title: Discoidin domain receptor 1 contributes to tumorigenesis through modulation of TGFBI expression.
abstract: Discoidin domain receptor 1 (DDR1) is a member of the receptor tyrosine kinase family. The receptor is activated upon binding to its ligand, collagen, and plays a crucial role in many fundamental processes such as cell differentiation, adhesion, migration and invasion. Although DDR1 is expressed in many normal tissues, upregulated expression of DDR1 in a variety of human cancers such as lung, colon and brain cancers is known to be associated with poor prognosis. Using shRNA silencing, we assessed the oncogenic potential of DDR1. DDR1 knockdown impaired tumor cell proliferation and migration in vitro and tumor growth in vivo. Microarray analysis of tumor cells demonstrated upregulation of TGFBI expression upon DDR1 knockdown, which was subsequently confirmed at the protein level. TGFBI is a TGFβ-induced extracellular matrix protein secreted by the tumor cells and is known to act either as a tumor promoter or tumor suppressor, depending on the tumor environment. Here, we show that exogenous addition of recombinant TGFBI to BXPC3 tumor cells inhibited clonogenic growth and migration, thus recapitulating the phenotypic effect observed from DDR1 silencing. BXPC3 tumor xenografts demonstrated reduced growth with DDR1 knockdown, and the same xenograft tumors exhibited an increase in TGFBI expression level. Together, these data suggest that DDR1 expression level influences tumor growth in part via modulation of TGFBI expression. The reciprocal expression of DDR1 and TGFBI may help to elucidate the contribution of DDR1 in tumorigenesis and TGFBI may also be used as a biomarker for the therapeutic development of DDR1 specific inhibitors.
authors.affiliation: Agensys Inc., an affiliate of Astellas Pharma Inc, Santa Monica, CA, United States of America.
authors.forename: Nandini
authors.initials: N
authors.lastname: Rudra-Ganguly
authors.affiliation: Agensys Inc., an affiliate of Astellas Pharma Inc, Santa Monica, CA, United States of America.
authors.forename: Christine
authors.initials: C
authors.lastname: Lowe
authors.affiliation: Agensys Inc., an affiliate of Astellas Pharma Inc, Santa Monica, CA, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Mattie
authors.affiliation: Agensys Inc., an affiliate of Astellas Pharma Inc, Santa Monica, CA, United States of America.
authors.forename: Mi Sook
authors.initials: MS
authors.lastname: Chang
authors.affiliation: ImaginAb Inc., Inglewood, CA, United States of America.
authors.forename: Daulet
authors.initials: D
authors.lastname: Satpayev
authors.affiliation: Agensys Inc., an affiliate of Astellas Pharma Inc, Santa Monica, CA, United States of America.
authors.forename: Alla
authors.initials: A
authors.lastname: Verlinsky
authors.affiliation: Agensys Inc., an affiliate of Astellas Pharma Inc, Santa Monica, CA, United States of America.
authors.forename: Zili
authors.initials: Z
authors.lastname: An
authors.affiliation: Agensys Inc., an affiliate of Astellas Pharma Inc, Santa Monica, CA, United States of America.
authors.forename: Liping
authors.initials: L
authors.lastname: Hu
authors.affiliation: Agensys Inc., an affiliate of Astellas Pharma Inc, Santa Monica, CA, United States of America.
authors.forename: Peng
authors.initials: P
authors.lastname: Yang
authors.affiliation: Agensys Inc., an affiliate of Astellas Pharma Inc, Santa Monica, CA, United States of America.
authors.forename: Pia
authors.initials: P
authors.lastname: Challita-Eid
authors.affiliation: Agensys Inc., an affiliate of Astellas Pharma Inc, Santa Monica, CA, United States of America.
authors.forename: David R
authors.initials: DR
authors.lastname: Stover
authors.affiliation: Agensys Inc., an affiliate of Astellas Pharma Inc, Santa Monica, CA, United States of America.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Pereira
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D000070818:Discoidin Domain Receptors; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016513:Mice, SCID; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics*; D000099222:betaIG-H3 Protein
chemical_list: D000070818:Discoidin Domain Receptors; D016326:Extracellular Matrix Proteins; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases; D011975:Receptors, Mitogen; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein