3D Cellular Architecture Modulates Tyrosine Kinase Activity, Thereby Switching CD95-Mediated Apoptosis to Survival

摘要

The death receptor CD95 is expressed in everycancer cell, thus providing a promising tool totarget cancer. Activation of CD95 can, however,lead to apoptosis or proliferation. Yet the moleculardeterminants of CD95’s mode of action remainunclear. Here, we identify an optimal distancebetween CD95Ligand molecules that enablesspecific clustering of receptor-ligand pairs,leading to efficient CD95 activation. Surprisingly,efficient CD95 activation leads to apoptosis in cancercells in vitro and increased tumor growth in vivo.We show that allowing a 3D aggregation ofcancer cells in vitro switches the apoptoticresponse to proliferation. Indeed, we demonstratethat the absence or presence of cell-cellcontacts dictates the cell response to CD95.Cell contacts increase global levels of phosphorylatedtyrosines, including CD95’s tyrosine. Atyrosine-to-alanine CD95 mutant blocks proliferationin cells in contact. Our study sheds lightinto the regulatory mechanism of CD95 activationthat can be further explored for anti-cancertherapies.