Unlocking The Heterogeneity of Sporadic Somatotropinomas: A Paradoxical Journey

Acromegaly is a progressive endocrine disorder predominantly caused by growth hormone-secreting pituitary neuroendocrine tumors (GH-PitNETs). These tumors arise from the monoclonal expansion of differentiated somatotroph cells and are usually sporadic. Although GH-PitNETs are typically benign, a considerable proportion (30%) may display invasive growth or resistance to standard medical therapy, leading to disease persistence and increased morbidity. Pharmacological treatment of GH-PitNETs mainly involves somatostatin receptor ligands (SRLs), which have a modest and inconsistent anti-tumoral effect and fail to normalize GH/IGF1 in about 50% of patients. Transsphenoidal surgery therefore remains the treatment of choice, as it can provide definitive cure. Once considered a clinically homogeneous condition, acromegaly is now recognized as a spectrum of distinct clinical and molecular GH-PitNET subtypes. Within this spectrum, a subgroup of patients exhibits a paradoxical increase in GH levels during an oral glucose tolerance test (OGTT). Clinically, these patients tend to have a milder phenotype, including smaller, less invasive tumors and a better response to first-generation SRLs. Molecularly, this phenomenon is associated in approximately 80% of cases with ectopic expression of the glucose-dependent insulinotropic polypeptide receptor (GIPR) and inappropriate activation of the GIP/GIPR axis. In this context, the present thesis focused on two main objectives. First, to investigate the molecular mechanisms regulating the ectopic expression of GIPR in these tumors, with particular attention to the role of the histone demethylase KDM1A, which has already been associated with the ectopic expression of this receptor in a form of adrenal hyperplasia. Second, to explore the molecular heterogeneity of sporadic GH-PitNETs through a multi-omic approach, with particular attention to patients who exhibit the paradoxical GH response, in order to identify the factors that distinguish them and contribute to their favorable clinical phenotype. From the first study, we did not identify pathogenic KDM1A variants in GH-PitNETs from 146 sporadic acromegaly patients. However, we observed recurrent KDM1A haploinsufficiency, which was associated with lower KDM1A expression and higher GIPR expression. This suggests that GIPR expression is not a primary alteration, but rather an epigenetically mediated consequence. The multi-omics analysis further highlighted the molecular and clinical heterogeneity of GH- PitNETs, leading to the identification of three distinct molecular clusters, each associated with specific clinical features and biological pathways: the Par-OGTT cluster, characterized by paradoxical GH response and GIPR overexpression; the gsp+ cluster, defined by GNAS mutations; and the invasive cluster, comprising dedifferentiated, sparsely granulated tumors characterized by larger size and invasive behavior. Overall, this study provides a comprehensive framework for understanding the molecular complexity of GH-PitNETs, offering mechanistic insights and potential translational applications for precision prognostics and personalized therapeutic strategies in patients with acromegaly.