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Your search keyword '"Kyla M. Grimshaw"' showing total 2 results
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1. Active PI3K pathway causes an invasive phenotype which can be reversed or promoted by blocking the pathway at divergent nodes.

Author

Jeffrey J Wallin, Jane Guan, Kyle A Edgar, Wei Zhou, Ross Francis, Anthony C Torres, Peter M Haverty, Jeffrey Eastham-Anderson, Sabrina Arena, Alberto Bardelli, Sue Griffin, John E Goodall, Kyla M Grimshaw, Klaus P Hoeflich, Christopher Torrance, Marcia Belvin, and Lori S Friedman

Subjects
Medicine, Science
Abstract

The PTEN/PI3K pathway is commonly mutated in cancer and therefore represents an attractive target for therapeutic intervention. To investigate the primary phenotypes mediated by increased pathway signaling in a clean, patient-relevant context, an activating PIK3CA mutation (H1047R) was knocked-in to an endogenous allele of the MCF10A non-tumorigenic human breast epithelial cell line. Introduction of an endogenously mutated PIK3CA allele resulted in a marked epithelial-mesenchymal transition (EMT) and invasive phenotype, compared to isogenic wild-type cells. The invasive phenotype was linked to enhanced PIP(3) production via a S6K-IRS positive feedback mechanism. Moreover, potent and selective inhibitors of PI3K were highly effective in reversing this phenotype, which is optimally revealed in 3-dimensional cell culture. In contrast, inhibition of Akt or mTOR exacerbated the invasive phenotype. Our results suggest that invasion is a core phenotype mediated by increased PTEN/PI3K pathway activity and that therapeutic agents targeting different nodes of the PI3K pathway may have dramatic differences in their ability to reverse or promote cancer metastasis.

Published
2012
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2. Active PI3K Pathway Causes an Invasive Phenotype Which Can Be Reversed or Promoted by Blocking the Pathway at Divergent Nodes

Author

Lori Friedman, Kyla M. Grimshaw, Sabrina Arena, Anthony C. Torres, Alberto Bardelli, Jeffrey Eastham-Anderson, Christopher Torrance, Peter M. Haverty, Sue Griffin, Jeffrey Wallin, Klaus P. Hoeflich, Kyle A. Edgar, Marcia Belvin, Jane Guan, John Goodall, Wei Zhou, and Ross Francis

Subjects
Basement Membrane, Phosphatidylinositol 3-Kinases, Cell Movement, Neoplasms, Molecular Cell Biology, Signaling in Cellular Processes, Cluster Analysis, Phosphoinositide-3 Kinase Inhibitors, Sulfonamides, Multidisciplinary, biology, Mechanisms of Signal Transduction, Cell migration, Signaling in Selected Disciplines, Phenotype, Signaling Cascades, Extracellular Matrix, Medicine, RNA Interference, Signal transduction, Research Article, Biotechnology, Signal Transduction, Epithelial-Mesenchymal Transition, Indazoles, Cell Survival, Class I Phosphatidylinositol 3-Kinases, Science, Phosphoinositide Signal Transduction, Signaling Pathways, Cell Growth, Genetic Mutation, Cell Line, Tumor, Genetics, Cancer Genetics, Gene silencing, PTEN, Humans, Protein Interaction Domains and Motifs, Epithelial–mesenchymal transition, Gene Silencing, Protein kinase B, Biology, PI3K/AKT/mTOR pathway, Oncogenic Signaling, Gene Expression Profiling, Mutation Types, Personalized Medicine, Human Genetics, Molecular biology, Enzyme Activation, Small Molecules, Mutation, Cancer research, biology.protein, Gene Function
Abstract

The PTEN/PI3K pathway is commonly mutated in cancer and therefore represents an attractive target for therapeutic intervention. To investigate the primary phenotypes mediated by increased pathway signaling in a clean, patient-relevant context, an activating PIK3CA mutation (H1047R) was knocked-in to an endogenous allele of the MCF10A non-tumorigenic human breast epithelial cell line. Introduction of an endogenously mutated PIK3CA allele resulted in a marked epithelial-mesenchymal transition (EMT) and invasive phenotype, compared to isogenic wild-type cells. The invasive phenotype was linked to enhanced PIP(3) production via a S6K-IRS positive feedback mechanism. Moreover, potent and selective inhibitors of PI3K were highly effective in reversing this phenotype, which is optimally revealed in 3-dimensional cell culture. In contrast, inhibition of Akt or mTOR exacerbated the invasive phenotype. Our results suggest that invasion is a core phenotype mediated by increased PTEN/PI3K pathway activity and that therapeutic agents targeting different nodes of the PI3K pathway may have dramatic differences in their ability to reverse or promote cancer metastasis.

Published
2012

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