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SUMMARY:Stem cell control in the Drosophila gut - Professor Bruce Edgar\, 
 Huntsman Cancer Institute\, University of Utah 
DTSTART:20161124T140000Z
DTEND:20161124T150000Z
UID:TALK67538@talks.cam.ac.uk
CONTACT:Caroline Newnham
DESCRIPTION:Cells in intestinal epithelia turn over rapidly due to wear an
 d 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 t
 o stress or damage the epithelium and supporting visceral muscle respond b
 y producing leptin/interleukin-like cytokines (Upd2\, Upd3) and EGF-like g
 rowth factors (Vn\, Krn\, Spi). These activate Jak/Stat and EGFR/Ras/MAPK 
 signaling in intestinal stem- and progenitor-cells\, and thereby promote I
 SC 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 biol
 ogy 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 ente
 rocytes and visceral muscle to produce the same stress-dependent cytokines
  and growth factors that mediate normal regeneration.  In the case of Notc
 h-depleted stem cell tumors the tumor initiating cells produce an autocrin
 e\, progenitor cell-specific EGFR ligand (Spitz)\, which supports early tu
 mor growth by triggering RAS/MAPK signaling and downstream effectors inclu
 ding the transcriptional repressor Capicua and the ETS-type transcriptiona
 l activators Pointed and Ets21C. After achieving a critical mass\, the tum
 ors induce JNK and YAP/Yki activity\, apoptosis\, and cytokine (Upd2\, Upd
 3) expression in these enterocytes\, and another EGFR ligand (Vn) in visce
 ral muscle. The activation of these stress-sensing signals involves the de
 lamination of enterocytes from the basement membrane and underlying viscer
 al muscle\, suggesting that it derives from mechanical stimuli. Genetic te
 sts show that Jnk\, Yki\, Upd2 and Upd3\, all of which are normally used w
 ithin the niche to support regenerative growth\, are also required in ente
 rocytes to propel stem cell tumor growth. Consistent with this requirement
 \, Notch-defective ISC tumors support rapid invasive growth if transplante
 d to sites outside of the intestine\, but only if they are provided with a
 ctivated Ras/MapK signaling. We outline a stepwise model for tumor develop
 ment in the fly’s intestinal stem cell niche and propose that niche appr
 opriation by differentiation-defective stem cells may be a common mechanis
 m of tumor initiation. \n \n
LOCATION:Biffen Lecture Theatre\, Department of Genetics\, Downing Site
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