Synergism between canoe and scribble mutations causes tumor-like overgrowth via Ras activation in neural stem cells and epithelia

Abstract

Over the past decade an intriguing connection between asymmetric cell division, stem cells and tumorigenesis has emerged. Neuroblasts, which are the neural stem cells of the Drosophila central nervous system, divide asymmetrically and constitute an excellent paradigm for investigating this connection further. Here we show that the simultaneous loss of the asymmetric cell division regulators Canoe (afadin in mammals) and Scribble in neuroblast clones leads to tumor-like overgrowth through both a severe disruption of the asymmetric cell division process and canoe lossmediated Ras-PI3K-Akt activation. Moreover, canoe loss also interacts synergistically with scribble loss to promote overgrowth in epithelial tissues, here just by activating the Ras-Raf-MAPK pathway. discs large 1 and lethal (2) giant larvae, which are functionally related to scribble, contribute to repress the Ras-MAPK signaling cascade in epithelia. Hence, our work uncovers novel cooperative interactions between all these well-conserved tumor suppressors that ensure tight regulation of the Ras signaling pathway.

A genome-wide Drosophila epithelial tumorigenesis screen identifies Tetraspanin 29Fb as an evolutionarily conserved suppressor of Ras-driven cancer

“…Interestingly, depletion of Tsp29Fb resulted in mislocalized Dlg at cell junctions, and ommatidial patterning defects in terminally-differentiating photoreceptor cells, implicating this protein in epithelial apico-basal polarity regulation and the control of epithelial architecture. It is possible that these effects of Tsp29Fb depletion on epithelial architecture directly affect EGFR/Ras activation, as Scrib depletion does in mammalian cells [ 68 , 69 ] and in Drosophila epithelial tissue [ 70 ]. Indeed, our results showing that Tsp29Fb genetically interacts with scrib support that notion that Tsp29Fb regulates, or functions with, Scrib/Dlg in cell polarity regulation in epithelial development and in the control of signaling pathways.…”

Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation

“…Oncogenic cooperation also occurs in the Drosophila larval brain. As in epithelial tissue, scribble neuroblast clones are eliminated in a JNK-dependent manner, but clones mutant for both scribble and the junction-actin cross-linker and asymmetric cell division regulator canoe display tumor-like overgrowth (Rives-Quinto et al, 2017). In this situation, ectopic Ras expression activates the PI3K-Atk1 signaling pathway.…”

Modelling Cooperative Tumorigenesis inDrosophila

“…It is likely that similar mechanisms are involved in the cooperation of Crb and Par module gene mutants with Ras V12 , as well as with Par1 and Notch Act , as occurs with scrib mutants with Ras V12 or Notch Act ; however formal demonstration is currently lacking. Interestingly, canoe ( cno , afadin/AF-6 in mammals), a gene involved in another type of cell polarity, asymmetric cell division [ 207 ], has been recently shown to cooperate with scrib , dlg, or lgl depletion in epithelial tumorigenesis [ 73 ]. Mechanistically, this synergistic interaction involves the activation of Ras-MAPK signalling, which implicates the wild-type function of Cno as well as Scrib, Dlg, and Lgl in the repression of Ras signalling [ 73 ], as occurs with the mammalian Cno (Afadin/AF-6) and Scrib [ 197 , 208 ].…”