The Initiator Methionine tRNA Drives Secretion of Type II Collagen from Stromal Fibroblasts to Promote Tumor Growth and Angiogenesis

Expression of the initiator methionine tRNA (tRNA(i)(Met)) is deregulated in cancer. Despite this fact, it is not currently known how tRNA(i)(Met) expression levels influence tumor progression. We have found that tRNA(i)(Met) expression is increased in carcinoma-associated fibroblasts, implicating deregulated expression of tRNA(i)(Met) in the tumor stroma as a possible contributor to tumor progression. To investigate how elevated stromal tRNA(i)(Met) contributes to tumor progression, we generated a mouse expressing additional copies of the tRNA(i)(Met) gene (2+tRNA(i)(Met) mouse). Growth and vascularization of subcutaneous tumor allografts was enhanced in 2+tRNA(i)(Met) mice compared with wild-type littermate controls. Extracellular matrix (ECM) deposited by fibroblasts from 2+tRNA(i)(Met) mice supported enhanced endothelial cell and fibroblast migration. SILAC mass spectrometry indicated that elevated expression of tRNA(i)(Met) significantly increased synthesis and secretion of certain types of collagen, in particular type II collagen. Suppression of type II collagen opposed the ability of tRNA(i)(Met)-overexpressing fibroblasts to deposit pro-migratory ECM. We used the prolyl hydroxylase inhibitor ethyl-3,4-dihydroxybenzoate (DHB) to determine whether collagen synthesis contributes to the tRNA(i)(Met)-driven pro-tumorigenic stroma in vivo. DHB had no effect on the growth of syngeneic allografts in wild-type mice but opposed the ability of 2+tRNA(i)(Met) mice to support increased angiogenesis and tumor growth. Finally, collagen II expression predicts poor prognosis in high-grade serous ovarian carcinoma. Taken together, these data indicate that increased tRNA(i)(Met) levels contribute to tumor progression by enhancing the ability of stromal fibroblasts to synthesize and secrete a type II collagen-rich ECM that supports endothelial cell migration and angiogenesis.