title: Src family kinases differentially influence glioma growth and motility.
abstract: Src-family kinase (SFK) signaling impacts multiple tumor-related properties, particularly in the context of the brain tumor glioblastoma. Consequently, the pan-SFK inhibitor dasatinib has emerged as a therapeutic strategy, despite physiologic limitations to its effectiveness in the brain. We investigated the importance of individual SFKs (Src, Fyn, Yes, and Lyn) to glioma tumor biology by knocking down individual SFK expression both in culture (LN229, SF767, GBM8) and orthotopic xenograft (GBM8) contexts. We evaluated the effects of these knockdowns on tumor cell proliferation, migration, and motility-related signaling in culture, as well as overall survival in the orthotopic xenograft model. The four SFKs differed significantly in their importance to these properties. In culture, Src, Fyn, and Yes knockdown generally reduced growth and migration and altered motility-related phosphorylation patterns while Lyn knockdown did so to a lesser extent. However the details of these effects varied significantly depending on the cell line: in no case were conclusions about the role of a particular SFK applicable to all of the measures or all of the cell types examined. In the orthotopic xenograft model, mice implanted with non-target or Src or Fyn knockdown cells showed no differences in survival. In contrast, mice implanted with Yes knockdown cells had longer survival, associated with reduced tumor cell proliferation. Those implanted with Lyn knockdown cells had shorter survival, associated with higher overall tumor burden. Together, our results suggest that Yes signaling directly affects tumor cell biology in a pro-tumorigenic manner, while Lyn signaling affects interactions between tumor cells and the microenvironment in an anti-tumor manner. In the context of therapeutic targeting of SFKs, these results suggest that pan-SFK inhibitors may not produce the intended therapeutic benefit when Lyn is present.
authors.affiliation: Department of Cancer Cell Biology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL 32224, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Lewis-Tuffin
authors.affiliation: Department of Cancer Cell Biology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL 32224, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Feathers
authors.affiliation: Department of Cancer Cell Biology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL 32224, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Hari
authors.affiliation: Department of Cancer Cell Biology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL 32224, USA.
authors.forename: Nisha
authors.initials: N
authors.lastname: Durand
authors.affiliation: Department of Cancer Cell Biology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL 32224, USA.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pathology, Johns Hopkins Hospital, 1800 Orleans Street, Baltimore, MD 21231, USA.
authors.forename: Fausto J
authors.initials: FJ
authors.lastname: Rodriguez
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Katie
authors.initials: K
authors.lastname: Bakken
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Brett
authors.initials: B
authors.lastname: Carlson
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Schroeder
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Jann N
authors.initials: JN
authors.lastname: Sarkaria
authors.affiliation: Department of Cancer Cell Biology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL 32224, USA. Electronic address: panos@mayo.edu.
authors.forename: Panos Z
authors.initials: PZ
authors.lastname: Anastasiadis
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib / Q000494:pharmacology / Q000627:therapeutic use*; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D019061:src-Family Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D019061:src-Family Kinases; D000069439:Dasatinib
keywords: Dasatinib; Glioblastoma; Lyn kinase; Migration; Proliferation; Src-family kinase