Fibroblast-like cells in mesothelioma can derive from tumor cells

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.