A novel human tumoroid 3D model of sustained ACTH-secreting cell cultures to study critically needed therapies for Cushing's disease

摘要

The pituitary gland is a master endocrine organ composed of distinct hormone-producing cell types that serve as sensors to integrate central and peripheral signals in order to fine-tune whole-body homeostasis and control multiple physiological functions including growth, reproduction, metabolism and stress [1]. Classically pituitary tumours have been considered rare and benign; however, they represent the most common intracranial neoplasms and are often aggressive. Moreover, these tumours are highly heterogeneous, displaying strikingly diverse clinical behaviours that parallel the different pituitary cell subtypes from which they arise [2]. Currently, the in vitro and in vivo pituitary tumour models available are highly limited and, in the case of the corticotroph tumours producing adrenocorticotropic hormone (ACTH), have been mainly restricted to ACTH-secreting murine cell lines (ie, AtT-20 and AtT-20/D16v-F2) and transgenic/ PDX mouse models (eg, Crh 120/ and POMC-SV40, among others), respectively [3]. However, extrapolation of the findings derived from these cell-lines and transgenic/PDX mice should be considered with caution as these surrogate murine corticotroph tumour models have been useful models for Cushing's disease but they cannot recapitulate precisely human corticotroph tumours. In this sense, various laboratories have made significant efforts to generate useful data using primary cell cultures from fresh surgically resected human corticotroph tumour tissues to translate it to humans [4]. However, these primary cell cultures have known limitations (eg, low viability and maintenance over time, which also typically lose ACTH hormone production after 1-2 weeks), which clearly emphasized the need to generate novel human models of long-term pituitary tumour cultures [5,6].