Malignant mesothelioma-associated inflammatory microenvironment promotes tumor progression via GPNMB

Our plain-English summary of Malignant mesothelioma-associated inflammatory microenvironment promotes tumor progression via GPNMB, by C. Belgiovine, E. Digifico, M. Erreni, et al (Journal of Translational Medicine, 2025).

The study

• Authors: C. Belgiovine, E. Digifico, M. Erreni, A.R. Putignano, L. Mannarino, S. Valentino, F. Grizzi, F. Pasqualini, C. Recordati, L. Bertola, P. Zucali, D. Pistillo, V. Paleari, A. Mantovani, M. D'Incalci, F. Marchesi, P. Allavena
• Journal: Journal of Translational Medicine
• Published: 2025;23(1):454
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Tumor-Associated Macrophages (TAMs) are the main immune component of the tumor stroma with heterogeneous functional activities, predominantly suppressing the immune response and promoting tumor progression, also via secretion of different factors. Among these, GPNMB (Glycoprotein non-metastatic B) is usually associated with disease progression in several tumor types. Malignant pleural mesothelioma (MPM) a severe neoplasia with poor prognosis, is characterized by an abundancy of TAMs, testifying the presence of a long-lasting inflammation which is pathogenetic of the disease. However, the role of GPNMB in MPM is unclear.

Methods: Clinical samples from patients with MPM were used to measure RNA and protein levels of GPNMB. The functional role of GPNMB in vivo was studied in an orthotopic mouse model of mesothelioma using the murine cell lines AB1 and AB22. Experiments included in vivo tumor growth in wild type and in GPNMB-deficient mice and blocking of GPNMB-induced signaling with anti-CD44 antibodies.

Results: We show that in human and murine MPM tissues the protein GPNMB is mainly produced by infiltrating TAMs. Gpnmb RNA levels in MPM patients from TCGA are significantly associated with lower survival. Using an orthotopic mouse model of mesothelioma we observed that in GPNMB-defective mice (DBA2/J mice) unable to produce the protein, tumors formed by AB1 and AB22 mesothelioma cells grow significantly less than in GPNMB-proficient mice (DBA2/J-Gpnmb+ mice), indicating that host GPNMB is involved in tumor progression. Likewise, the ectopic expression of GPNMB in AB1 and AB22 cells causes an acceleration of tumor growth in vivo, significantly different compared to mock-transduced cells. Treatment of tumor-bearing mice with blocking anti-CD44 (a major receptor for GPNMB) results in a significant reduction of tumor growth.

Conclusions: Overall, these results indicate that the protein GPNMB, a product and marker gene of TAMs, is a driver of mesothelioma progression and may constitute a promising therapeutic target.

© 2025. The Author(s).

In plain English

This laboratory study examined the protein GPNMB (Glycoprotein non-metastatic B) in malignant pleural mesothelioma (MPM), a disease the authors link to chronic inflammation from inhaled asbestos fibres. Using 85 MPM patients from TCGA, higher Gpnmb mRNA was significantly associated with lower survival (p = 0.019), as were CD44 (p = 0.019) and IL-33 (p = 0.045); patients low for both GPNMB and CD44 had better survival (p = 0.001). Plasma GPNMB measured by ELISA was significantly higher in 72 chemo-naive MPM patients than in 86 healthy donors, but plasma levels were not significantly related to survival (p = 0.43). Immunohistochemistry in 28 surgical MPM samples showed GPNMB most often in the stroma, and an RNAscope experiment in two MPM cases showed Gpnmb RNA in CD68-positive macrophages rather than cancer cells. In an orthotopic mouse model using the murine lines AB1 and AB22, tumours from both lines grew significantly less in GPNMB-deficient mice and grew faster when the cells were made to express GPNMB. In mice injected with AB22 cells, a blocking anti-CD44 antibody significantly reduced tumour growth. The authors concluded GPNMB is a driver of mesothelioma progression and a possible therapeutic target.

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 combining analysis of human mesothelioma tissue and plasma samples, TCGA gene-expression/survival analysis, in vitro cell work, and in vivo experiments in an orthotopic mouse mesothelioma model
• Who was studied: 28 patients with pathologically confirmed pleural malignant mesothelioma (tissue) and 72 chemo-naive MPM patients (plasma) at IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy, with 86 healthy volunteer plasma controls; 85 MPM patients from the TCGA database; plus mice (BALB/c, BALB/c x DBA/2J GPNMB KO and GPNMB WT) and human and murine mesothelioma cell lines
• Exposure: Not an exposure study: the factor studied was GPNMB produced by tumour-associated macrophages or expressed ectopically in tumour cells; the murine mesothelioma cell lines used had been generated in BALB/c mice by intraperitoneal injection of crocidolite asbestos fibres
• Main results:
  • In 85 TCGA MPM patients, higher Gpnmb mRNA was significantly associated with lower survival (p = 0.019), as were CD44 (p = 0.019) and IL-33 (p = 0.045)
  • Patients classified as GPNMB-low/CD44-low had significantly better survival (p = 0.001, log-rank test)
  • Plasma GPNMB was significantly higher in the 72 MPM patients than in the 86 healthy donors (p < 0.001)
  • Plasma GPNMB levels, unlike intra-tumour mRNA, were not significantly related to patient survival (p = 0.43)
  • In the 28 surgical MPM samples GPNMB staining was most often in the stroma, with tumour-cell positivity detected in 13 of 28 samples
  • An RNAscope experiment in two distinct human MPM cases showed Gpnmb RNA in CD68-positive macrophages, with cancer cells predominantly negative
  • None of five human MPM patient-derived cell lines produced relevant GPNMB (maximum 0.25 ng/mL), but their conditioned medium stimulated significantly higher GPNMB production by human monocyte-derived macrophages
  • AB1 and AB22 tumours were significantly smaller in GPNMB-defective (GPNMB KO) mice than in GPNMB WT mice (5 mice per group)
  • GPNMB-transduced AB1 and AB22 cells produced 12.5 and 2.5 ng/mL GPNMB respectively; in vitro, AB22-GPNMB cells grew more than AB22-Mock, while AB1-GPNMB cells showed no evident change in proliferation
  • Only GPNMB-expressing AB1 and AB22 cells formed self-renewing spheres, and the dissociated spheres expressed the stemness markers CD117 and CD199
  • In vivo, GPNMB-transduced AB1 cells grew significantly faster than mock-transduced cells, and similar findings were obtained with AB22 cells
  • In mice injected with AB22 cells, treatment with anti-CD44 mAb (10 mg/kg, days 8, 11, 14, 17 and 20) significantly reduced tumour growth compared with an irrelevant antibody, and less tumour area stained for GPNMB
• The authors' conclusion: The authors concluded that GPNMB, a product and marker gene of tumour-associated macrophages, drives mesothelioma progression and may be a promising therapeutic target, with blockade of CD44 suggested as a possible strategy
• Limitations the authors state:
  • The authors noted the lack of increased in vitro proliferation of GPNMB-transduced AB1 cells and suggested, without demonstrating it, that high osteopontin production by these cells may have masked the effect of GPNMB
  • The authors reported that plasma GPNMB levels, unlike tumour mRNA, did not reach statistical significance for patient survival
  • Correlation analysis showed no significant association between GPNMB and CD44 or GPNMB and IL33 expression, and the strongest correlation (CD44 with IL33) was described as weak

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Macrophage, Glycoprotein, Disease Progression, Pleural Mesothelioma, Prognosis, Inflammation.

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• Podoplanin promotes progression of malignant pleural mesothelioma by regulating motility and focus formation — S. Takeuchi, K. Fukuda, et al. (2017)
• The Dark Side of the Force: When the Immune System Is the Fuel of Tumor Onset — E. Digifico, S. Balinzo, et al. (2021)
• Beyond foreign-body-induced carcinogenesis: impact of reactive oxygen species derived from inflammatory cells in tumorigenic conversion and tumor progression — F. Okada (2007)
• Pirfenidone decreases mesothelioma cell proliferation and migration via inhibition of ERK and AKT and regulates mesothelioma tumor microenvironment in vivo — C. Li, V. Rezov, et al. (2018)
• Important functional role of the protein osteopontin in the progression of malignant pleural mesothelioma — E. Digifico, M. Erreni, et al. (2023)

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