Tumor microenvironment defines the invasive phenotype of AIP-mutation-positive pituitary tumors.
Sayka BarryEivind CarlsenPedro MarquesCraig E StilesEmanuela GadaletaDan M BerneyFederico RoncaroliClaude ChelalaAntonia SolomouMaria HerincsFrancisca CaimariAshley B GrossmanTatjana Crnogorac-JurcevicOliver HaworthCarles Gaston-MassuetMarta KorbonitsPublished in: Oncogene (2019)
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.
Keyphrases
- growth hormone
- endothelial cells
- single cell
- stem cells
- liver injury
- epithelial mesenchymal transition
- electronic health record
- mesenchymal stem cells
- adipose tissue
- drug induced
- induced apoptosis
- machine learning
- regulatory t cells
- liver fibrosis
- metabolic syndrome
- skeletal muscle
- dna methylation
- signaling pathway
- small molecule
- insulin resistance
- protein kinase
- stress induced
- amyotrophic lateral sclerosis
- late onset
- diabetic rats