title: Cancer-Associated Fibroblasts Induce a Collagen Cross-link Switch in Tumor Stroma.
abstract: Intratumoral collagen cross-links heighten stromal stiffness and stimulate tumor cell invasion, but it is unclear how collagen cross-linking is regulated in epithelial tumors. To address this question, we used Kras(LA1) mice, which develop lung adenocarcinomas from somatic activation of a Kras(G12D) allele. The lung tumors in Kras(LA1) mice were highly fibrotic and contained cancer-associated fibroblasts (CAF) that produced collagen and generated stiffness in collagen gels. In xenograft tumors generated by injection of wild-type mice with lung adenocarcinoma cells alone or in combination with CAFs, the total concentration of collagen cross-links was the same in tumors generated with or without CAFs, but coinjected tumors had higher hydroxylysine aldehyde-derived collagen cross-links (HLCC) and lower lysine-aldehyde-derived collagen cross-links (LCCs). Therefore, we postulated that an LCC-to-HLCC switch induced by CAFs promotes the migratory and invasive properties of lung adenocarcinoma cells. To test this hypothesis, we created coculture models in which CAFs are positioned interstitially or peripherally in tumor cell aggregates, mimicking distinct spatial orientations of CAFs in human lung cancer. In both contexts, CAFs enhanced the invasive properties of tumor cells in three-dimensional (3D) collagen gels. Tumor cell aggregates that attached to CAF networks on a Matrigel surface dissociated and migrated on the networks. Lysyl hydroxylase 2 (PLOD2/LH2), which drives HLCC formation, was expressed in CAFs, and LH2 depletion abrogated the ability of CAFs to promote tumor cell invasion and migration.
  
  
  CONCLUSIONS
  CAFs induce a collagen cross-link switch in tumor stroma to influence the invasive properties of tumor cells.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pankova
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: NC Oral Health Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Terajima
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Schliekelman
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Brandi N
authors.initials: BN
authors.lastname: Baird
authors.affiliation: Department of Bioengineering, Rice University, Houston, Texas.
authors.forename: Monica
authors.initials: M
authors.lastname: Fahrenholtz
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Bioengineering, Rice University, Houston, Texas.
authors.forename: Bartley J
authors.initials: BJ
authors.lastname: Gill
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas.
authors.forename: Tegy J
authors.initials: TJ
authors.lastname: Vadakkan
authors.affiliation: Department of Surgery, The Methodist Hospital Research Institute, Houston, Texas.
authors.forename: Min P
authors.initials: MP
authors.lastname: Kim
authors.affiliation: Department of Molecular Medicine and Tissue Injury Defense Research Center, Ewha Womans University School of Medicine, Seoul, Korea.
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Ahn
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jonathon D
authors.initials: JD
authors.lastname: Roybal
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Edwin Roger
authors.initials: ER
authors.lastname: Parra Cuentas
authors.affiliation: Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jaime
authors.initials: J
authors.lastname: Rodriguez
authors.affiliation: Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.affiliation: Department of Medicine and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Don L
authors.initials: DL
authors.lastname: Gibbons
authors.affiliation: Department of Pathology, Texas Children's Hospital, Houston, Texas.
authors.forename: John M
authors.initials: JM
authors.lastname: Hicks
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Dickinson
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, North Carolina.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: West
authors.affiliation: Department of Bioengineering, Rice University, Houston, Texas.
authors.forename: K Jane
authors.initials: KJ
authors.lastname: Grande-Allen
authors.affiliation: Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Samir M
authors.initials: SM
authors.lastname: Hanash
authors.affiliation: NC Oral Health Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas. jkurie@mdanderson.org Mitsuo_Yamauchi@unc.edu.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Yamauchi
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas. jkurie@mdanderson.org Mitsuo_Yamauchi@unc.edu.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Kurie
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D018920:Coculture Techniques; D003094:Collagen / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D051379:Mice; D009374:Neoplasms, Experimental; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000473:pathology*
chemical_list: D003094:Collagen; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; C582419:lysyl hydroxylase 2, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)