 Colon tumour cell death causes mTOR dependence by paracrine P2X4 stimulationMark Schmitt,
Fatih Ceteci,
Jalaj Gupta,
Marina Pesic,
Tim W. Böttger,
Adele M. Nicolas,
Kilian B. Kennel,
Esther Engel,
Matthias Schewe,
Asude Callak Kirisözü,
Valentina Petrocelli,
Yasamin Dabiri,
Julia Varga,
Mallika Ramakrishnan,
Madina Karimova,
Andrea Ablasser,
Toshiro Sato,
Melek C. Arkan,
Frederic J. Sauvage and
Florian R. Greten ()
Nature, 2022, vol. 612, issue 7939, 347-353 Abstract: Abstract Solid cancers exhibit a dynamic balance between cell death and proliferation ensuring continuous tumour maintenance and growth1,2. Increasing evidence links enhanced cancer cell apoptosis to paracrine activation of cells in the tumour microenvironment initiating tissue repair programs that support tumour growth3,4, yet the direct effects of dying cancer cells on neighbouring tumour epithelia and how this paracrine effect potentially contributes to therapy resistance are unclear. Here we demonstrate that chemotherapy-induced tumour cell death in patient-derived colorectal tumour organoids causes ATP release triggering P2X4 (also known as P2RX4) to mediate an mTOR-dependent pro-survival program in neighbouring cancer cells, which renders surviving tumour epithelia sensitive to mTOR inhibition. The induced mTOR addiction in persisting epithelial cells is due to elevated production of reactive oxygen species and subsequent increased DNA damage in response to the death of neighbouring cells. Accordingly, inhibition of the P2X4 receptor or direct mTOR blockade prevents induction of S6 phosphorylation and synergizes with chemotherapy to cause massive cell death induced by reactive oxygen species and marked tumour regression that is not seen when individually applied. Conversely, scavenging of reactive oxygen species prevents cancer cells from becoming reliant on mTOR activation. Collectively, our findings show that dying cancer cells establish a new dependency on anti-apoptotic programs in their surviving neighbours, thereby creating an opportunity for combination therapy in P2X4-expressing epithelial tumours. Date: 2022 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:612:y:2022:i:7939:d:10.1038_s41586-022-05426-1 Ordering information: This journal article can be ordered from DOI: 10.1038/s41586-022-05426-1 Access Statistics for this article Nature is currently edited by Magdalena Skipper More articles in Nature from Nature |
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