F. Caprioglio, F. De Marchis, A. Lamarca, L.S. Colley, A. Carretta, D. Finocchiaro, F. Mercalli, A. Molinario, G. Arrigoni, R. Boldorini, M.P. Crippa, R. Mezzapelle, M.E. Bianchi
• Journal: Cell Death and Differentiation
• Published: 2026;33(6):1203-1217
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Pleural mesothelioma (PM) is an aggressive cancer that originates from mesothelial cells lining the pleura. To identify the different cell types in mesothelioma and their relationships, we performed single-cell RNAseq analyses of non-malignant pleura biopsies, PM biopsies and PM patient-derived organoids. Gene expression profiles of mesothelial and mesothelioma cells are very similar, suggesting that mesothelioma cells retain most properties of mesothelial cells. Surprisingly, in PM patient-derived organoids mesothelioma cells can acquire a fibroblast-like gene expression profile. Indeed, in most of the original PM biopsies a fraction of cells within the cluster of cancer-associated fibroblasts (CAFs) appear derived from tumor cells, with which they share the same genomic rearrangements. We confirmed by immunohistochemistry, and thus at the protein level, that cancer-derived fibroblast-like cells (CDFs) express smooth muscle actin, as most CAFs do, but have lost the same tumor suppressor proteins as the cognate mesothelioma cells. We propose that mesothelioma cells can become CDFs because they retain the ability of mesothelial cells to differentiate into fibroblasts. CDFs are thus tumor cells with fibroblast-like gene expression associated to tumors, and fulfil the definition of CAFs. CAFs generally support tumor progression, and in most tumors derive from resident fibroblasts or circulating mesenchymal cells. Our finding that a subset of CAFs derive from tumor cells, at least in mesothelioma, challenges current understanding of CAF origin. We suggest that interfering with the mesothelioma-to-CAF transition might offer an avenue to moderate tumor progression and resistance to therapy.

© 2025. The Author(s).

In plain English

This laboratory study examined cells from pleural mesothelioma tissue at two Italian hospitals. The authors sequenced RNA in single cells from three non-cancerous pleura samples, five mesothelioma biopsies, and lab-grown cultures (organoids) from three patients. Mesothelioma cells' gene activity largely overlapped that of normal mesothelial cells. In the organoids, about half the cells had a fibroblast-like gene profile yet carried tumor genetic changes. Some cancer-associated fibroblasts in biopsies also carried tumor changes. In one patient, 7 of 7 did. In another, 67 had a high and 28 a low estimated probability of the tumor's chromosome 9 change. In published data from 13 more patients, the authors found such cells in 6 of 12 informative patients (10 of 17 overall). Protein staining in four more patients found these cells were 20 to 86% of cells positive for smooth muscle actin. That marker can also tag vessel cells and misses some fibroblasts. The authors concluded that mesothelioma cells can turn into fibroblast-like cells within tumors. They said prognostic effects need proving in future studies. Asbestos exposure was recorded but not analyzed.

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: Laboratory study of human tissue: single-cell RNA sequencing of pleural biopsies and patient-derived organoids, reanalysis of a published single-cell dataset, and immunohistochemistry (protein staining)
• Who was studied: Pleural mesothelioma and non-malignant pleura samples came from the Thoracic Surgery units of IRCCS Ospedale San Raffaele and Maggiore della Carità hospital, Italy. Single-cell sequencing covered 3 non-malignant pleura samples (from patients with pleurisy, pneumothorax and lung adenocarcinoma), 5 mesothelioma biopsies and organoids from 3 patients. Published data from 13 pleural mesothelioma patients were reanalyzed. Multiplex staining was done on 5 specimens. Dates of collection were not given.
• Exposure: No exposure was studied; the study examined cell types within tumors. Table 1 records asbestos exposure status for the first cohort: Yes for MOSR8, MOSR9, MOSR10 and MOSR12, No for MOSR3, and not available for MOSR11. This information was not analyzed.
• Main results:
  • Mesothelioma cells and normal mesothelial cells intermingled in the same cluster, suggesting substantial overlap in gene expression.
  • In the patient-derived organoids, about half of the cells had a fibroblast gene signature while carrying the copy number changes of mesothelioma cells.
  • In biopsy MOSR9, 67 cancer-associated fibroblasts had a high probability, and 28 a low probability, of carrying the tumor's chromosome 9 loss of heterozygosity.
  • In biopsy MOSR12, all 7 cancer-associated fibroblasts had tumor copy number changes.
  • In biopsy MOSR10, 47 of 49 cancer-associated fibroblasts were scored as lacking tumor changes. In MOSR3, 24 of 29 fibroblast-like cells had tumor changes. In MOSR8, neither of the two fibroblast-like cells did.
  • In the reanalyzed published dataset of 13 patients, 6 of 12 informative patients had fibroblast-like cells with the tumor's copy number changes.
  • Across both cohorts, fibroblast-like cells with tumor changes were found in 10 of 17 informative mesothelioma patients.
  • The two samples with more fibroblast-like cells than tumor cells (ratios of 10 and 5) were both sarcomatoid.
  • Multiplex protein staining covered four further patients with sarcomatoid or biphasic mesothelioma. The number of cancer-derived fibroblast-like cells ranged from 63 to 1827. These made up 20 to 86% of cells expressing smooth muscle actin (αSMA), and 4 to 41% of tumor cells.
  • The proportion of these cells varied between different regions of a single tumor (patient MOSR85).
• The authors' conclusion: The authors concluded that mesothelioma cells can differentiate within the tumor into fibroblast-like cells, which they called Cancer-Derived Fibroblast-like cells. They expect these cells to affect prognosis and perhaps treatment response, but said this must be proven by future clinical studies.
• Limitations the authors state:
  • None of the non-malignant pleura samples fully represents normal pleura.
  • Biopsy size limited the number of cells that could be recovered.
  • Classical double staining is difficult to quantify.
  • Some cells counted as cancer-associated fibroblasts by smooth muscle actin staining might be vessel-associated cells, and not all such fibroblasts express this marker.
  • More patients are needed to determine whether these cells are more common in sarcomatoid than in epithelioid mesothelioma.

Topics

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

Medical terms in this study, explained in our Lexicon: Fibroblast, Mesothelioma, Pleural Mesothelioma, Mesothelial Cells, Pleura, Immunohistochemistry.

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