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Cell Rep. 2019 Nov 19;29(8):2295-2306.e6. doi: 10.1016/j.celrep.2019.10.054.

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

Author information

1
Department of Molecular Neurobiology, German Cancer Research Center (DFKZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany.
2
Physical Chemistry of Biosystems, Institute of Physical Chemistry, Heidelberg University, 69120 Heidelberg, Germany.
3
Department of Molecular Neurobiology, German Cancer Research Center (DFKZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany.
4
Department for Bioinformatics and Functional Genomics, Bioquant and Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, 69120 Heidelberg, Germany; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 267, 69120 Heidelberg, Germany.
5
Section Molecular Immunology, Institute of Immunology, Heidelberg University, 69120 Heidelberg, Germany.
6
Apogenix AG, Im Neuenheimer Feld 584, 69120 Heidelberg, Germany.
7
Department of Neurosurgery, University Hospital Ulm, 89312 Günzburg, Germany.
8
Physical Chemistry of Biosystems, Institute of Physical Chemistry, Heidelberg University, 69120 Heidelberg, Germany. Electronic address: tanaka@uni-heidelberg.de.
9
Department of Molecular Neurobiology, German Cancer Research Center (DFKZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany. Electronic address: a.martin-villalba@dkfz-heidelberg.de.

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, leading to efficient CD95 activation. Surprisingly, efficient CD95 activation leads to apoptosis in cancer cells in vitro and increased tumor growth in vivo. We show that allowing a 3D aggregation of cancer cells in vitro switches the apoptotic response to proliferation. Indeed, we demonstrate that the absence or presence of cell-cell contacts dictates the cell response to CD95. Cell contacts increase global levels of phosphorylated tyrosines, including CD95's tyrosine. A tyrosine-to-alanine CD95 mutant blocks proliferation in cells in contact. Our study sheds light into the regulatory mechanism of CD95 activation that can be further explored for anti-cancer therapies.

KEYWORDS:

CD95; CD95 ligand; apoptosis; cancer; cell-cell contact; death receptors; supported membrane; survival; tyrosine kinase

PMID:
31747602
DOI:
10.1016/j.celrep.2019.10.054
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