title: Whole Genome Sequencing of Newly Established Pancreatic Cancer Lines Identifies Novel Somatic Mutation (c.2587G>A) in Axon Guidance Receptor Plexin A1 as Enhancer of Proliferation and Invasion.
abstract: The genetic profile of human pancreatic cancers harbors considerable heterogeneity, which suggests a possible explanation for the pronounced inefficacy of single therapies in this disease. This observation has led to a belief that custom therapies based on individual tumor profiles are necessary to more effectively treat pancreatic cancer. It has recently been discovered that axon guidance genes are affected by somatic structural variants in up to 25% of human pancreatic cancers. Thus far, however, some of these mutations have only been correlated to survival probability and no function has been assigned to these observed axon guidance gene mutations in pancreatic cancer. In this study we established three novel pancreatic cancer cell lines and performed whole genome sequencing to discover novel mutations in axon guidance genes that may contribute to the cancer phenotype of these cells. We discovered, among other novel somatic variants in axon guidance pathway genes, a novel mutation in the PLXNA1 receptor (c.2587G>A) in newly established cell line SB.06 that mediates oncogenic cues of increased invasion and proliferation in SB.06 cells and increased invasion in 293T cells upon stimulation with the receptor's natural ligand semaphorin 3A compared to wild type PLXNA1 cells. Mutant PLXNA1 signaling was associated with increased Rho-GTPase and p42/p44 MAPK signaling activity and cytoskeletal expansion, but not changes in E-cadherin, vimentin, or metalloproteinase 9 expression levels. Pharmacologic inhibition of the Rho-GTPase family member CDC42 selectively abrogated PLXNA1 c.2587G>A-mediated increased invasion. These findings provide in-vitro confirmation that somatic mutations in axon guidance genes can provide oncogenic gain-of-function signals and may contribute to pancreatic cancer progression.
authors.affiliation: Thoracic & GI Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, United States of America.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sorber
authors.affiliation: Thoracic & GI Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, United States of America.
authors.forename: Yaroslav
authors.initials: Y
authors.lastname: Teper
authors.affiliation: Thoracic & GI Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, United States of America.|Department of Biology and Center for Cancer Research, Tuskegee University, Tuskegee, Alabama 36088, United States of America.
authors.forename: Abisola
authors.initials: A
authors.lastname: Abisoye-Ogunniyan
authors.affiliation: Genetics Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892, United States of America.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Waterfall
authors.affiliation: Genetics Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892, United States of America.
authors.forename: Sean
authors.initials: S
authors.lastname: Davis
authors.affiliation: Genetics Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892, United States of America.
authors.forename: J Keith
authors.initials: JK
authors.lastname: Killian
authors.affiliation: Genetics Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892, United States of America.
authors.forename: Marbin
authors.initials: M
authors.lastname: Pineda
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, United States of America.
authors.forename: Satyajit
authors.initials: S
authors.lastname: Ray
authors.affiliation: Thoracic & GI Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, United States of America.
authors.forename: Matt R
authors.initials: MR
authors.lastname: McCord
authors.affiliation: Thoracic & GI Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, United States of America.
authors.forename: Holger
authors.initials: H
authors.lastname: Pflicke
authors.affiliation: Molecular Cytogenetic Section, MCGP, Center for Cancer Research, National Cancer Institute, NIH, Frederick, Maryland 21702, United States of America.
authors.forename: Sandra Sczerba
authors.initials: SS
authors.lastname: Burkett
authors.affiliation: Genetics Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892, United States of America.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
authors.affiliation: Thoracic & GI Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, United States of America.
authors.forename: Udo
authors.initials: U
authors.lastname: Rudloff
mesh_terms: D000368:Aged; D001369:Axons / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002877:Chromosomes, Human / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D008024:Ligands; D008297:Male; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D034622:RNA Interference; D011956:Receptors, Cell Surface / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D032681:Spectral Karyotyping; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
chemical_list: D008024:Ligands; D009419:Nerve Tissue Proteins; C492116:PLXNA1 protein, human; D011956:Receptors, Cell Surface; D020764:cdc42 GTP-Binding Protein