THE ROLE OF THE MEVALONATE PATHWAY ENZYME IDI1 IN CUTANEOUS MELANOMA PROGRESSION

Cutaneous melanoma is an aggressive malignancy of epidermal melanocytes, characterized by a high tendency for distant metastasis, which is the major cause of morbidity and mortality in patients. Although targeted and immune checkpoint therapies have improved outcomes, drug resistance and heterogeneous responses continue to present significant challenges in the clinic, and therefore survival rates remain poor. Patient prognosis is highly dependent on metastatic burden, highlighting the urgent need to elucidate the mechanisms driving melanoma metastasis to enable the development of more effective prevention or treatment strategies. Here, we identify IDI1, an enzyme of the mevalonate pathway, as a critical regulator of tumour growth and metastasis. IDI1 is highly expressed in primary tumours, correlating with poor prognosis, and is elevated in circulating tumour cells (CTCs) compared to primary tumours, underscoring its involvement in blood-borne metastasis. In a genetic mouse model, IDI1 deletion delays melanoma onset, reduces tumour growth, and impairs invasion in the skin. Tail vein assays further demonstrate that loss of IDI1 significantly impairs colonisation and metastatic outgrowth of melanoma cells in the lungs, the most common distant metastatic sites in patients. In vitro, IDI1 loss strongly impairs adhesion to collagen- and fibronectin-coated surfaces, which are among the major extra-cellular matrix components utilised by cancer cells for migration, adhesion and proliferation mechanisms. Mechanistically, IDI1 loss inhibits the FAK/SRC–mTORC1 signalling axis to impair metastatic competence. Together, these findings establish IDI1 as a central regulator of multiple steps in the metastatic cascade — consistent with the critical role of this signalling axis across different metastatic stages — with CTC colonisation of the lungs being the most severely affected. Overall, this study highlights IDI1 as both a prognostic marker and a potential therapeutic target in cutaneous melanoma. Targeting IDI1 or its downstream effectors may indicate a novel therapeutic strategy to limit melanoma progression and metastasis, and improve clinical outcomes.