Abstract
Collagens are the most abundant proteins in the body and comprise the basement membranes and stroma through which cancerous invasion occurs; however, a pro-neoplastic function for mutant collagens is undefined. Here we identify COL11A1 mutations in 66 of 100 cutaneous squamous cell carcinomas (cSCCs), the second most common U.S. cancer, concentrated in a triple helical region known to produce trans-dominant collagens. Analysis of COL11A1 and other collagen genes found that they are mutated across common epithelial malignancies. Knockout of mutant COL11A1 impairs cSCC tumorigenesis in vivo. Compared to otherwise genetically identical COL11A1 wild-type tissue, gene-edited mutant COL11A1 skin is characterized by induction of β1 integrin targets and accelerated neoplastic invasion. In mosaic tissue, mutant COL11A1 cells enhanced invasion by neighboring wild-type cells. These results suggest that specific collagens are commonly mutated in cancer and that mutant collagens may accelerate this process.
Highlights
Cancers of the epithelial tissues that line body surfaces account for more than 90% of human malignancies and the vast majority of cancer mortality [1]
The collagen mutations evident in databases, such as those of the cancer genome atlas (TCGA), have been largely overlooked, perhaps because collagen proteins are encoded by large genes that may be susceptible to accumulating background mutations during carcinogenesis
We evaluated the association between this 264-gene signature upregulated by mutant COL11A1 and survival in head and neck SCC, which like cutaneous squamous cell carcinomas (cSCCs) is a malignancy of stratified epithelium but which differs from cSCC in that it presently has long-term survival data available
Summary
Cancers of the epithelial tissues that line body surfaces account for more than 90% of human malignancies and the vast majority of cancer mortality [1]. Mutations in collagen genes themselves, have not been widely noted in cancer An exception to this is COL2A1, which was observed in one study to be mutated in 37% of spontaneous human chondrosarcomas [8]. Mutant COL11A1, has not been characterized in cancer and a functional role for the COL11A1 protein in promoting neoplastic progression to cancerous invasion in tissue has not been studied. After assessment for models that accurately reflect the tissue architecture and gene background mutation rate differences in each tumor type, expression observed in spontaneous cSCC arising in humans analysis of cancer sequencing data from TCGA found COL11A1 [18,19,20]. In TCGA data, collagen gene mice using human A431 cSCC cells, which contain a G598A mutations were found widely across other common epithelial mutation in COL11A1 representative of the glycine substitutions cancers.
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