Aneuploidy facilitates dysplastic and tumorigenic phenotypes in the Drosophila gut

Abstract

Aneuploidy has been strongly linked to cancer development, and published evidence has suggested that aneuploidy can have an oncogenic or a tumor suppressor role depending on the tissue context. Using the Drosophila midgut as a model, we have recently described that adult intestinal stem cells (ISCs), do not activate programmed cell death upon aneuploidy induction, leading to an increase in ISC proliferation rate, and tissue dysplasia. How aneuploidy impacts ISCs in intestinal tumorigenic models remains to be investigated, and it represents a very important biological question to address since data from multiple in vivo models suggests that the cellular impact of aneuploidy is highly dependent on the cellular and tissue context. Using manipulation of different genetic pathways such as EGFR, JAK-STAT and Notch that cause dysplastic phenotypes in the Drosophila gut, we found that concomitant aneuploidy induction by impairment of the Spindle Assembly Checkpoint (SAC) consistently leads to a more severe progression of intestinal dysplasia or tumorigenesis. This is characterized by an accumulation of progenitor cells, high tissue cell density and higher stem cell proliferation rates, revealing an additive or synergistic effect depending on the misregulated pathway in which aneuploidy was induced. Thus, our data suggests that in the Drosophila gut, both dysplasia and tumorigenic phenotypes can be fueled by inducing genomic instability of resident stem cells.

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“…Studies have shown that aneuploidy in ISCs has contrasting effects, either causing ISC overproliferation to form gut dysplasia ( Resende et al 2018 ; Brás et al 2021 ) or ISC loss due to premature differentiation ( Gogendeau et al 2015 ). Our results were apparently against the notion that aneuploidy increased ISC proliferation.…”

“…As compared with the other proliferative cells ( Morais da Silva et al 2013 ), studies indicated that adult stem cells might tolerate aneuploidy instead of activating apoptosis ( Mantel et al 2007 ; Harper et al 2010 ). Subsequently, aneuploidy could induce the differentiation of ISCs ( Gogendeau et al 2015 ) or promote their proliferation and gut dysplasia ( Resende et al 2018 ; Brás et al 2021 ) in Drosophila .…”

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“…Aneuploidy can result in failure to survive, developmental abnormalities, or the initiation and development of diseases such as cancer, depending on its sternness [14][15][16]. Some studies have shown that aneuploidy induced by SAC damage in the midgut of drosophila will lead to abnormal intestinal development or tumorigenesis [17]. The SAC mechanism is used by cells during mitosis to guarantee that all chromosomes have enough time to attach to spindle microtubules before the cell divides [5,18].…”