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

Barry, S., Carlsen, E., Marques, P., Stiles, C., Gadaleta, E., Berney, D., Roncaroli, F., Chelala, C., Solomou, A., Herincs, M., Caimari, F., Grossman, A., Crnogorac-Jurcevic, T., Haworth, O., Gaston-Massuet, C. and Korbonits, M. 2019. Tumor microenvironment defines the invasive phenotype of AIP-mutation-positive pituitary tumors. Oncogene. 38, pp. 5381-5395. https://doi.org/10.1038/s41388-019-0779-5

TitleTumor microenvironment defines the invasive phenotype of AIP-mutation-positive pituitary tumors
TypeJournal article
AuthorsBarry, S., Carlsen, E., Marques, P., Stiles, C., Gadaleta, E., Berney, D., Roncaroli, F., Chelala, C., Solomou, A., Herincs, M., Caimari, F., Grossman, A., Crnogorac-Jurcevic, T., Haworth, O., Gaston-Massuet, C. and Korbonits, M.
Abstract

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 (AipFlox/Flox;Hesx1Cre/+) 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 AIPpos 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.

KeywordsAIP, pituitary tumors, microenvironment
JournalOncogene
Journal citation38, pp. 5381-5395
ISSN0950-9232
Year2019
PublisherNature Publishing Group
Publisher's version
Digital Object Identifier (DOI)https://doi.org/10.1038/s41388-019-0779-5
Publication dates
Published12 Mar 2019
LicenseCC BY 4.0

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