We are interested in assessing whether mammalian cells have retained the signaling pathways and migration behavior that Dictyostelium use when they relay chemotactic signals during chemotaxis. Our work focuses on two aspects of neutrophil chemotaxis. First, we set out to determine the mechanism by which chemoattractants increase cAMP production. In Dictyostelium, ACA activation requires inputs from heterotrimeric G proteins, phosphoinositide-3 kinase (PI3K), and the target of rapamycin complex 2 (TORC2). A second project is aimed at understanding the role of signal relay during neutrophil chemotaxis. Chemokines have also been implicated in the progression of cancer, particularly during breast cancer metastasis. Moreover, a shift from mesenchymal (collective) to amoeboid movement is observed during metastasis. As cancer cells transition from clusters to single, amoeboid-like cells, they often migrate in a head-to-tail fashion and form files of cells that move along paths of least resistance. Metastatic cancer cells therefore revert to a very primitive and efficient mode of migration shared by hematopoietic and Dictyostelium cells. We hypothesize that the invasive potential of breast cancer cells is related to their ability to upregulate their chemotactic machinery, and is coupled to a dedifferentiation program that leads to primitive chemotactic behaviors such as amoeboid-like single cell migration and sheet/group migration.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011216-05
Application #
8763407
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2013
Total Cost
$984,212
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Majumdar, Ritankar; Sixt, Michael; Parent, Carole A (2014) New paradigms in the establishment and maintenance of gradients during directed cell migration. Curr Opin Cell Biol 30:33-40
Moissoglu, Konstadinos; Majumdar, Ritankar; Parent, Carole A (2014) Cell migration: sinking in a gradient. Curr Biol 24:R23-5
Liu, Lunhua; Gritz, Derek; Parent, Carole A (2014) PKC*II acts downstream of chemoattractant receptors and mTORC2 to regulate cAMP production and myosin II activity in neutrophils. Mol Biol Cell 25:1446-57
Parent, Carole A; Weiner, Orion D (2013) The symphony of cell movement: how cells orchestrate diverse signals and forces to control migration. Curr Opin Cell Biol 25:523-5
Afonso, Philippe V; McCann, Colin P; Kapnick, Senta M et al. (2013) Discoidin domain receptor 2 regulates neutrophil chemotaxis in 3D collagen matrices. Blood 121:1644-50
Lammermann, Tim; Afonso, Philippe V; Angermann, Bastian R et al. (2013) Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo. Nature 498:371-5
Bagorda, Anna; Parent, Carole A (2008) Eukaryotic chemotaxis at a glance. J Cell Sci 121:2621-4
Garcia, G L; Parent, C A (2008) Signal relay during chemotaxis. J Microsc 231:529-34