Cell mixing induced by myc is required for competitive tissue invasion and destruction

Abstract

Cell-cell intercalation is used in several developmental processes to shape the normal body plan. There is no clear evidence that intercalation is involved in pathologies. Here we use the proto-oncogene myc to study a process analogous to early phase of tumour expansion: myc-induced cell competition. Cell competition is a conserved mechanism driving the elimination of slow-proliferating cells (so-called 'losers') by faster-proliferating neighbours (so-called 'winners') through apoptosis and is important in preventing developmental malformations and maintain tissue fitness. Here we show, using long-term live imaging of myc-driven competition in the Drosophila pupal notum and in the wing imaginal disc, that the probability of elimination of loser cells correlates with the surface of contact shared with winners. As such, modifying loser-winner interface morphology can modulate the strength of competition. We further show that elimination of loser clones requires winner-loser cell mixing through cell-cell intercalation. Cell mixing is driven by differential growth and the high tension at winner-winner interfaces relative to winner-loser and loser-loser interfaces, which leads to a preferential stabilization of winner-loser contacts and reduction of clone compactness over time. Differences in tension are generated by a relative difference in F-actin levels between loser and winner junctions, induced by differential levels of the membrane lipid phosphatidylinositol (3,4,5)-trisphosphate. Our results establish the first link between cell-cell intercalation induced by a proto-oncogene and how it promotes invasiveness and destruction of healthy tissues.

Modulation of junction tension by tumor-suppressors and proto-oncogenes regulates cell-cell contacts

“…Our experimental results and previous findings show that Myc overexpression leads to clone rounding and a reduction of cell-cell contacts with neighboring wt cells (Prober and Edgar, 2002). Although we did not study Mycmediated cell competition and our experimental setup was different from that of Levayer et al (2015), it would be relevant to analyze whether Myc-mediated cell competition also depends on additional mechanisms associated with reduced cell-cell contact formation owing to a decrease of MyoII level. Lastly, our findings on Yki suggest the existence of a possible negative feedback between Yki activation and cell junction tension.…”

“…Our findings on the mechanisms of clone rounding provide information on cell competition and on a possible negative feedback between proliferation and tension regulation. In the context of cell competition, it has been recently reported that a clonal decrease of Myc levels, or a clonal increase of Myc levels in conjunction with an inhibition of apoptosis, promotes clone fragmentation and cell mixing; such cell-cell mixing increases cell-cell contacts and depends on reduced levels of F-actin, independently of changes in MyoII levels (Levayer et al, 2015). Our experimental results and previous findings show that Myc overexpression leads to clone rounding and a reduction of cell-cell contacts with neighboring wt cells (Prober and Edgar, 2002).…”

Survival of the Fittest: Essential Roles of Cell Competition in Development, Aging, and Cancer

“…For instance, expression of the loseA and loseB isoforms of fwe in a subset of cells is sufficient to induce their elimination in the Drosophila wing imaginal disc epithelia [28], while only the loseB isoform can induce loser status in neurons [33,39,42]. It has been recently shown that loser elimination correlates with the relative concentrations of fwe loseA or loseB isoforms in winner and loser cells, as well as the surface contact shared between winner and loser cells [45]. This finding suggests that each cell can compute and compare fwe loseA or loseB levels with all its neighbors.…”

“…In this situation, fitness comparison would require direct contact between winner and loser cells. Accordingly, several studies of the pattern of loser cell elimination have suggested that the recognition and killing process acts at a short range [16,17,19,36,44] or is strictly contactdependent [28,45,46].…”

Active JNK-dependent secretion of Drosophila Tyrosyl-tRNA synthetase by loser cells recruits haemocytes during cell competition

“…Here we focus on the last steps of this cell selection process, when 'unfit cells' that did not obtain enough survival factors are excluded from the tissue and engulfed by other cells [9][10][11][12] . In particular, we address the question whether the chemotactic signals originated from the dying cells direct their own engulfment.…”