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Adrenal (Excluding Mineralocorticoids)

SAT-420 - Single‑nuclei mapping identifies a sonic hedgehog (SHH) signature in cortisol- producing adenomas with PRKACA mutations

Saturday, June 13, 2026
9:30 AM - 4:30 PM CT
Cushing syndrome (CS) − an archetype of metabolic syndrome, represents a constellation of signs and symptoms associated with hypercortisolism. Adrenal CS is associated with ~35% of benign adrenal tumors referred to as cortisol-producing adenomas (CPAs). Among known cortisol-driver mutations, PRKACA (catalytic subunit α of PKA) and CTNNB1 (β-catenin) are the frequently mutated genes in CPAs. To elucidate mechanisms underlying these genotypes, we performed single-nuclei (sn)-transcriptomics on 5 CPAs [mutant PRKACA (mPRKACA), n=3; mutant CTNNB1 (mCTNNB1), n=2] and bulk RNA sequencing (RNAseq) on 23 CPAs [mPRKACA, n=12; mCTNNB1, n=11] for validation. Both genotypes exhibited significant cellular heterogeneity across 9 distinct clusters. We also identified satellite clusters showing cell populations including adrenal medulla, endothelial cells, capsular cells, stromal cells and immune cells. As opposed to mCTNNB1 CPAs, mPRKACA CPAs demonstrated a significantly higher proportion of cells belonging to a highly steroidogenic cluster, characterized by elevated expression of steroidogenic enzymes at the single-cell level, collectively reflecting the overall increased steroidogenic output observed in bulk RNAseq. Bulk RNAseq confirmed upregulation of key cortisol biosynthesis enzymes HSD3B2 and CYP17A1 in mPRKACA CPAs. Interestingly, the mPRKACA CPAs exhibited strong stromal and capsular signatures, consisting of cells exhibiting a robust sonic hedgehog (SHH) signature, including increased expression of SHH targets such as GLI1, HHIP, BOC and PTCH1. This is consistent with a bidirectional SHH-WNT paracrine relay – a well-established phenomenon in normal adrenal physiology, wherein SHH secreted by WNT-responsive cortical cells signals to capsular/stromal cells, which in turn produce WNT ligands (e.g., RSPO3, WNT2B) that feed back to cortical cells to maintain progenitor identity and sustained SHH expression. Preservation of this axis in mPRKACA tumors suggests continued dependence on capsular/stromal niche communication to sustain steroidogenesis. Conversely, the absence of a prominent stroma/capsular signature in mCTNNB1 CPAs suggests that constitutive CTNNB1 activation in these tumors renders WNT signaling autonomous, thereby bypassing the SHH-dependent paracrine input from the capsular cell niche normally required for maintaining WNT activity and steroidogenic identity in cortical cells. Overall, sn-transcriptomic and bulk RNAseq analysis revealed distinct transcriptomic signatures between the major CPA genotypes that may be promising targets for understanding mechanisms by which specific tumor cell populations mediate disease phenotype in patients with adrenal CS.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*