Drosophila SPARC Is a Self-Protective Signal Expressed by Loser Cells during Cell Competition

Abstract

During development and aging, animals suffer insults that modify the fitness of individual cells. In Drosophila, the elimination of viable but suboptimal cells is mediated by cell competition, ensuring that these cells do not accumulate during development. In addition, certain genes such as the Drosophila homolog of human c-myc (dmyc) are able to transform cells into supercompetitors, which eliminate neighboring wild-type cells by apoptosis and overproliferate, leaving total cell numbers unchanged. Here we have identified Drosophila Sparc as an early marker transcriptionally upregulated in loser cells that provides a transient protection by inhibiting Caspase activation in outcompeted cells. Overall, we describe the unexpected existence of a physiological mechanism that counteracts cell competition during development.

Mechanisms and mechanics of cell competition in epithelia

“…The nature of this signal is still unknown. One approach towards its identification has been to take advantage of cell competition in cell culture, where biochemical purification is feasible 23,73 . However, as it is being debated whether the behaviour of cultured cells accurately reflects that of cells within tissues, we do not discuss these studies further.…”

“…Another, non-mutually exclusive possibility is that cell competition may be more readily detected in epithelia because of their planar organization. The discovery of cell competition and most of the sub sequent mechanistic insight came from studies of D. melano gaster appendages 13,14,[16][17][18][19][20][21][22][23] in which it is relatively easy to generate genetic mosaics 24 that confront cells with different features, including growth rates. This can be achieved, for example, by genetically reducing or boosting translational activity in a clone of cells within the tissue 13,14,25,26 .…”

How winner cells cause the demise of loser cells

“…These labels are membrane tags that give information on the cellular ''health status''; however, as yet the molecules that allow cells to recognize this code are still not known. The corollary in loser cells is the upregulation of the protein SPARC (secreted protein acidic and rich in cysteine), which transiently protects losers from being eliminated by apoptosis [22]. Both Flower and SPARC have been recently related with cancer in the context of cell competition [23,24], supporting the connection between the competitive process and tumor formation [19].…”

“…It is required for distinguishing loser cells from winner cells after competition for resources [21,22]. The different isoforms of Flower tag cells as Losers (expressing the Lose-A and/or Lose-B isoforms) or winners (cells expressing the ubi isoform) but the eventual death of the loser cells depends on the context and a cell-cell comparison on the relative levels of Lose and/or ubi expressed by neighboring cells [21] (Fig.…”

“…This was a peculiar type of ancient war in which the Aztec warriors were trained to prefer capturing their enemies in battle rather than killing them. Therefore, losers were not killed immediately, but captured, then marked as ''losers'' with blue paint and eventually sacrificed (or saved) later during an independent ritual [21,22,28].…”