Drosophila intestinal tumors disrupt adjacent healthy tissue by stimulating mechanical stress.
Major Finding: Drosophila intestinal tumors disrupt adjacent healthy tissue by stimulating mechanical stress.
Mechanism: Upregulation of Relish/Rel signaling in neighboring enterocytes creates a proapoptotic environment.
Impact: Tumor cells can create an inflammatory feedback loop with nearby cells, resulting in tumor growth advantage.
Maintaining homeostasis in tissues involves the careful balance of cell proliferation, differentiation, maintenance of stem cell populations, and removal of damaged cells. However, little is known about the mechanisms that control growth when homeostasis fails in scenarios such as tumorigenesis. Zhou, Valentini, and Boutros studied a Drosophila tumor model wherein RNAi-mediated depletion of BMP signaling generated intestinal tumors where transcripts involved in cell adhesion, immune response, and other regeneration and stress response pathways were enriched compared with healthy intestinal tissue. Tumor cells induced mechanical stress on neighboring enterocytes via DE-cadherin and myosin dysregulation, resulting in non–cell-autonomous activation of Relish (NFκB homolog) signaling, delamination, and activation of ROCK-associated JNK signaling. Staining revealed high levels of cleaved caspase-3 in enterocytes adjacent to tumor cells, indicative of induction of apoptosis and cell death, whereas loss of Relish blocked the upregulation of proapoptotic genes. Dying enterocytes produce cytokines that activate JAK/STAT signaling in tumor cells, creating a feedback loop ultimately promoting tumor growth. Interrogation of RNA-sequencing data to identify upstream effectors of Relish in enterocytes in the presence of tumor cells showed that expression of the peptidoglycan recognition protein PGRP-LA, a mediator of immune activation, was induced in the intestine. Loss of PGRP-LA reduced tumor-induced cell death in enterocytes and impaired intestinal tumor growth, also suppressing induction of proapoptotic genes and extending the life span of intestinal tumor–bearing Drosophila. Administering inhibitors of Rho-associated protein kinase (ROCK), which phosphorylates myosin, resulted in a significant inhibition of tumor growth, stress, immune activation, and proapoptotic activity. In summary, this work demonstrates that intestinal tumor cells can disrupt adjacent healthy cells by stimulating mechanical stress and promoting an inflammatory feedback loop to gain a growth advantage.
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