Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma.
Epithelial tumor metastasis is preceded by an accumulation of collagen cross-links that heighten stromal stiffness and stimulate the invasive properties of tumor cells. However, the biochemical nature of collagen cross-links in cancer is still unclear. Here, we postulated that epithelial tumorigenesis is accompanied by changes in the biochemical type of collagen cross-links. Utilizing resected human lung cancer tissues and a p21CIP1/WAF1-deficient, K-rasG12D-expressing murine metastatic lung cancer model, we showed that, relative to normal lung tissues, tumor stroma contains higher levels of hydroxylysine aldehyde-derived collagen cross-links (HLCCs) and lower levels of lysine aldehyde-derived cross-links (LCCs), which are the predominant types of collagen cross-links in skeletal tissues and soft tissues, respectively. Gain- and loss-of-function studies in tumor cells showed that lysyl hydroxylase 2 (LH2), which hydroxylates telopeptidyl lysine residues on collagen, shifted the tumor stroma toward a high-HLCC, low-LCC state, increased tumor stiffness, and enhanced tumor cell invasion and metastasis. Together, our data indicate that LH2 enhances the metastatic properties of tumor cells and functions as a regulatory switch that controls the relative abundance of biochemically distinct types of collagen cross-links in the tumor stroma.
Chen, Y; Terajima, M; Yang, Y; Sun, L; Ahn, Y-H; Pankova, D; Puperi, DS; Watanabe, T; Kim, MP; Blackmon, SH; Rodriguez, J; Liu, H; Behrens, C; Wistuba, II; Minelli, R; Scott, KL; Sanchez-Adams, J; Guilak, F; Pati, D; Thilaganathan, N; Burns, AR; Creighton, CJ; Martinez, ED; Zal, T; Grande-Allen, KJ; Yamauchi, M; Kurie, JM
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