Tissue-Intrinsic Tumor Hotspots: Terroir for Tumorigenesis

Abstract

Epithelial tissues are highly organized systems with a remarkable homeostatic ability to maintain morphology through regulation of cellular proliferation and tissue integrity. This robust self-organizing system is progressively disrupted during tumor development. Recent studies of conserved tumor-suppressor genes in Drosophila showed how pro-tumor cells deviate from the robustly organized tissue microenvironment to take the first steps into becoming aggressive tumors. Here we review the ‘tumor hotspot’ hypothesis that explains how the tissue-intrinsic local microenvironment has a pivotal role in the initial stage of tumorigenesis in Drosophila epithelia and discuss comparable mechanisms in mammalian tissues.

Oncogenic cooperation between Yorkie and the conserved microRNAmiR-8in the wing disc ofDrosophila

“…Consistently, recent studies have shown that the hinge is a hotspot in the formation of epithelial tumors (Khan et al, 2013;Tamori and Deng, 2017;Tamori et al, 2016). The results shown here provide a new example supporting the notion that the hinge is an oncogenic hotspot (Tamori and Deng, 2017).…”

“…Given that miR-8 and Yki are oncogenic partners in the hinge, downregulation of miR-8 in those cells might also provide a mechanism to prevent the formation of neoplastic tumors in a context of Yki upregulation. Hinge cells in the wing disc are protected against apoptosis (a central tumor suppressor mechanism) and can survive external apoptotic inputs, including irradiation, drug-induced apoptosis and cell competition (Tamori and Deng, 2017;Tamori et al, 2016;Su, 2016, 2017). Consistently, recent studies have shown that the hinge is a hotspot in the formation of epithelial tumors (Khan et al, 2013;Tamori and Deng, 2017;Tamori et al, 2016).…”

“…Hinge cells in the wing disc are protected against apoptosis (a central tumor suppressor mechanism) and can survive external apoptotic inputs, including irradiation, drug-induced apoptosis and cell competition (Tamori and Deng, 2017;Tamori et al, 2016;Su, 2016, 2017). Consistently, recent studies have shown that the hinge is a hotspot in the formation of epithelial tumors (Khan et al, 2013;Tamori and Deng, 2017;Tamori et al, 2016). The results shown here provide a new example supporting the notion that the hinge is an oncogenic hotspot (Tamori and Deng, 2017).…”

Two-Faced: Roles of JNK Signalling During Tumourigenesis in the Drosophila Model

“…Interestingly, it was shown that polyploid cells also form in Ras85D V12 /scrib −/− tumours due to CycB downregulation, and blocking their formation inhibits the invasive behaviours of these tumours (Cong et al, 2018). (6) Jun N-terminal kinase signalling can be important in tumourigenesis at transition zones -where different epithelial cell populations meet, which are often hotspots for tumourigenesis (reviewed in Tamori and Deng, 2017). One such zone occurs in the Drosophila larvae at a site where polyploid salivary gland cells meet the diploid imaginal ring cells, where tumourigenesis occurs after transient whole animal N ACT expression due to upregulation of TNF-JNK and Jak-STAT signalling (Yang et al, 2019).…”

Modelling Cooperative Tumorigenesis inDrosophila

“…Whilst there is evidence that wild-type epithelial cells engulf the scrib mutant dying cells [ 54 ], hemocytes play the predominant role in this process, as well as in cell competition due to variations in dMyc or ribosomal protein levels [ 145 , 146 ]. Furthermore, in tumour development, microenvironmental “hot-spots” have been revealed where the tumour has a greater chance of progressing, which has parallels with mammalian systems [ 27 , 147 ]. Molecularly, the “hot-spots” are due to endogenously higher levels of Jak-Stat signalling and the presence of a stiff basement membrane extracellular matrix, resulting in extrusion of the tumour cells apically, where they survive ( Figure 2(b) ).…”