Colon tumor cell death causes mTOR dependence by paracrine P2X(4) stimulation
- 2022-11-16.
/pmc/articles/PMC7613947/ /pubmed/36385525
Solid 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.