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

• Published in: PloS one Vol. 11; no. 3; p. e0149833
• Main Authors: Sorber, Rebecca, Teper, Yaroslav, Abisoye-Ogunniyan, Abisola, Waterfall, Joshua J, Davis, Sean, Killian, J Keith, Pineda, Marbin, Ray, Satyajit, McCord, Matt R, Pflicke, Holger, Burkett, Sandra Sczerba, Meltzer, Paul S, Rudloff, Udo
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10.03.2016; Public Library of Science (PLoS)
• Subjects: Aged; Axon guidance; Axons - metabolism; Biology and Life Sciences; Cancer; Cancer therapies; cdc42 GTP-Binding Protein - metabolism; Cdc42 protein; Cell Line, Tumor; Cell lines; Cell Proliferation; Cell survival; Chromosomes, Human - genetics; Cues; Cytoskeleton; DNA Mutational Analysis; DNA sequencing; E-cadherin; Female; Gene Expression Regulation, Neoplastic; Gene sequencing; Genes; Genetic aspects; Genetics; Genome, Human; Genomes; Guanine nucleotide-binding protein; Guanosine triphosphatases; Guanosinetriphosphatase; Humans; Immunohistochemistry; Immunophenotyping; Ligands; Male; MAP kinase; Medical research; Medicine and Health Sciences; Melanoma; Metalloproteinase; Mutation; Mutation - genetics; Neoplasm Invasiveness; Nerve Tissue Proteins - genetics; Oncology; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Pharmacology; Physiological aspects; Receptors, Cell Surface - genetics; Regulatory approval; Research and analysis methods; RNA Interference; Signal Transduction - drug effects; Signaling; Spectral Karyotyping; Studies; Transfection; Tumor cell lines; Vimentin; United States; United States > US; Maryland
• DOI: 10.1371/journal.pone.0149833
• ISSN: 1932-6203

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.