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实验室

10:30-11:30, Tuesday, October 30, 2018

Speaker: Bruce Edgar Ph.D.

Professor,

Huntsman Cancer Institute,

University of Utah

Topic: Stress response, regeneration and tumorigenesis in the Drosophila intestine

Host:     Rongwen Xi, Ph.D.

Abstract

Cells in intestinal epithelia turn over rapidly due to wear and tear from digestion. Gut homeostasis is maintained by intestinal stem cells (ISC) that divide to replenish the epithelium. Using the Drosophila intestine, or midgut, we find that when gut epithelial enterocytes (ECs) are subjected to stress or damage, the epithelium responds by activating stress-dependent signaling via the JNK, P38MAK, and Hippo/Yki pathways. These pathways trigger the production of leptin/interleukin-like cytokines (Upd2, Upd3) and EGFR pathway activators (Vn, Krn, Spi, Rho) in ECs, which activate Jak/Stat and EGFR/Ras/Erk signaling in intestinal stem- and progenitor-cells, thereby promoting progenitor cell growth, division, and differentiation to drive gut epithelial renewal. EGFR signaling promotes ISC proliferation, and the growth of progeny cells, by triggering Ras/Mek/Erk signaling and downstream effectors including the transcriptional repressor Capicua and the ETS-type transcriptional activators Pointed and Ets21C. This ECISC feedback signaling network is essential for regenerative gut renewal following the ingestion of pathogens or toxins, but it can also prove deleterious during aging and tumorigenesis. For instance, damage caused by stem cell tumors stimulates surrounding enterocytes and visceral muscle to produce the same damage-dependent cytokines and growth factors that mediate normal regeneration. Stem-cell derived tumors induce JNK, P38 and YAP/Yki activity, apoptosis, and cytokine (Upd2, Upd3) expression in tumor-adjacent enterocytes, and another EGFR ligand (Vein) in visceral muscle. The activation of these stress-sensing signals depends upon the delamination of enterocytes from the basement membrane and underlying visceral muscle, suggesting that it derives from mechanical stimuli, but ROS signaling is also involved. Genetic tests show that Jnk, Yki, Upd2 and Upd3, all of which are normally used within the niche to support regenerative growth, are also required in enterocytes to propel stem cell tumor growth. Finally, new findings on the role of the steroid hormone, ecdysone, in controlling sexually di-morphic ISC proliferation and gut growth will be discussed.