SAT-304 Pituitary Stem Cells May Drive Adenomas Causing Cushing’s Disease

Abstract

Introduction:Cell rests of self-renewing Sox2+ progenitor cells have been identified in the normal pituitary glands1, however their role in human pituitary tumorigenesis is not understood. Adrenocorticotropic hormone (ACTH) producing microadenomas that cause Cushing’s disease frequently (~70%) lack pathogenic genetic mutations.2 In mice, targeted expression of oncogenic β-catenin in Sox2+ cells generate microadenomas. Interestingly, the Sox2+ cells reside within the adjacent normal gland and drive adenomas in a paracrine fashion.3 We hypothesized that Sox2+ progenitors in human pituitary gland may drive the formation of microadenomas that cause Cushing’s disease (CD). Methods:Four ACTH producing adenomas and two non-functional adenomas (NFPA) with separately annotated adjacent normal tissue (henceforward called ‘microenvironment’) were procured for this study (NCT00060541). We performed RNA deep sequencing (RNAseq) and compared expression of lineage-specific markers and progenitor markers using two-sample T-tests after testing for variance equality and using Welch’s approximation for degrees of freedom. Results:We found expected overexpression of ACTH preprohormone POMC in CD adenomas compared to adjacent microenvironment (?-fold) and NFPA (?-fold). The microenvironment in Cushing’s disease showed increased expression of progenitor markers including SOX2, SOX9, CDH1, GRFA2, and KLF4 compared with microenviroment in NFPA. Likewise, the Cushing’s disease microenvironment showed increased expression ofPOMC (26.98 - fold, P = 0.004) as well as PRLR (FC 17.39, P = 0.006) and GH1 (FC 29.91, P = 0.003) implying that increased Sox2+ progenitors contribute to terminally differentiated corticotrope, lactotroph and somatotroph lineages in-vivo. Conclusions:We report increased expression of several progenitor markers and concomitant elevation in tissues-specific markers in the microenvironment of Cushing’s disease patients. Our results indicate that increased pituitary progenitors in the microenvironment of human corticotropinomas may signal in paracrine fashion and may contribute to the pathogenesis of Cushing’s disease.