1. Department of Pathology and The John and Rebecca Moores Cancer Center, The University of California at San Diego, La Jolla, California 92093-0803, USA
2. Department of Genetics and Tumor Cell Biology, and
3. Department of Molecular Pharmacology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
4. *These authors contributed equally to this work

Correspondence to: Dwayne G. Stupack^1,4Jill M. Lahti² Correspondence and requests for materials should be addressed to D.G.S. (Email: dstupack@ucsd.edu) or J.M.L. (Email: jill.lahti@stjude.org).

Abstract

Neuroblastoma, the most common paediatric solid tumour, arises from defective neural crest cells¹. Genetic alterations occur frequently in the most aggressive neuroblastomas¹. In particular, deletion or suppression of the proapoptotic enzyme caspase-8 is common in malignant, disseminated disease, although the effect of this loss on disease progression is unclear^{2, 3, 4}. Here we show that suppression of caspase-8 expression occurs during the establishment of neuroblastoma metastases in vivo, and that reconstitution of caspase-8 expression in deficient neuroblastoma cells suppressed their metastases. Caspase-8 status was not a predictor of primary tumour growth; rather, caspase-8 selectively potentiated apoptosis in neuroblastoma cells invading the collagenous stroma at the tumour margin. Apoptosis was initiated by unligated integrins by means of a process known as integrin-mediated death⁵. Loss of caspase-8 or integrin rendered these cells refractory to integrin-mediated death, allowed cellular survival in the stromal microenvironment, and promoted metastases. These findings define caspase-8 as a metastasis suppressor gene that, together with integrins, regulates the survival and invasive capacity of neuroblastoma cells.

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