title: Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma.
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 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.
authors: Yulong
authors: Y
authors: Chen
authors: Masahiko
authors: M
authors: Terajima
authors: Yanan
authors: Y
authors: Yang
authors: Li
authors: L
authors: Sun
authors: Young-Ho
authors: YH
authors: Ahn
authors: Daniela
authors: D
authors: Pankova
authors: Daniel S
authors: DS
authors: Puperi
authors: Takeshi
authors: T
authors: Watanabe
authors: Min P
authors: MP
authors: Kim
authors: Shanda H
authors: SH
authors: Blackmon
authors: Jaime
authors: J
authors: Rodriguez
authors: Hui
authors: H
authors: Liu
authors: Carmen
authors: C
authors: Behrens
authors: Ignacio I
authors: II
authors: Wistuba
authors: Rosalba
authors: R
authors: Minelli
authors: Kenneth L
authors: KL
authors: Scott
authors: Johannah
authors: J
authors: Sanchez-Adams
authors: Farshid
authors: F
authors: Guilak
authors: Debananda
authors: D
authors: Pati
authors: Nishan
authors: N
authors: Thilaganathan
authors: Alan R
authors: AR
authors: Burns
authors: Chad J
authors: CJ
authors: Creighton
authors: Elisabeth D
authors: ED
authors: Martinez
authors: Tomasz
authors: T
authors: Zal
authors: K Jane
authors: KJ
authors: Grande-Allen
authors: Mitsuo
authors: M
authors: Yamauchi
authors: Jonathan M
authors: JM
authors: Kurie
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000401:mortality / Q000556:secondary; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000401:mortality / Q000556:secondary; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D004790:Enzyme Induction; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D008297:Male; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000502:physiology*; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor / Q000378:metabolism; D059016:Tumor Microenvironment; D015854:Up-Regulation
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D003094:Collagen; C479138:PLOD2 protein, human; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase