Loss of Kindlin-1 drives a more aggressive phenotype in cutaneous squamous cell carcinoma
Kindler syndrome (KS) is a rare genodermatosis resulting from loss-of-function mutations in FERMT1, the gene that encodes Kindlin-1. KS patients have a high propensity to develop aggressive and metastatic cutaneous squamous cell carcinoma (SCC). In this study, we show that loss of Kindlin-1 in a mouse model of cutaneous SCC leads to increased migration, invasion and degradation of collagen. Loss of Kindlin-1 increased tumor growth in vivo and in 3D spheroids, which was associated with the development of a hypoxic tumor environment and increased glycolysis. One of the most highly upregulated genes in Kindlin-1-depleted tumors was Mmp13, and the increased expression of MMP13 was responsible for driving the increased migration and invasion of the Kindlin-1-depleted SCC cells. These results provide evidence that Kindlin-1 loss in SCC can promote migration and invasion through the upregulation of MMP13, and offer novel insights into how Kindlin-1 loss leads to the development of a hypoxic environment that is permissive for tumor growth. Overall design: RNA samples extracted from tumors derived from cutaneous squamous cell carcinoma expressing Kindlin-1 (wild type-WT) were compared to tumors with Kindlin-1 knockout (Nulls) to assess differences in expression.