Nov 24, 2016
from 02:00 PM to 03:00 PM
|Where||Biffen Lecture Theatre, underneath Dept of Genetics|
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Title: Stem cell control in the Drosophila gut
Professor Bruce Edgar, Huntsman Cancer Institute, University of Utah.
Cells in intestinal epithelia turn over rapidly due to wear and tear from digestion as well as environmental insults, such as infection. 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 enterocytes (ECs) in the gut epithelium are subjected to stress or damage the epithelium and supporting visceral muscle respond by producing leptin/interleukin-like cytokines (Upd2, Upd3) and EGF-like growth factors (Vn, Krn, Spi). These activate Jak/Stat and EGFR/Ras/MAPK signaling in intestinal stem- and progenitor-cells, and thereby promote ISC division, progenitor cell differentiation, and gut epithelial renewal. Damage sensing and cytokine production in the epithelium involves JNK, p38MAP-Kinase, YAP/Yki, and ROS signaling. We have investigated the biology of stem cell-derived tumors generated by altering factors that affect differentiation (Notch) or cell growth and proliferation (Ack, Src, Ras). In each of these cases transformed stem cells stimulate surrounding enterocytes and visceral muscle to produce the same stress-dependent cytokines and growth factors that mediate normal regeneration. In the case of Notch-depleted stem cell tumors the tumor initiating cells produce an autocrine, progenitor cell-specific EGFR ligand (Spitz), which supports early tumor growth by triggering RAS/MAPK signaling and downstream effectors including the transcriptional repressor Capicua and the ETS-type transcriptional activators Pointed and Ets21C. After achieving a critical mass, the tumors induce JNK and YAP/Yki activity, apoptosis, and cytokine (Upd2, Upd3) expression in these enterocytes, and another EGFR ligand (Vn) in visceral muscle. The activation of these stress-sensing signals involves the delamination of enterocytes from the basement membrane and underlying visceral muscle, suggesting that it derives from mechanical stimuli. 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. Consistent with this requirement, Notch-defective ISC tumors support rapid invasive growth if transplanted to sites outside of the intestine, but only if they are provided with activated Ras/MapK signaling. We outline a stepwise model for tumor development in the fly’s intestinal stem cell niche and propose that niche appropriation by differentiation-defective stem cells may be a common mechanism of tumor initiation.
Host: Alexis Braun