Tumor microenvironment defines the invasive phenotype of AIP-mutation-positive pituitary tumors

• Published in: Oncogene 2019-07, Vol.38 (27), p.5381-5395
• Main Authors: Barry, Sayka, Carlsen, Eivind, Marques, Pedro, Stiles, Craig E., Gadaleta, Emanuela, Berney, Dan M., Roncaroli, Federico, Chelala, Claude, Solomou, Antonia, Herincs, Maria, Caimari, Francisca, Grossman, Ashley B., Crnogorac-Jurcevic, Tatjana, Haworth, Oliver, Gaston-Massuet, Carles, Korbonits, Márta
• Format: Article
• Language: English
• Subjects: 13/1; 13/105; 13/109; 13/21; 13/51; 13/95; 14/19; 14/63; 38/39; 38/77; 631/80/86/820; 692/53/2422; 82/29; Animals; Apoptosis; Biomarkers, Tumor - metabolism; Bone marrow; Bone tumors; Brain cancer; Brain tumors; Care and treatment; CCR5 protein; Cell Biology; Chemokine CCL5 - metabolism; Epithelial-Mesenchymal Transition; Gene expression; Gene mutations; Genetic aspects; Genotype & phenotype; Growth hormones; Health aspects; Human Genetics; Humans; Internal Medicine; Intracellular Signaling Peptides and Proteins - genetics; Leukocyte migration; Macrophages; Medicine; Medicine & Public Health; Mesenchyme; Mice; Mice, Knockout; Molecular modelling; Mutation; Neoplasm Invasiveness; Oncology; Phenotypes; Pituitary; Pituitary gland; Pituitary gland tumors; Pituitary Neoplasms - genetics; Receptors, CCR5 - metabolism; Somatotropin; Therapeutic applications; Tumor Microenvironment; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-019-0779-5

The molecular mechanisms leading to aryl hydrocarbon receptor interacting protein ( AIP ) mutation-induced aggressive, young-onset growth hormone-secreting pituitary tumors are not fully understood. In this study, we have identified that AIP -mutation-positive tumors are infiltrated by a large number of macrophages compared to sporadic tumors. Tissue from pituitary-specific Aip -knockout ( Aip Flox/Flox ;Hesx1 Cre/+ ) mice recapitulated this phenotype. Our human pituitary tumor transcriptome data revealed the “epithelial-to-mesenchymal transition (EMT) pathway” as one of the most significantly altered pathways in AIP pos tumors. Our in vitro data suggest that bone marrow-derived macrophage-conditioned media induces more prominent EMT-like phenotype and enhanced migratory and invasive properties in Aip -knockdown somatomammotroph cells compared to non-targeting controls. We identified that tumor-derived cytokine CCL5 is upregulated in AIP -mutation-positive human adenomas. Aip -knockdown GH3 cell-conditioned media increases macrophage migration, which is inhibited by the CCL5/CCR5 antagonist maraviroc. Our results suggest that a crosstalk between the tumor and its microenvironment plays a key role in the invasive nature of AIP -mutation-positive tumors and the CCL5/CCR5 pathway is a novel potential therapeutic target.