Lamback et al. explored how genes involved in pro-opiomelanocortin C (POMC) processing differ between non-functioning corticotroph tumours and functioning corticotroph tumours, particularly those carrying USP8 mutations. The authors found that non-functioning tumours expressed lower levels of TBX19, POMC, PCSK1 and PAX6, suggesting these tumours are less differentiated and less capable of producing and processing adrenocorticotrophin (ACTH). Interestingly, PCSK1N, which inhibits ACTH processing, remained similarly expressed across tumour types, potentially contributing to the reduced hormonal activity seen in non-functioning tumours.

Among functioning tumours, USP8-mutated and wild-type tumours showed similar POMC expression, challenging the idea that USP8 mutations simply increase ACTH production through epidermal growth factor receptor-driven POMC transcription. Instead, USP8-mutated tumours demonstrated higher PCSK1 and lower PCSK1N expression, changes that may enhance the conversion of POMC into ACTH and explain their higher secretory activity. In fact, PCSK1N was the only gene significantly associated with secretion index, showing that lower PCSK1N expression correlated with greater ACTH secretion.

Overall, the findings suggest that altered downstream POMC processing, rather than POMC expression itself, may play a key role in determining corticotroph tumour behaviour. The study also identifies PCSK1N as a potential new regulator of ACTH secretion and a possible future therapeutic target in Cushing’s disease.

Read the full article in Endocrine Oncology https://doi.org/10.1530/EO-26-0003