德国肿瘤生物学与实验治疗研究所Florian R. Greten研究小组发现，结肠肿瘤细胞死亡通过旁分泌P2X4刺激引起mTOR依赖性。该项研究成果于2022年11月16日在线发表在《自然》杂志上。

研究人员证明了化疗诱导的肿瘤细胞在患者来源的结直肠肿瘤类器官中死亡，导致ATP释放，触发P2X4（也称为P2RX4），并在邻近的癌细胞中介导一个mTOR依赖性的促生存程序，这使幸存的肿瘤上皮细胞对mTOR抑制敏感。持续存在的上皮细胞中诱发的mTOR成瘾是由于活性氧的产生升高，以及随后对邻近细胞死亡的DNA损伤的增加。因此，抑制P2X4受体或直接阻断mTOR可防止诱导S6磷酸化，并与化疗协同作用，导致活性氧诱导的大量细胞死亡和明显的肿瘤消退，这在单独应用时是看不到的。相反，清除活性氧可防止癌细胞对mTOR激活的依赖。

这些研究结果表明，垂死的癌细胞在其存活的邻居中建立了对抗凋亡程序的新依赖，从而为P2X4表达的上皮性肿瘤的联合治疗创造了机会。

据悉，实体癌表现出细胞死亡和增殖之间的动态平衡，从而确保肿瘤的持续维持和增长。越来越多的证据表明，癌细胞凋亡的增强与肿瘤微环境中细胞的旁分泌激活有关，启动了支持肿瘤生长的组织修复程序，然而，死亡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潜在地促进治疗的抗性尚不清楚。

附：英文原文

Title: Colon tumour cell death causes mTOR dependence by paracrine P2X4 stimulation

Author: Schmitt, Mark, Ceteci, Fatih, Gupta, Jalaj, Pesic, Marina, Bttger, Tim W., Nicolas, Adele M., Kennel, Kilian B., Engel, Esther, Schewe, Matthias, Callak Kirisz, Asude, Petrocelli, Valentina, Dabiri, Yasamin, Varga, Julia, Ramakrishnan, Mallika, Karimova, Madina, Ablasser, Andrea, Sato, Toshiro, Arkan, Melek C., de Sauvage, Frederic J., Greten, Florian R.

Issue&Volume: 2022-11-16

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.

DOI: 10.1038/s41586-022-05426-1

Source: https://www.nature.com/articles/s41586-022-05426-1