Researchers in Milan, Italy, have discovered that mesothelioma tumor cells can transform themselves into fibroblast-like cells within their own tumors, challenging traditional understanding of how this rare cancer’s microenvironment develops.
Using advanced single-cell RNA sequencing, scientists at IRCCS Ospedale San Raffaele compared cells from healthy pleura tissue, confirmed mesothelioma tumors, and patient-derived mini-organs grown in the lab. Published in Cell Death and Differentiation, their study identified a population of cells they called Cancer-Derived Fibroblast-like cells (CDFs). These cells carry the same genetic mutations and chromosomal abnormalities as mesothelioma cells while expressing genes typical of normal fibroblasts, effectively allowing the cancer cells to disguise themselves as connective tissue cells that produce collagen and other fibers.
The researchers found that mesothelioma tumor cells have gene expression patterns closely resembling normal mesothelial cells, the thin layer lining body cavities such as the chest and abdomen. This similarity makes it difficult to distinguish cancerous cells from benign ones using genetic activity alone. Analysis of pleural tissue from patients with pleurisy, lung adenocarcinoma, and pneumothorax confirmed that normal mesothelial cells express both epithelial and mesenchymal markers derived from the embryonic mesoderm. The key difference between healthy pleura and mesothelioma tissue was in cell quantity: normal pleura has a single layer of mesothelial cells, whereas mesothelioma tissue contains dense, three-dimensional masses of genetically identical tumor cells.
Laboratory-grown mesothelioma organoids confirmed the existence of CDFs. Tumor cells and fibroblast-like cells within the same organoid shared identical chromosomal copy number variations, indicating a common origin. Patient biopsies further validated these findings, showing cells expressing fibroblast proteins while lacking tumor suppressors MTAP or BAP1, which are absent in that patient’s cancer cells.
This discovery overturns the long-held assumption that cancer-associated fibroblasts (CAFs) arise only from normal fibroblasts or bone marrow cells. Instead, some CAFs in mesothelioma are derived directly from tumor cells. The prevalence of these CDFs varies among patients, with some tumors containing large numbers and others fewer.
Researchers suggest this transformation may occur through a process similar to the mesothelial-to-mesenchymal transition seen in pancreatic cancer and peritoneal metastases. The findings indicate that mesothelioma cells have a high degree of cellular plasticity, enabling them to adopt nearly normal cell identities and potentially resist conventional cancer therapies.
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