Solid cancers exhibit a dynamic balance between cell death and proliferation ensuring continuous tumour maintenance and growth^1,2. Increasing evidence links enhanced cancer cell apoptosis to paracrine activation of cells in the tumour microenvironment initiating tissue repair programs that support tumour growth^3,4, 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.

实体癌在细胞死亡和增殖之间表现出动态平衡，确保肿瘤持续维持和生长^1,2 。越来越多的证据将癌细胞凋亡增强与肿瘤微环境中细胞的旁分泌激活联系起来，从而启动支持肿瘤生长的组织修复程序^3,4 ，但垂死的癌细胞对邻近肿瘤上皮的直接影响以及这种旁分泌效应如何可能导致治疗耐药性。不清楚。在这里，我们证明，化疗诱导的患者来源的结直肠肿瘤类器官中的肿瘤细胞死亡会导致 ATP 释放，触发 P2X4（也称为 P2RX4）在邻近癌细胞中介导 mTOR 依赖性促生存程序，从而使存活的肿瘤上皮细胞对mTOR 抑制。持久性上皮细胞中诱导的 mTOR 成瘾是由于活性氧的产生增加以及随后因邻近细胞死亡而导致的 DNA 损伤增加所致。因此，抑制 P2X4 受体或直接阻断 mTOR 可以防止 S6 磷酸化的诱导，并与化疗协同作用，导致活性氧诱导的大量细胞死亡，以及单独应用时看不到的显着肿瘤消退。相反，清除活性氧可以防止癌细胞变得依赖 mTOR 激活。总的来说，我们的研究结果表明，垂死的癌细胞对其幸存的邻居的抗凋亡程序建立了新的依赖性，从而为表达 P2X4 的上皮肿瘤的联合治疗创造了机会。