Transcriptome-Wide Analysis of Pituitary and Ectopic Adrenocorticotropic Hormone-Secreting Tumors.

Simple Summary: Endogenous Cushing's syndrome is a rare disorder caused by excessive cortisol most commonly due to elevated ACTH produced by neuroendocrine tumors. These tumors most commonly arise in the pituitary gland (Cushing's disease) but can also originate in other parts of the body (ectopic ACTH syndrome). Distinguishing between pituitary and ectopic causes is essential for choosing the best treatment, yet current tools are not always optimal. Our research compares the transcriptome patterns of pituitary and ectopic tumors to discover unique markers and possible new drug targets. This research provides new insights into specific molecules and pathways linked to each tumor type, common mechanisms of ACTH-secretion, and suggests promising diagnostics and treatment targets for future research. The analysis of the experimental efficacy of existing medications registered for other oncological disorders may provide new perspectives for these rare orphan disorders in cases where traditional treatment options have been exhausted. Background/Objectives: Endogenous Cushing's syndrome (CS) is a rare neuroendocrine disorder often resulting from adrenocorticotropic hormone (ACTH) production by a pituitary or ectopic tumor. The biological mechanisms underlying ACTH-secreting tumors, especially non-pituitary, remain poorly understood. This study aimed to explore the transcriptomic profiles of pituitary and ectopic ACTH-secreting tumors (ASTs) to identify potential biomarkers for differential diagnosis and new therapeutic targets. Methods: In this study, we performed a transcriptome-wide analysis of twenty-pituitary, one pancreatic, and six lung ASTs, along with seven pituitary, eight pancreatic, and eight lung healthy control tissue samples, respectively. Results: The transcriptomic analysis revealed distinct profiles between pituitary and ectopic ACTH-secreting tumors. In all ASTs, except for the pancreatic sample, we found an overexpression of the TBX19 and PITX1 transcription factor genes, which promote the overexpression of POMC. The transcriptional profiles of ectopic lung ASTs showed marked overexpression of the gastrin-releasing peptide and calcitonin genes, which may be potentially useful for diagnostic purposes. We identified several transcriptionally activated molecular pathways in ASTs that might be targetable with existing medications to treat cancer, the most potentially promising of which are RET inhibitors and an IL6R inhibitor. We also predicted and experimentally validated that corticotropinomas express ganglioside 2 molecules, offering new therapeutic targets for Cushing's disease. Conclusions: This study provides new insights into the molecular features of ACTH-secreting tumors and identifies potential diagnostic markers and therapeutic targets. Distinct transcriptomic profiles in pituitary and ectopic tumors highlight unique biomarkers that may improve diagnostic accuracy and facilitate the development of targeted therapies for ACTH-dependent CS. [ABSTRACT FROM AUTHOR]