Unraveling the role of OTOS in mixed pituitary neuroendocrine tumors secreting growth hormone and prolactin

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2025.

The human pituitary gland controls the production of several vital hormones, including growth hormone (GH) and prolactin (PRL). In some people, this control breaks down due to rare tumors called pituitary neuroendocrine tumors (PitNETs), which can lead to excessive hormone production and serious health problems. A very rare genetic disease called X-linked acrogigantism (X-LAG) causes early and extreme growth due to high levels of GH and PRL, linked to a mutated gene called GPR101. Recent research has identified another gene, OTOS, that may play an important role in both X-LAG and more common forms of PitNETs. OTOS produces a protein called otospiralin, which is found at high levels in the pituitary, especially in tumors that produce both GH and PRL. In patients with X-LAG, OTOS appears in the same regions as GPR101, suggesting the two may be connected. However, almost nothing is known about what OTOS actually does in the pituitary or whether it contributes to disease. This project aims to understand the role of OTOS in both healthy and diseased pituitary tissue. We will study where the otospiralin protein is found inside cells, how it behaves, and which other proteins it interacts with. We will also see what happens when OTOS is increased or decreased in tumor cells taken from patients. Finally, we will use 3D pituitary organoids (a mass of tissue that mimics key biological properties of the organ) grown from stem cells—including some from X-LAG patients—to model the gene’s function in a highly realistic system. Our goal is to discover whether OTOS contributes to hormone overproduction or tumor growth. If so, it could serve as a new biological marker to help doctors diagnose or track these tumors. In the future, this research could open the door to new treatments for people with X-LAG and related pituitary disorders.