Cutaneous squamous cell carcinoma (cSCC) is a highly prevalent malignancy. Local and distant metastases occur in 2-5% of cases, which is associated with significant morbidity and mortality. Due to the high volume of primary cSCC, most patients are not monitored for metastasis. Distinguishing low- from high-risk cancers would allow early prediction of metastatic potential and thus improve clinical management. Further, as immunotherapy is contraindicated in immunocompromised patients and fails in ~50% of immunocompetent patients, other systemic treatments for metastatic cSCC are needed. The overarching goal of our cSCC research programme is to define the molecular mechanisms driving disease progression and identify biomarkers predictive of metastasis to enable better clinical prognostication and therapies. To date we have conducted whole-genome sequencing (WGS), RNAseq and methylome analyses on high-risk non-metastasising primary and metastatic cSCC samples (plus patient-derived cell lines). We found novel patterns of mutations not described in previous studies using panel and whole exome sequencing approaches and reported signatures that distinguish histologically similar oral SCC from cSCC1-4. The majority of cSCCs contain amplifications and copy-number alterations of known oncogenes, but most occur at low individual prevalence. Integration of WGS and RNASeq data from metastasising versus non-metastasising primary tumours is revealing trends in associations of cellular subtypes to genetic alterations linked to metastatic potential. Further, metastasising primary cSCCs generally show different methylation patterns to non-metastasising primary tumours. However, due to the high heterogeneity and mutational burden we have uncovered in cSCC using these bulk multi-omics methodologies, it is proving difficult to definitively identify robust biomarkers that distinguish those tumours that will or will not metastasise. We have thus embarked on single-cell approaches to refine these cellular subtypes and interactions that drive metastasis in cSCC. We are also utilising our cell culture platforms for drug response profiling against novel biomarkers associated with metastasis.