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 Thilaganathan & 7 others Alan R. Burns, Chad J. Creighton, Elisabeth D. Martinez, Tomasz Zal, K. Jane Grande-Allen, Mitsuo Yamauchi, Jonathan M. Kurie

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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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2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine
Collagen
Neoplasms
Aldehydes
Lysine
Lung Neoplasms
Hydroxylysine
Neoplasm Metastasis
Carcinogenesis

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Chen, Y., Terajima, M., Yang, Y., Sun, L., Ahn, Y. H., Pankova, 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

Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma. / Chen, Yulong; Terajima, Masahiko; Yang, Yanan; Sun, Li; Ahn, Young Ho; Pankova, Daniela; Puperi, Daniel S.; Watanabe, Takeshi; Kim, Min P.; Blackmon, Shanda H.; Rodriguez, Jaime; Liu, Hui; Behrens, Carmen; Wistuba, Ignacio I.; Minelli, Rosalba; Scott, Kenneth L.; Sanchez-Adams, Johannah; Guilak, Farshid; Pati, Debananda; Thilaganathan, Nishan; Burns, Alan R.; Creighton, Chad J.; Martinez, Elisabeth D.; Zal, Tomasz; Grande-Allen, K. Jane; Yamauchi, Mitsuo; Kurie, Jonathan M.

In: Journal of Clinical Investigation, Vol. 125, No. 3, 02.03.2015, p. 1147-1162.

Research output: Contribution to journalArticle

Chen, Y, Terajima, M, Yang, Y, Sun, L, Ahn, YH, 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 2015, 'Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma', Journal of Clinical Investigation, vol. 125, no. 3, pp. 1147-1162. https://doi.org/10.1172/JCI74725
Chen Y, Terajima M, Yang Y, Sun L, Ahn YH, Pankova D et al. Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma. Journal of Clinical Investigation. 2015 Mar 2;125(3):1147-1162. https://doi.org/10.1172/JCI74725
Chen, Yulong ; Terajima, Masahiko ; Yang, Yanan ; Sun, Li ; Ahn, Young Ho ; Pankova, Daniela ; Puperi, Daniel S. ; Watanabe, Takeshi ; Kim, Min P. ; Blackmon, Shanda H. ; Rodriguez, Jaime ; Liu, Hui ; Behrens, Carmen ; Wistuba, Ignacio I. ; Minelli, Rosalba ; Scott, Kenneth L. ; Sanchez-Adams, Johannah ; Guilak, Farshid ; Pati, Debananda ; Thilaganathan, Nishan ; Burns, Alan R. ; Creighton, Chad J. ; Martinez, Elisabeth D. ; Zal, Tomasz ; Grande-Allen, K. Jane ; Yamauchi, Mitsuo ; Kurie, Jonathan M. / Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma. In: Journal of Clinical Investigation. 2015 ; Vol. 125, No. 3. pp. 1147-1162.
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AU - Wistuba, Ignacio I.

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AU - Scott, Kenneth L.

AU - Sanchez-Adams, Johannah

AU - Guilak, Farshid

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AU - Thilaganathan, Nishan

AU - Burns, Alan R.

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