Niche appropriation by Drosophila intestinal stem cell tumors. Parthive H. Patel^1,2, Devanjali Dutta², Bruce A. Edgar^1,2. 1) Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA USA; 2) German Cancer Research Center (DKFZ) and Center for Molecular Biology Heidelberg (ZMBH) Alliance, Heidelberg, Germany.

   The importance of immune cells, fibroblasts, and vasculature recruited to the tumor microenvironment is widely appreciated, but how stem-derived tumor initiating cells interact with the stem cell niche prior to this, during tumor initiation, is poorly understood. Here we investigate intestinal stem cell (ISC) tumors generated in Drosophila by blocking Notch signaling. These differentiation-defective cells produce an autocrine, progenitor cell-specific EGFR ligand (Spitz), which supports early tumor growth. After achieving a critical mass the tumors induce JNK signaling and cytokines (Upd2,3) in neighboring enterocytes, and another EGFR ligand (Vein) in visceral muscle. These paracrine signals, normally used within the niche to support regenerative growth, accelerate tumor growth. Niche stress caused by the growing tumors enhances JNK activation and cytokine expression, driving a vicious cycle that would normally be kept in check by differentiation. We propose that niche appropriation by differentiation-defective stem cells may be a common mechanism of tumor initiation.