Caspase 8 and Integrins in Tumor Progression During the previous funding period, we demonstrated that caspase 8 association with unligated integrins in vivo promoted apoptosis, and that down-regulation of caspase 8 or integrins in neuroblastoma promoted tumor metastasis. Confirming the roll of apoptosis in these studies, we made the paradoxical observation that, among apoptosis-resistant cells, the expression of caspase 8 significantly enhanced integrin-mediated migration in vitro and metastasis in vivo. The overall goal of this proposal is therefore to understand how caspase 8 apoptotic vs nonapoptotic function is regulated. As an initiator caspase, caspase 8 triggers apoptosis downstream of death receptors, toll-like receptors and integrins. Its expression is frequently lost among aggressive neuroblastoma and other neuroendocrine tumors. This has prompted clinical strategies seeking to restore or amplify its expression. However, caspase 8 is not sufficient for apoptosis, but requires a compliant downstream caspase cascade. Among apoptosis-compromised cells, we provide evidence that caspase 8 expression actually functions to enhance tumor metastasis. This surprising result warrants reconsideration of the concept that simple upregulation of caspase 8 is universally beneficial;rather, it may exacerbate disease progression. While nonapoptotic functions of caspase 8 within the immune and vascular compartments are known, the mechanisms committing caspase 8 to these functions are not. Here, we provide preliminary results showing that enhanced cell migration occurs concurrent with caspase 8 tyrosine phosphorylation and localization in focal adhesion contacts following integrin ligation.
AIM 1 of this proposal will characterize the specific caspase 8 tyrosine residues phosphorylated during adhesion, and identify those critical for migration.
AIM 2 will evaluate which tyrosine residues influence caspase 8 catalytic and proapoptotic activities, including protein-protein interactions. Finally, AIM 3 will test the impact of these regulatory tyrosine residues on disease progression in vivo. Together, the results of these studies will reveal molecular mechanisms of caspase 8 regulation important for the development of anti-metastatic therapies.
The protein caspase 8 is well known to be involved in programmed cell death, and its expression is suppressed among aggressive neuroendocrine tumors. However, caspase 8 can also promote cell migration, and we show that it actually enhances the spread of death-resisting cells, which may explain why it is frequently upregulated in carcinoma. This proposal seeks to understand the molecular mechanisms that control caspase 8 switching between these two roles.
|Sayyah, Jacqueline; Bartakova, Alena; Nogal, Nekeisha et al. (2014) The Ras-related protein, Rap1A, mediates thrombin-stimulated, integrin-dependent glioblastoma cell proliferation and tumor growth. J Biol Chem 289:17689-98|
|Graf, R P; Keller, N; Barbero, S et al. (2014) Caspase-8 as a regulator of tumor cell motility. Curr Mol Med 14:246-54|
|Díaz, Jorge; Mendoza, Pablo; Ortiz, Rina et al. (2014) Rab5 is required in metastatic cancer cells for Caveolin-1-enhanced Rac1 activation, migration and invasion. J Cell Sci 127:2401-6|
|McCabe, K E; Bacos, K; Lu, D et al. (2014) Triggering necroptosis in cisplatin and IAP antagonist-resistant ovarian carcinoma. Cell Death Dis 5:e1496|
|Cheresh, David A; Stupack, Dwayne G (2014) Tumor angiogenesis: putting a value on plastic GEMMs. Circ Res 114:9-11|
|Stupack, Dwayne G (2013) Caspase-8 as a therapeutic target in cancer. Cancer Lett 332:133-40|
|Ward, Kristy K; Tancioni, Isabelle; Lawson, Christine et al. (2013) Inhibition of focal adhesion kinase (FAK) activity prevents anchorage-independent ovarian carcinoma cell growth and tumor progression. Clin Exp Metastasis 30:579-94|
|Graf, Ryon; Barbero, Simone; Keller, Nadine et al. (2013) Src-inducible association of CrkL with procaspase-8 promotes cell migration. Cell Adh Migr 7:362-9|
|Huang, M; Anand, S; Murphy, E A et al. (2012) EGFR-dependent pancreatic carcinoma cell metastasis through Rap1 activation. Oncogene 31:2783-93|
|Thalhauser, Craig J; Lowengrub, John S; Stupack, Dwayne et al. (2010) Selection in spatial stochastic models of cancer: migration as a key modulator of fitness. Biol Direct 5:21|
Showing the most recent 10 out of 21 publications