Belgiovine Cristina, Digifico Elisabeth, Erreni Marco, Putignano Anna Rita, Mannarino Laura, Valentino Sonia, Grizzi Fabio, Pasqualini Fabio, Recordati Camilla, Bertola Luca, Zucali Paolo, Pistillo Daniela, Paleari Valentina, Mantovani Alberto, D'Incalci Maurizio, Marchesi Federica, Allavena Paola
IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano (Milan), Italy.
Lab. Molecular Mechanisms of Innate Immunity and Nucleic Acid Sensing, Department of Biology and Biotechnology "L. Spallanzani", Via Ferrata 9, 27100, Pavia, Italy.
J Transl Med. 2025 Apr 18;23(1):454. doi: 10.1186/s12967-025-06407-4.
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.
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.
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.
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.
肿瘤相关巨噬细胞（TAM）是肿瘤基质的主要免疫成分，具有异质性功能活性，主要通过分泌不同因子抑制免疫反应并促进肿瘤进展。其中，糖蛋白非转移性B（GPNMB）通常与多种肿瘤类型的疾病进展相关。恶性胸膜间皮瘤（MPM）是一种预后不良的严重肿瘤，其特征是大量TAM的存在，证明了导致该疾病的长期炎症的存在。然而，GPNMB在MPM中的作用尚不清楚。
使用MPM患者的临床样本测量GPNMB的RNA和蛋白质水平。利用小鼠细胞系AB1和AB22，在间皮瘤原位小鼠模型中研究GPNMB在体内的功能作用。实验包括野生型和GPNMB缺陷小鼠体内肿瘤生长情况，以及用抗CD44抗体阻断GPNMB诱导的信号传导。
我们发现，在人和小鼠的MPM组织中，蛋白质GPNMB主要由浸润的TAM产生。来自癌症基因组图谱（TCGA）的MPM患者中，Gpnmb RNA水平与较低的生存率显著相关。使用间皮瘤原位小鼠模型，我们观察到在无法产生该蛋白质的GPNMB缺陷小鼠（DBA2/J小鼠）中，由AB1和AB22间皮瘤细胞形成的肿瘤生长明显低于GPNMB正常的小鼠（DBA2/J-Gpnmb+小鼠），这表明宿主GPNMB参与肿瘤进展。同样，GPNMB在AB1和AB22细胞中的异位表达导致体内肿瘤生长加速，与mock转导细胞相比有显著差异。用阻断性抗CD44（GPNMB的主要受体）治疗荷瘤小鼠可显著降低肿瘤生长。
总体而言，这些结果表明蛋白质GPNMB作为TAM的产物和标记基因，是间皮瘤进展的驱动因素，可能是一个有前景的治疗靶点。
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