Tumor Establishment Requires Tumor Autonomous and Non-Autonomous Decoupling of EGF Signaling from Apoptosis

Abstract

During organ turnover, robust mechanisms enforce a balanced equilibrium between cell division and death. Nascent tumors must destabilize these mechanisms to subvert cell equilibrium for cancerous growth. The nature of these destabilizing events is central to understanding how new tumors become established and may suggest strategies for cancer prevention. One of the best characterized mechanisms for cell equilibrium is that of the adult Drosophila intestine. In this organ, division is coupled to death because Rhomboid, a protease that cleaves mitogenic EGFs for secretion, is induced in cells undergoing apoptotic elimination. In Drosophila, as in mammals, intestinal stem cells give rise to adenomas following loss of adenomatous polyposis coli (APC). Examining Drosophila APC-/- tumorigenesis, we find that pre-tumor cells destabilize cell equilibrium by uncoupling rhomboid from apoptosis, which creates feed-forward amplification of EGF signaling for tumor establishment. Prior to tumor formation, APC-/- cells induce rhomboid in surrounding cells via activation of the stress signal JNK. During subsequent growth, APC-/- tumors induce rhomboid within the tumor itself via loss of E-cadherin and consequent activity of p120-catenin. Chronic induction of rhomboid in both tumor and surrounding cells leads to constitutive activation of EGFR and is essential for tumors to progress. Thus, incipient tumors combine non-autonomous and autonomous strategies to deregulate rhomboid and destabilize cell equilibrium. Since Rhomboid, EGFR, and E cadherin are associated with colorectal cancer in humans, our findings may shed light on how human colorectal tumors progress.