title: Aberrant RSPO3-LGR4 signaling in Keap1-deficient lung adenocarcinomas promotes tumor aggressiveness.
abstract: The four R-spondins (RSPO1-4) and their three related receptors LGR4, 5 and 6 (LGR4-6) have emerged as a major ligand-receptor system with critical roles in development and stem cell survival through modulation of Wnt signaling. Recurrent, gain-of-expression gene fusions of RSPO2 (to EIF3E) and RSPO3 (to PTPRK) occur in a subset of human colorectal cancer. However, the exact roles and mechanisms of the RSPO-LGR system in oncogenesis remain largely unknown. We found that RSPO3 is aberrantly expressed at high levels in approximately half of Keap1-mutated lung adenocarcinomas (ADs). This high RSPO3 expression is driven by a combination of demethylation of its own promoter region and deficiency in Keap1 instead of gene fusion as in colon cancer. Patients with RSPO3-high tumors (~9%, 36/412) displayed much poorer survival than the rest of the cohort (median survival of 28 vs 163 months, log-rank test P<0.0001). Knockdown (KD) of RSPO3, LGR4 or their signaling mediator IQGAP1 in lung cancer cell lines with Keap1 deficiency and high RSPO3-LGR4 expression led to reduction in cell proliferation and migration in vitro, and KD of LGR4 or IQGAP1 resulted in decrease in tumor growth and metastasis in vivo. These findings suggest that aberrant RSPO3-LGR4 signaling potentially acts as a driving mechanism in the aggressiveness of Keap1-deficient lung ADs.
authors.affiliation: Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.|Texas Therapeutics Institute, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: X
authors.initials: X
authors.lastname: Gong
authors.affiliation: Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.|Texas Therapeutics Institute, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yi
authors.affiliation: Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.|Texas Therapeutics Institute, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Carmon
authors.affiliation: Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.|Texas Therapeutics Institute, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Crumbley
authors.affiliation: Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.|Texas Therapeutics Institute, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: W
authors.initials: W
authors.lastname: Xiong
authors.affiliation: Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.|Texas Therapeutics Institute, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.|Texas Therapeutics Institute, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: X
authors.initials: X
authors.lastname: Fan
authors.affiliation: Divison of Oncology, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Guo
authors.affiliation: Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.|Texas Therapeutics Institute, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: An
authors.affiliation: Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.|Center for Clinical and Translational Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA.|Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX, USA.|School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Chang
authors.affiliation: Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.|Texas Therapeutics Institute, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Q J
authors.initials: QJ
authors.lastname: Liu
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D000072019:Kelch-Like ECH-Associated Protein 1; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009367:Neoplasm Staging; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D019699:Thrombospondins / Q000096:biosynthesis* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000098907:R-Spondins
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000072019:Kelch-Like ECH-Associated Protein 1; D015514:Oncogene Proteins, Fusion; D043562:Receptors, G-Protein-Coupled; D019699:Thrombospondins; C431364:KEAP1 protein, human; C411562:LGR4 protein, human; C475438:RSPO3 protein, human; D000098907:R-Spondins