| 000 | 02927 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 |
_c1873 _d1873 |
||