Cushing’s Disease Manifestation in USP8-Mutated Corticotropinoma May Be Mediated by Interactions Between WNT Signaling and SST Trafficking

In the current work, we aimed to evaluate the association of clinical data of Cushing's disease (CD) patients with <i>USP8</i> mutation status and to study USP8-related molecular mechanisms connected to the regulation of corticotropinoma growth and activity. 35 CD patients were enrolled; the sequencing of exon 14 in <i>USP8</i> revealed variants in eighteen adenomas, two of which were described for the first time in CD. <i>USP8</i> variants were more common in women (94% vs. 76%; <i>p</i> = 0.001), and microadenomas and tumor recurrence were prevalent in the <i>USP8</i>-mutant group (44% vs. 29%; <i>p</i> = 0.04 and 44% vs. 22%; <i>p</i> = 0.0015). Preoperative ACTH and serum cortisol did not differ in the <i>USP8</i>-WT and <i>USP8</i>-mutant patients. All <i>USP8</i>-mutant adenomas were SST5-positive, and 73% of them were double-positive (SST5+/SST2+). A total of 50% of <i>USP8</i>-WT adenomas were double-negative (SST5-/SST2-), and 40% of them were SST5-positive. Analysis of transcriptome was performed for nine <i>USP8</i>-mutant and six <i>USP8</i>-WT adenomas and revealed the that the bidirectional dysregulation of Wnt signaling, including both the agonist RSPO2 and antagonist SFRP1, in the <i>USP8</i>-mutant corticotropinomas was downregulated. These alterations may indicate the existence of regulatory connections between USP8 enzyme activity, Wnt signaling, EGFR signaling and somatostatin receptors' trafficking, which can explain, at least in part, the clinical manifestations of CD in patients with corticotropinomas harboring <i>USP8</i> variants.