title: Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types.
abstract: Deregulation of the β-catenin signaling has long been associated with cancer. Intracellular components of this pathway, including axin, APC, and β-catenin, are frequently mutated in a range of human tumors, but the contribution of specific extracellular ligands that promote cancer development through this signaling axis remains unclear. We conducted a reporter-based screen in a panel of human tumors to identify secreted factors that stimulate β-catenin signaling. Through this screen and further molecular characterization, we found that R-spondin (RSPO) proteins collaborate with Wnt proteins to activate β-catenin. RSPO family members were expressed in several human tumors representing multiple malignancies, including ovarian, pancreatic, colon, breast, and lung cancer. We generated specific monoclonal antibody antagonists of RSPO family members and found that anti-RSPO treatment markedly inhibited tumor growth in human patient-derived tumor xenograft models, either as single agents or in combination with chemotherapy. Furthermore, blocking RSPO signaling reduced the tumorigenicity of cancer cells based on serial transplantation studies. Moreover, gene-expression analyses revealed that anti-RSPO treatment in responsive tumors strongly inhibited β-catenin target genes known to be associated with cancer and normal stem cells. Collectively, our results suggest that the RSPO family is an important stimulator of β-catenin activity in many human tumors and highlight a new effective approach for therapeutically modulating this fundamental signaling axis.
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, California. cecile.chartier@oncomed.com.
authors.forename: Cecile
authors.initials: C
authors.lastname: Chartier
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, California.
authors.forename: Janak
authors.initials: J
authors.lastname: Raval
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, California.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Axelrod
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, California.
authors.forename: Chris
authors.initials: C
authors.lastname: Bond
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, California.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cain
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, California.
authors.forename: Cristina
authors.initials: C
authors.lastname: Dee-Hoskins
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, California.
authors.forename: Shirley
authors.initials: S
authors.lastname: Ma
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, California.
authors.forename: Marcus M
authors.initials: MM
authors.lastname: Fischer
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, California.
authors.forename: Jalpa
authors.initials: J
authors.lastname: Shah
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, California.
authors.forename: Jie
authors.initials: J
authors.lastname: Wei
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, California.
authors.forename: May
authors.initials: M
authors.lastname: Ji
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, California.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lam
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, California.
authors.forename: Michelle
authors.initials: M
authors.lastname: Stroud
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, California.
authors.forename: Wan-Ching
authors.initials: WC
authors.lastname: Yen
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, California.
authors.forename: Pete
authors.initials: P
authors.lastname: Yeung
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, California.
authors.forename: Belinda
authors.initials: B
authors.lastname: Cancilla
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, California.
authors.forename: Gilbert
authors.initials: G
authors.lastname: O'Young
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, California.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, California.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Kapoun
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, California.
authors.forename: John
authors.initials: J
authors.lastname: Lewicki
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, California.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hoey
authors.affiliation: OncoMed Pharmaceuticals Inc., Redwood City, California.
authors.forename: Austin
authors.initials: A
authors.lastname: Gurney
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D019699:Thrombospondins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; C495270:CTNNB1 protein, human; D019699:Thrombospondins; D051153:Wnt Proteins; D051176:beta Catenin