The transcriptional response to tumorigenic polarity loss in Drosophila

Abstract

Loss of polarity correlates with progression of epithelial cancers, but how plasma membrane misorganization drives oncogenic transcriptional events remains unclear. The polarity regulators of the Drosophila Scribble (Scrib) module are potent tumor suppressors and provide a model for mechanistic investigation. RNA profiling of Scrib mutant tumors reveals multiple signatures of neoplasia, including altered metabolism and dedifferentiation. Prominent among these is upregulation of cytokine-like Unpaired (Upd) ligands, which drive tumor overgrowth. We identified a polarity-responsive enhancer in upd3, which is activated in a coincident manner by both JNK-dependent Fos and aPKC-mediated Yki transcription. This enhancer, and Scrib mutant overgrowth in general, are also sensitive to activity of the Polycomb Group (PcG), suggesting that PcG attenuation upon polarity loss potentiates select targets for activation by JNK and Yki. Our results link epithelial organization to signaling and epigenetic regulators that control tissue repair programs, and provide insight into why epithelial polarity is tumor-suppressive.DOI: http://dx.doi.org/10.7554/eLife.03189.001

JAK/STAT signalling mediates cell survival in response to tissue stress

“…Previous reports and our studies demonstrate that the JAK/STAT ligands upd1, upd2 and upd3 are transcriptionally upregulated in response to stress from physical injury (Katsuyama et al, 2015;Pastor-Pareja et al, 2008) or tumorous growth (Wu et al, 2010;Bunker et al, 2015), indicating that pathway upregulation may be driven by JNK-dependent Upd gene transcription. We found that transcription of Upd genes is highly elevated in Eiger-stimulated discs, whereas transcription of dome, hop and Stat92E is not (Fig.…”

“…JAK/STAT activity is not required for compensatory proliferation JAK/STAT has been reported to play a role in promoting cell proliferation in wild-type (Bach et al, 2003;Tsai and Sun, 2004;Mukherjee et al, 2005), tumorous (Classen et al, 2009;Wu et al, 2010;Davie et al, 2015;Bunker et al, 2015;Amoyel et al, 2014) and surgically injured discs (Katsuyama et al, 2015). To test whether JAK/STAT is generally required to drive compensatory proliferation, we quantified mitotic events after Eiger stimulation in discs with impaired JAK/STAT signalling.…”

“…A proliferative function for JAK/STAT was suggested by early studies of tissue growth during disc development (Bach et al, 2003;Tsai and Sun, 2004;Mukherjee et al, 2005). Subsequently, JAK/STAT has been widely implicated in promoting proliferation of neoplastic cells (Classen et al, 2009;Wu et al, 2010;Davie et al, 2015;Bunker et al, 2015;Amoyel et al, 2014) and aberrant nonautonomous proliferation of wild-type cells in fly models of tumorigenesis (Vaccari and Bilder, 2005;Herz et al, 2006;Moberg et al, 2005). Activation of Upd gene transcription upon tissue damage has been linked to compensatory proliferation in imaginal discs and adult guts (Jiang et al, 2009;Pastor-Pareja et al, 2008;Katsuyama et al, 2015;Wu et al, 2010;Lin et al, 2009;Bunker et al, 2015;Santabárbara-Ruiz et al, 2015).…”

“…Subsequently, JAK/STAT has been widely implicated in promoting proliferation of neoplastic cells (Classen et al, 2009;Wu et al, 2010;Davie et al, 2015;Bunker et al, 2015;Amoyel et al, 2014) and aberrant nonautonomous proliferation of wild-type cells in fly models of tumorigenesis (Vaccari and Bilder, 2005;Herz et al, 2006;Moberg et al, 2005). Activation of Upd gene transcription upon tissue damage has been linked to compensatory proliferation in imaginal discs and adult guts (Jiang et al, 2009;Pastor-Pareja et al, 2008;Katsuyama et al, 2015;Wu et al, 2010;Lin et al, 2009;Bunker et al, 2015;Santabárbara-Ruiz et al, 2015). Other studies suggest that JAK/STAT is involved in cell competition, where signalling either promotes 'winner' cell state (Schroeder et al, 2013;Rodrigues et al, 2012) or compensatory proliferation in response to 'loser' cell elimination (Kolahgar et al, 2015).…”

Apoptosis restores cellular density by eliminating a physiologically or genetically induced excess of enterocytes in the Drosophila midgut

“…To fine-tune the read-out of our study, we included two other genes encoding cytokines, upd1 and upd3, which are known to be induced by both JNK and/or Yki signaling in ECs following ingestion of Pe or large amounts of Ecc and to be responsible for ISC proliferation upon damage (Buchon et al, 2009a,b;Bunker et al, 2015;Jiang et al, 2009;Karpowicz et al, 2010;Osman et al, 2012;Patel et al, 2015;Ren et al, 2010;Shaw et al, 2010;Staley and Irvine, 2010). We found that small amounts of Btk activated upd1, but not upd3, whereas small amounts of Ecc activated upd1 (although not significant in our statistical test) and upd3 (Fig.…”