000			02925 am a22004213u 4500
042			_adc
100	1	0	_aSchmitt, Mark _eauthor _91732
700	1	0	_aCeteci, Fatih _eauthor _91733
700	1	0	_aGupta, Jalaj _eauthor _91734
700	1	0	_aPesic, Marina _eauthor _91735
700	1	0	_aBöttger, Tim W. _eauthor _91736
700	1	0	_aNicolas, Adele M. _eauthor _91737
700	1	0	_aKennel, Kilian B. _eauthor _91738
700	1	0	_aEngel, Esther _eauthor _91739
700	1	0	_aSchewe, Matthias _eauthor _91740
700	1	0	_aKirisozu, Asude _eauthor _91741
700	1	0	_aPetrocelli, Valentina _eauthor _91742
700	1	0	_aDabiri, Yasamin _eauthor _91743
700	1	0	_aVarga, Julia _eauthor _91744
700	1	0	_aRamakrishnan, Mallika _eauthor _91745
700	1	0	_aKarimova, Madina _eauthor _91746
700	1	0	_aAblasser, Andrea _eauthor _91747
700	1	0	_aSato, Toshiro _eauthor _91748
700	1	0	_aArkan, Melek C. _eauthor _91749
700	1	0	_ade Sauvage, Frederic J. _eauthor _91750
700	1	0	_aGreten, Florian R. _eauthor _91751
245	0	0	_aColon tumor cell death causes mTOR dependence by paracrine P2X(4) stimulation
260			_c2022-11-16.
500			_a/pmc/articles/PMC7613947/
500			_a/pubmed/36385525
520			_aSolid cancers display dynamic balance between cell death and proliferation assuring continuous tumor maintenance and growth (1, 2). Increasing evidence links enhanced cancer cell apoptosis to paracrine activation of cells in the tumor microenvironment initiating tissue repair programs that support tumor growth(3, 4), yet the direct effects of dying cancer cells on neighboring tumor epithelia and how this potentially contributes to therapy resistance are unclear. Here we demonstrate that chemotherapy-induced tumor cell death in patient-derived colorectal tumor organoids causes ATP release triggering a P2x4-mediated mTOR dependent pro-survival program in neighboring cancer cells, which renders surviving tumor epithelia sensitive to mTOR inhibition. The induced mTOR addiction in persisting epithelial cells is due to an elevated ROS production and subsequent increased DNA damage in response to death of neighboring cells. Accordingly, inhibition of the P2X4 receptor or direct mTOR blockade prevent induction of S6 phosphorylation and synergize with chemotherapy to cause massive ROS-induced cell death and marked tumor regression that is not seen when individually applied. Conversely, ROS scavenging prevents cancer cells from becoming reliant on mTOR activation. Collectively, we show that dying cancer cells establish a new dependency on anti-apoptotic programs in their surviving neighbors thereby creating a novel opportunity for combination therapy in P2X4 expressing epithelial tumors.
540			_a
546			_aen
690			_aArticle
655	7		_aText _2local
786	0		_nNature
856	4	1	_uhttp://dx.doi.org/10.1038/s41586-022-05426-1 _zConnect to this object online.
999			_c830 _d830