Cell migration and invasion are critical aspects of tumor metastasis that are incompletely understood. Recently, we have found that the apoptosis regulator, caspase-8, enhances cell migration and invasion of tumor cells, as well as modulating other aspects of cytoskeletal regulation, including calpain activation, Rac activation, generation of lamellipodia, and cell adhesion. We propose to elucidate the mechanisms whereby caspase-8 controls these processes. In the first specific aim, we will determine how caspase-8 controls calpain activation, particularly the effects of caspase-8 on the phosphorylation and activation of calpains by adhesion complexes.
In specific aim 2, we will examine the hypotheses that caspase-8 enhances Rac activation by stimulating the calpain-mediated cleavage of guanine nucleotide exchange factors (GEFs) for Rac and/or by regulating the p85 subunit of PI3- Kinase.
Specific aim 3 utilizes a genetically defined and well-characterized mouse model for human breast cancer to test the effects of caspase-8 on tumor metastasis. Caspase-8 expression is retained in most human tumor types. It may coordinate the opposing processes of apoptosis vs. cell motility signaling, which are carried out by the mature or unprocessed forms of the enzyme, respectively. It is important to understand the ramifications of this novel function of caspase-8 for oncogenesis and the treatment of human cancer.
|Cieply, Benjamin; Koontz, Colton; Frisch, Steven M (2015) CD44S-hyaluronan interactions protect cells resulting from EMT against anoikis. Matrix Biol 48:55-65|
|Park, Sun Hee; Riley 4th, Philip; Frisch, Steven M (2013) Regulation of anoikis by deleted in breast cancer-1 (DBC1) through NF-ÎºB. Apoptosis 18:949-62|
|Cieply, Benjamin; Farris, Joshua; Denvir, James et al. (2013) Epithelial-mesenchymal transition and tumor suppression are controlled by a reciprocal feedback loop between ZEB1 and Grainyhead-like-2. Cancer Res 73:6299-309|
|Frisch, Steven M; Schaller, Michael; Cieply, Benjamin (2013) Mechanisms that link the oncogenic epithelial-mesenchymal transition to suppression of anoikis. J Cell Sci 126:21-9|
|Cieply, Benjamin; Riley 4th, Philip; Pifer, Phillip M et al. (2012) Suppression of the epithelial-mesenchymal transition by Grainyhead-like-2. Cancer Res 72:2440-53|
|Kumar, Sanjeev; Park, Sun Hee; Cieply, Benjamin et al. (2011) A pathway for the control of anoikis sensitivity by E-cadherin and epithelial-to-mesenchymal transition. Mol Cell Biol 31:4036-51|
|Frisch, Steven M (2008) Caspase-8: fly or die. Cancer Res 68:4491-3|