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
| Title | Tumor microenvironment defines the invasive phenotype of AIP-mutation-positive pituitary tumors |
|---|---|
| Type | Journal article |
| Authors | 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. |
| 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. |
| Keywords | AIP, pituitary tumors, microenvironment |
| Journal | Oncogene |
| Journal citation | 38, pp. 5381-5395 |
| ISSN | 0950-9232 |
| Year | 2019 |
| Publisher | Nature Publishing Group |
| Publisher's version | |
| Digital Object Identifier (DOI) | https://doi.org/10.1038/s41388-019-0779-5 |
| Publication dates | |
| Published | 12 Mar 2019 |
| Funder | Wellcome Trust |
| License | CC BY 4.0 |