A chronic interorgan wound response appropriated by Drosophila tumors to induce intestinal inflammation

Abstract

Tumors exploit wound healing pathways not only to foster progression but also to lethally disrupt systemic physiology. A prominent example is malignant activation of the clotting cascade, causing pathology through unclear mechanisms that extend beyond thrombosis. Here we show that tumors in a coagulopathy-inducing Drosophila cancer model remotely disrupt intestinal stem cell (ISC) homeostasis. This paraneoplastic, tumor-gut communication axis induces intestinal dysplasia and barrier dysfunction, mimicking remote chronic injury that we show activates inflammation in ISCs via EGFR signaling. Unlike the interorgan responses observed with acute injury, which involves Jak/STAT signaling to activate regenerative ISC proliferation, dysregulated division in both tumor-bearing and chronically injured flies is sustained only by EGFR activation. We also present evidence that deposition of clot material locally onto gut stroma links tumor-driven coagulopathy to intestinal inflammation. Collectively, these findings distinguish mechanisms of remote responses to chronic versus transient stresses. Furthermore, they show how tumor-initiated, dysregulated wound healing programs can drive tissue-specific, pathological inflammation in a host.