Cutaneous squamous cell carcinoma (cSCC) is an extremely common and morbid skin cancer with metastatic spread in 5% of cases. Given Australia has the highest burden of cSCC in the world, this is truly our national disease, yet we alarmingly know very little about it. Current clinical tools provide an unreliable prognosis, whilst disfiguring surgery and radiotherapy remain the only treatment options for metastatic disease. It is unknown what drives this metastatic behaviour as the molecular landscape of metastatic cSCC remains profoundly unexplored and commercial cell lines are non-existent.
Our research has attempted, for the first time, to establish and characterise patient-derived metastatic cSCC cell cultures for the identification of potential biomarkers of disease and therapeutic targets. A biomarker would serve as a revolutionary prognostic tool and supplementary therapies may negate the morbidity of current practices.
Following extensive optimisation and validation, a world-first cell line of cSCC was established from nodal metastases. This cell line has been subjected to whole genome sequencing (WGS) and a multitude of expression analyses, including RNA-seq. In addition, the efficacies of novel and established chemotherapeutics against the cell line have been investigated.
WGS data reported cSCC as having one of the highest mutational frequencies of any cancer type. Using a 770 gene cancer progression panel, substantial expressional variation was evident between the cell line and other fresh-frozen cSCC, suggesting multiple pathways are being exploited for metastasis. Specifically, the urokinase plasminogen activation system (UPAS) was interrogated due to its known role in metastasis across many cancer types. Additional expressional analyses confirmed overexpression of key proteins of the UPA system, which were subsequently seen to be targetable in a 3D organotypic model, thus highlighting this system as a target of interest. These novel results have advanced our understanding of cSCC and offer truly tangible clinical significance to the hundreds of thousands of Australians diagnosed with skin cancer each year.