title: Fibulin-2 is a driver of malignant progression in lung adenocarcinoma.
abstract: The extracellular matrix of epithelial tumors undergoes structural remodeling during periods of uncontrolled growth, creating regional heterogeneity and torsional stress. How matrix integrity is maintained in the face of dynamic biophysical forces is largely undefined. Here we investigated the role of fibulin-2, a matrix glycoprotein that functions biomechanically as an inter-molecular clasp and thereby facilitates supra-molecular assembly. Fibulin-2 was abundant in the extracellular matrix of human lung adenocarcinomas and was highly expressed in tumor cell lines derived from mice that develop metastatic lung adenocarcinoma from co-expression of mutant K-ras and p53. Loss-of-function experiments in tumor cells revealed that fibulin-2 was required for tumor cells to grow and metastasize in syngeneic mice, a surprising finding given that other intra-tumoral cell types are known to secrete fibulin-2. However, tumor cells grew and metastasized equally well in Fbln2-null and -wild-type littermates, implying that malignant progression was dependent specifically upon tumor cell-derived fibulin-2, which could not be offset by other cellular sources of fibulin-2. Fibulin-2 deficiency impaired the ability of tumor cells to migrate and invade in Boyden chambers, to create a stiff extracellular matrix in mice, to cross-link secreted collagen, and to adhere to collagen. We conclude that fibulin-2 is a driver of malignant progression in lung adenocarcinoma and plays an unexpected role in collagen cross-linking and tumor cell adherence to collagen.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, University of Texas M D Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Brandi N
authors.initials: BN
authors.lastname: Baird
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Schliekelman
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Ahn
authors.forename: Yulong
authors.initials: Y
authors.lastname: Chen
authors.forename: Jonathon D
authors.initials: JD
authors.lastname: Roybal
authors.forename: Bartley J
authors.initials: BJ
authors.lastname: Gill
authors.forename: Dhruva K
authors.initials: DK
authors.lastname: Mishra
authors.forename: Baruch
authors.initials: B
authors.lastname: Erez
authors.forename: Michael
authors.initials: M
authors.lastname: O'Reilly
authors.forename: Yanan
authors.initials: Y
authors.lastname: Yang
authors.forename: Mayuri
authors.initials: M
authors.lastname: Patel
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Nishan
authors.initials: N
authors.lastname: Thilaganathan
authors.forename: Irina V
authors.initials: IV
authors.lastname: Larina
authors.forename: Mary E
authors.initials: ME
authors.lastname: Dickinson
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: West
authors.forename: Don L
authors.initials: DL
authors.lastname: Gibbons
authors.forename: Diane D
authors.initials: DD
authors.lastname: Liu
authors.forename: Min P
authors.initials: MP
authors.lastname: Kim
authors.forename: John M
authors.initials: JM
authors.lastname: Hicks
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.forename: Samir M
authors.initials: SM
authors.lastname: Hanash
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Kurie
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D046529:Microscopy, Electron, Transmission; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; C084612:fibulin 2