Epithelial Tumors Originate in Tumor Hotspots, a Tissue-Intrinsic Microenvironment

Abstract

Malignant tumors are caused by uncontrolled proliferation of transformed mutant cells that have lost the ability to maintain tissue integrity. Although a number of causative genetic backgrounds for tumor development have been discovered, the initial steps mutant cells take to escape tissue integrity and trigger tumorigenesis remain elusive. Here, we show through analysis of conserved neoplastic tumor-suppressor genes (nTSGs) in Drosophila wing imaginal disc epithelia that tumor initiation depends on tissue-intrinsic local cytoarchitectures, causing tumors to consistently originate in a specific region of the tissue. In this “tumor hotspot” where cells constitute a network of robust structures on their basal side, nTSG-deficient cells delaminate from the apical side of the epithelium and begin tumorigenic overgrowth by exploiting endogenous Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling activity. Conversely, in other regions, the “tumor coldspot” nTSG-deficient cells are extruded toward the basal side and undergo apoptosis. When the direction of delamination is reversed through suppression of RhoGEF2, an activator of the Rho family small GTPases, and JAK/STAT is activated ectopically in these coldspot nTSG-deficient cells, tumorigenesis is induced. These data indicate that two independent processes, apical delamination and JAK/STAT activation, are concurrently required for the initiation of nTSG-deficient-induced tumorigenesis. Given the conservation of the epithelial cytoarchitecture, tumorigenesis may be generally initiated from tumor hotspots by a similar mechanism.

Cell Extrusion: A Stress-Responsive Force for Good or Evil in Epithelial Homeostasis

“…While scrib basal extrusion is tumor suppressive, hyperactivating scrib cell extrusion drove aberrant apical extrusion and lethal, luminal tumors (Figure 4c) (Vaughen and Igaki, 2016), underscoring that balanced extrusion rates are critical for homeostasis. This strongly parallels recent findings from scrib-RNAi experiments in wing discs, where scrib KD cells selectively overgrow when extruded apically at tumor “hotspots” characterized by dense, basal extracellular matrix (Tamori et al, 2016). Thus, luminal scrib tumors can avoid engulfment by neighboring cells (Ohsawa et al, 2011) or circulating hemocytes (Pastor-Pareja et al, 2008) while simultaneously capitalizing on endogenous JAK/STAT signaling at hotspots (Tamori et al, 2016).…”

Slit-Robo Repulsive Signaling Extrudes Tumorigenic Cells from Epithelia

“…Cell extrusion and cell competition are intimately linked to tissue homeostasis and tumor progression (Gu and Rosenblatt, 2012; Ballesteros-Arias et al, 2013; Enomoto et al, 2015), and the direction of cell extrusion can dictate whether a cancer is initiated or suppressed (Hogan et al, 2009; Slattum and Rosenblatt, 2014; Tamori et al, 2016). We also found that modulating extrusive signaling either promoted or suppressed scrib tumorigenesis (Figure 7): while plain Robo2 or Ena hyperactivation triggered basal epithelial cell extrusion followed by cell death (Figures 5B, 5C, and S4S–S4Tʹ), Robo2-Ena activation in scrib mutant cells unexpectedly accelerated both basal and apical extrusion into the lumen (Figures 4G–4L).…”

“…We speculate that the aberrant polarity of scrib cells permits a tumor-suppressive, basal cell-extrusion mechanism to deleteriously promote randomized cell extrusion and luminal tumorigenesis. Indeed, luminal extrusion was recently identified as a causal mechanism of scrib tumorigenesis in the Drosophila wing disc (Tamori et al, 2016). …”

Mechanisms of cell competition emerging from Drosophila studies

“…This ‘tumor-suppressive competition’ is partially independent of caspase-dependent apoptosis [36,37]. Although apoptosis does contribute, mutant cells are also removed by extrusion from mosaic epithelia, in both apical and basal directions [38**,39**]. …”

“…Here cells delaminate apically and can grow as neoplastic tumors by exploiting apical Jak-Stat signaling [38**]. …”