Endocrine Abstracts

Adrenocortical carcinoma (ACC) is a rare but aggressive endocrine malignancy with limited therapeutic options and poor prognosis. Complete surgical resection is the only curative treatment, with 5-year survival reaching 80% in early-stage disease (1). However, 25–30% of patients present with metastatic disease, where survival falls below 15% despite radiotherapy and mitotane-based chemotherapy (1,2). 5-year survival across all patients is less than 40% (3). Deeper understanding of ACC pathophysiology is vital to enable advances in management. Recently our group identified the transmembrane protein, delta-like non-canonical Notch ligand 1 (DLK1) to be highly expressed in ACC, where it maintains tumour cells in an undifferentiated state and is associated with worse recurrence-free survival (4,5). Using proteomic screening, we discovered that Non-Muscle Myosin IIa (NMIIa), an actomyosin motor protein coded for by the MYH9 gene with known roles in regulating division, adhesion, and mechanotransduction (6), is the predominant interactor of DLK1 in ACC cells. While NMIIa is reported as a tumour promoter in several cancers including oesophageal and pancreatic (7,8), in head and neck squamous cell carcinoma it exerts tumour-suppressive effects by enhancing nuclear shuttling of p53 (9). This suggests NMIIa function in cancer is context-dependent and mediated by interacting partners. We also show that higher NMIIa expression enhances the negative prognostic effect of higher DLK1 expression in ACC. Additionally, NMIIa inhibition with the specific small molecule inhibitor blebbistatin in H295R cells unexpectedly promotes proliferation in a dose-dependent manner, suggesting that NMIIa motor activity normally restrains proliferation. These findings highlight NMIIa as a context-dependent regulator in ACC: while its motor activity suppresses proliferation, we hypothesise that the NMIIa-DLK1 interaction supports maintenance of a less differentiated cell type. Further studies are ongoing to interrogate this further.

1. DOI: 10.1530/JME-18-0122

2. DOI: 10.1038/s41388-020-1358-5

3. DOI: 10.3389/fendo.2023.1250033

4. DOI: 10.1530/ERC-21-0208

5. DOI: 10.1016/j.jsbmb.2019.105422

6. DOI: 10.3389/fchem.2014.00045

7. DOI: 10.52547/ibj.25.5.310

8. DOI: 10.1111/j.1442-2050.2011.01261.x

9. DOI: 10.1126/science.1248627