Mesothelioma researchers from Milan, Italy, have discovered that mesothelioma cells can transform themselves into fibroblast-like cells within their tumors. Their findings challenge the conventional understanding of how the rare cancer’s microenvironment forms and functions.
Research Shifts Traditional View of Mesothelioma Tumors
Using groundbreaking single-cell RNA sequencing, scientists from the IRCCS Ospedale San Raffaele in Milan, Italy, compared cells from non-cancerous pleura tissue, confirmed mesotheliomas, and patient-derived, miniature versions of organs created in the laboratory. Writing in the journal Cell Death and Differentiation, they found that cells that had mutated into mesothelioma, which they named Cancer-Derived Fibroblast-like cells (CDFs), shared the same genetic mutations and chromosomal abnormalities as mesothelioma tumor cells while still expressing genes typical of normal fibroblasts. This essentially means the cancer cells disguised themselves with characteristics of the cells in connective tissue that produce collagen and other fibers.
According to the researchers, mesothelioma tumor cells showed remarkably similar gene expression patterns to cells from the mesothelium — the thin layer of cells lining body cavities like the chest and abdomen. This similarity makes it extremely difficult to use genetic activity to distinguish normal, benign cells from cancerous cells. In analyzing pleural tissue samples from patients with pleurisy, lung adenocarcinoma, and pneumothorax to identify normal mesothelial cell characteristics, they found that these cells express both epithelial markers and mesenchymal markers derived from the body’s embryonic mesodermal layer.
The main difference they identified between normal pleura and mesothelioma samples was in the quantity of mesothelial cells rather than the quality. Normal pleuras contain few mesothelial cells arranged in a single layer, while mesothelioma biopsies contain extensive three-dimensional masses of cancer cells sharing the same genetic markers.
Mesothelioma Patient-Derived Organoids Confirmed CDF Discovery
Mesothelioma patient-derived organoids grown in laboratory settings from biopsy samples revealed that both tumor cells and fibroblast-like cells within the same organoid displayed identical patterns of chromosomal copy number variations. This means that they have a shared origin rather than coming from separate cell populations. The researchers confirmed that CDFs exist in actual patient biopsies by identifying cells expressing a protein present in activated fibroblasts, while simultaneously lacking tumor suppressor proteins MTAP or BAP1 that are absent in that patient’s cancer cells.
The discovery means that mesothelioma CAFs—cancer-associated fibroblasts previously thought to derive from normal fibroblasts or bone marrow cells—can actually include cells originating from the tumor itself. They found that significant differences in the prevalence of those CFs among mesothelioma patients, with some having substantial numbers of these cancer-derived fibroblast-like cells and others having fewer.
The researchers theorize that the transformation probably occurs through a process similar to the mesothelial-to-mesenchymal transition observed when normal mesothelial cells become fibroblasts in pancreatic cancer and peritoneal metastases. This suggests that mesothelioma’s unique cellular plasticity allows its tumor cells to adopt “almost normal” cellular identities, and may be why they are able to resist the effects of traditional cancer treatments.
If you or someone you love has been diagnosed with mesothelioma or another asbestos-related disease, state-of-the-art research like this holds the key to a better future. For information on resources and assistance available to you, contact the Patient Advocates at Mesothelioma.net today, at 1-800-692-8608.
