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Principal Investigator: PARTHA ROY
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $381,058
Funding agency: National Cancer Institute
Breast cancer the most frequently diagnosed non-skin cancer in women, ranks second among
cancer deaths in women in the United States. The vast majority of these deaths are due to
metastasis. Dysregulated expression and/or activity of actin-regulatory proteins contribute to the
motile phenotype that enables metastatic dissemination of breast cancer cells. The goal of this
study is to gain fundamental mechanistic insights into how profilin1, a major regulator of actin
cytoskeleton, influences cell signaling at the membrane-cytosol interface that are important for
early steps of breast cancer metastasis. We propose two specific aims in the project. In Aim 1,
we will elucidate how profilin1’s binding to cell membrane alters membrane phosphoinositide
dynamics in cells. In aim 2, we will further establish a causal connection between profilin1-
dependent modulation of membrane phosphoinositide signaling and phosphoinositide-directed
pro-migratory signaling axis in regulating metastatic dissemination of breast cancer cells from the
primary tumor. These studies will utilize a comprehensive experimental approach combining high-
resolution live cell imaging of lipid biosensors, imaging of membrane diffusion dynamics of
proteins at the single molecule level, intravital imaging of cancer cell dissemination and clinical
sample analyses. A succesful completion of this study will provide novel mechanisms for breast
cancer dissemination.
Terms: <1-Phosphatidylinositol 3-Kinase><AKT><Actin-Binding Protein><Actins><Adenocarcinoma><Akt protein><Animals><Assay><Behavior><Binding><Bioassay><Biochemical><Biological Assay><Biology><Biosensor><Brachydanio rerio><Breast Cancer><Breast Cancer Cell><Breast Metastasis><Cancers><Cell Body><Cell Communication and Signaling><Cell Locomotion><Cell Migration><Cell Movement><Cell Signaling><Cell membrane><Cell-Extracellular Matrix><Cells><Cellular Matrix><Cellular Migration><Cellular Motility><Cessation of life><Clinical><Cytoplasmic Membrane><Cytoskeletal System><Cytoskeleton><Cytosol><Danio rerio><Data><Death><Dephosphorylation><Diagnosis><Diffusion><Down-Regulation><ECM><Extracellular Matrix><Family><Generations><Goals><Human><Hydrolysis><INPPL1><INPPL1 gene><Image><Immunofluorescence><Immunofluorescence Immunologic><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><In Vitro><Inositide Phospholipids><Inositol Phosphoglycerides><Inositol Phospholipids><Inositol Polyphosphate Phosphatase-Like 1><Intracellular Communication and Signaling><Invaded><Knowledge><L-Proline><Lecithinase C><Link><Lipids><MMAC1><MMAC1 protein><Malignant><Malignant - descriptor><Malignant Adenoma><Malignant Breast Neoplasm><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Mediating><Membrane><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Metastatic breast cancer><Modeling><Modern Man><Molecular><Molecular Interaction><Motility><Mutated in Multiple Advanced Cancers 1><Neoplasm Metastasis><PHTS gene><PHTS protein><PI(3,4)P2><PI(3,4,5)P3><PI-3 Kinase><PI3-Kinase><PI3CG><PI3KGamma><PI3k><PIK3><PIK3CG><PIK3CG gene><PTEN><PTEN gene><PTEN protein><PTEN1><Pathway interactions><Phenotype><Phosphatase and Tensin Homolog><Phosphatase and Tensin Homolog Deleted on Chromosome 10><Phosphatases><Phosphatidyl Inositol><Phosphatidylinositol 3-Kinase><Phosphatidylinositol-3-OH Kinase><Phosphatidylinositols><Phosphohydrolases><Phosphoinositide 3-Hydroxykinase><Phosphoinositides><Phospholipase C><Phosphomonoesterases><Phosphoric Monoester Hydrolases><Physiologic><Physiological><Plasma Membrane><Primary Neoplasm><Primary Tumor><Proline><Protein Dephosphorylation><Protein Dynamics><Protein Kinase B><Proteins><Proto-Oncogene Proteins c-akt><PtdIns><PtdIns 3-Kinase><RAC-PK protein><Regulation><Regulatory Protein><Resolution><Role><SH2-Containing Inositol Phosphatase 2><SHIP2><Sampling><Secondary Neoplasm><Secondary Tumor><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Study models><Testing><Time><Tumor Cell><Tumor Cell Biology><Tumor Cell Invasion><Tumor Invasion><Type I Phosphatidylinositol Kinase><Type III Phosphoinositide 3-Kinase><United States><Up-Regulation><Upregulation><VASP><Woman><Women's mortality><Zebra Danio><Zebra Fish><Zebrafish><antagonism><antagonist><arm><biological sensor><biological signal transduction><breast cancer metastasis><breast tumor cell><c-akt protein><cancer cell><cancer metastasis><cancer progression><cell motility><death among females><death among women><death in females><death in women><death rate among women><death rate in women><diffused><diffuses><diffusing><diffusions><female death><female mortality><gain of function><genetic regulatory protein><imaging><in vivo><insight><intra-vital imaging><intracellular skeleton><intravital imaging><lipophosphodiesterase I><live cell image><live cell imaging><live cellular image><live cellular imaging><malignancy><malignant breast tumor><membrane structure><migration><mortality among females><mortality among women><mortality in females><mortality in women><mouse model><murine model><mutated in multiple advanced cancers 1 protein><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><novel><pathway><phosphatase and tensin homologue on chromosome ten><phosphatidylcholine cholinephosphohydrolase><phosphoinositide-3,4,5-triphosphate><phosphoinositide-3,4-bisphosphate><plasmalemma><profilin><profilin 1><profilin I><proto-oncogene protein RAC><proto-oncogene protein akt><rac protein kinase><recruit><regulatory gene product><related to A and C-protein><residence><residential building><residential site><resolutions><single molecule><social role><tumor cell metastasis><tumor progression><vasodilator-stimulated phosphoprotein><women's death><women's death rate>