Loss of heparan sulfate in the niche leads to tumor-like germ cell growth in the Drosophila testis

Abstract

The stem cell niche normally prevents aberrant stem cell behaviors that lead to cancer formation. Recent studies suggest that some cancers are derived from endogenous populations of adult stem cells that have somehow escaped from normal control by the niche. However, the molecular mechanisms by which the niche retains stem cells locally and tightly controls their divisions are poorly understood. Here, we demonstrate that the presence of heparan sulfate (HS), a class glygosaminoglycan chains, in the Drosophila germline stem cell niche prevents tumor formation in the testis. Loss of HS in the niche, called the hub, led to gross changes in the morphology of testes as well as the formation of both somatic and germline tumors. This loss of hub HS resulted in ectopic signaling events in the Jak/Stat pathway outside the niche. This ectopic Jak/Stat signaling disrupted normal somatic cell differentiation, leading to the formation of tumors. Our finding indicates a novel non-autonomous role for niche HS in ensuring the integrity of the niche and preventing tumor formation.

Establishment and characterization of Drosophila cell lines mutant for heparan sulfate modifying enzymes

“…These tools in combination with sophisticated molecular genetic techniques in this model enable us to manipulate HSPGs in vivo in a temporally and spatially controlled manner (Kamimura et al 2011;Takemura and Nakato 2015). Using these tools, essential roles of HSPGs in many developmental processes have been defined, including morphogen gradient formation (Cadigan 2002;Yan and Lin 2009;Nakato and Li 2016), stem cell control (Hayashi et al 2009;Dejima et al 2011;Levings et al 2016), regeneration (Takemura and Nakato 2017) and tumor formation (Levings and Nakato 2017).…”

Heparan sulfate maintains adult midgut homeostasis in Drosophila

“…We explored the underlying mechanism of how HS in ECs regulates midgut homeostasis. HS is required for the activation of many signaling pathways, including Wg, JAK/STAT, and BMP (Binari et al, 1997; Jackson et al, 1997; Bellaiche et al, 1998; Lin and Perrimon, 1999, 2000, 2002; Fujise et al, 2003; Belenkaya et al, 2004; Bornemann et al, 2004; Takei et al, 2004; Kamimura et al, 2006; Filmus et al, 2008; Yan and Lin, 2009; Liu et al, 2010; Dani et al, 2012; Zhang et al, 2013; Levings and Nakato, 2018; Mii et al, 2017; Yu et al, 2017). Interestingly, the majority of these signaling pathways positively regulate ISC proliferation and differentiation, while Dpp signaling negatively regulates ISC proliferation and differentiation (Lin et al, 2008; Jiang and Edgar, 2009; Jiang et al, 2009, 2011; Guo et al, 2013; Li et al, 2013a, b, 2014; Tian and Jiang, 2014; Tian et al, 2015; Zhou et al, 2015).…”

“…HS is generated in a stepwise manner by many conserved HS synthetic and modification enzymes, including Gal transferases, the exostosin (EXT) proteins (Tout‐velu [Ttv], Sister of ttv [Sotv], Brother of ttv [Botv)], Sulfateless [Sfl], and Sugarless [Sgl]), and compromising the function of these synthetic enzymes leads to the reduction of HS levels and disruption of HSPG functions (Esko and Lindahl, 2001; Esko and Selleck, 2002; Lin, 2004). Previous studies show that HSPGs play critical roles in the distribution and activation of important morphogens, such as Wg, Hh, Upd, and Dpp, thereby affecting many developmental processes (Binari et al, 1997; Jackson et al, 1997; Bellaiche et al, 1998; Lin and Perrimon, 1999, 2000, 2002; Fujise et al, 2003; Belenkaya et al, 2004; Bornemann et al, 2004; Takei et al, 2004; Kamimura et al, 2006; Filmus et al, 2008; Yan and Lin, 2009; Liu et al, 2010; Dani et al, 2012; Zhang et al, 2013; Levings and Nakato, 2018; Mii et al, 2017; Yu et al, 2017). Although HS chains are critical for the functions of HSPGs, its role in intestinal homeostasis regulation under physiological conditions is not fully understood.…”

Heparan sulfate negatively regulates intestinal stem cell proliferation in Drosophila adult midgut

“…We explored the underlying mechanism of how HS controls midgut homeostasis. HS is required for the activation of many signaling pathways, including Wg, JAK/STAT, Notch and BMP (Belenkaya et al, 2004; Bellaiche et al, 1998; Binari et al, 1997; Bornemann et al, 2004; Dani et al, 2012; Filmus et al, 2008; Fujise et al, 2003; Jackson et al, 1997; Kamimura et al, 2006; Levings and Nakato, 2017; Lin and Perrimon, 1999, 2000, 2002; Liu et al, 2010; Mii et al, 2017; Takei et al, 2004; Yan and Lin, 2009; Yu et al, 2017; Zhang et al, 2013). Interestingly, the majority of these signaling pathways positively regulate ISC proliferation and differentiation, while Dpp signaling negatively regulates ISC proliferation and differentiation (Guo et al, 2013; Jiang and Edgar, 2009; Jiang et al, 2011, 2009; Li et al, 2013a,b, 2014; Lin et al, 2008; Tian and Jiang, 2014; Tian et al, 2015; Zhou et al, 2015).…”

“…HS is synthesized by a series of conserved HS biosynthetic and modifying enzymes, including Gal transferases, the exostosin (EXT) proteins [Tout-velu (Ttv), Sister of ttv (Sotv), Brother of ttv (Botv)], Sulfateless (Sfl) and Sugarless (Sgl) (Esko and Lindahl, 2001; Esko and Selleck, 2002; Lin, 2004). Previous studies demonstrate that HSPGs are required for the distribution of several well-known morphogens, including Wg, Hh, Upd and Dpp (Belenkaya et al, 2004; Bellaiche et al, 1998; Binari et al, 1997; Bornemann et al, 2004; Dani et al, 2012; Filmus et al, 2008; Fujise et al, 2003; Jackson et al, 1997; Kamimura et al, 2006; Levings and Nakato, 2017; Lin and Perrimon, 1999, 2000, 2002; Liu et al, 2010; Mii et al, 2017; Takei et al, 2004; Yan and Lin, 2009; Yu et al, 2017; Zhang et al, 2013). Although HS plays important roles in the functions of HSPGs, its role(s) in regulating ISC proliferation and differentiation under physiological conditions remains elusive.…”