Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma

Yulong Chen, Masahiko Terajima, Yanan Yang, Li Sun, Young Ho Ahn, Daniela Pankova, Daniel S. Puperi, Takeshi Watanabe, Min P. Kim, Shanda H. Blackmon, Jaime Rodriguez, Hui Liu, Carmen Behrens, Ignacio I. Wistuba, Rosalba Minelli, Kenneth L. Scott, Johannah Sanchez-Adams, Farshid Guilak, Debananda Pati, Nishan ThilaganathanAlan R. Burns, Chad J. Creighton, Elisabeth D. Martinez, Tomasz Zal, K. Jane Grande-Allen, Mitsuo Yamauchi, Jonathan M. Kurie

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58 Scopus citations

Abstract

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 crosslinks. 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.

Original languageEnglish (US)
Pages (from-to)1147-1162
Number of pages16
JournalJournal of Clinical Investigation
Volume125
Issue number3
DOIs
StatePublished - Mar 2 2015

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ASJC Scopus subject areas

  • Medicine(all)

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Chen, Y., Terajima, M., Yang, Y., Sun, L., Ahn, Y. H., Pankova, D., Puperi, D. S., Watanabe, T., Kim, M. P., Blackmon, S. H., Rodriguez, J., Liu, H., Behrens, C., Wistuba, I. I., Minelli, R., Scott, K. L., Sanchez-Adams, J., Guilak, F., Pati, D., ... Kurie, J. M. (2015). Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma. Journal of Clinical Investigation, 125(3), 1147-1162. https://doi.org/10.1172/JCI74725