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

Abstract

The death receptor CD95 is expressed in every cancer cell, thus providing a promising tool to target cancer. Activation of CD95 can, however, lead to apoptosis or proliferation. Yet the molecular determinants of CD95's mode of action remain unclear. Here, we identify an optimal distance between CD95Ligand molecules that enables specific clustering of receptor-ligand pairs, leadingto efficient CD95 activation. Surprisingly, efficientCD95 activation leads to apoptosis in cancer cells invitro and increased tumor growth invivo. We show that allowing a 3D aggregation of cancercells invitro switches the apoptotic response to proliferation. Indeed, we demonstrate that the absence or presence of cell-cell contactsdictates the cell response to CD95. Cellcontacts increase global levels of phosphorylated tyrosines, including CD95's tyrosine. A tyrosine-to-alanine CD95 mutant blocks proliferation in cellsin contact. Our study sheds light intothe regulatory mechanism of CD95 activation that canbe further explored for anti-cancer therapies.