Spontaneous Cell Competition in Immortalized Mammalian Cell Lines.

Cell competition is a form of cell-cell interaction by which cells compare relative levels of fitness, resulting in the active elimination of less-fit cells, "losers," by more-fit cells, "winners." Here, we show that in three routinely-used mammalian cell lines - U2OS, 3T3, and MDCK cells - sub-clones arise stochastically that exhibit context-dependent competitive behavior. Specifically, cell death is elicited when winner and loser sub-clones are cultured together but not alone. Cell competition and elimination in these cell lines is caspase-dependent and requires cell-cell contact but does not require de novo RNA synthesis. Moreover, we show that the phenomenon involves differences in cellular metabolism. Hence, our study demonstrates that cell competition is a common feature of immortalized mammalian cells in vitro and implicates cellular metabolism as a mechanism by which cells sense relative levels of "fitness."

Organ-Size Regulation in Mammals.

The control of organism and organ size is a central question in biology. Despite the attention it has received, our understanding of how adult organ size is determined and maintained is still incomplete. Early work has shown that both autonomous and regulated mechanisms drive vertebrate organ growth, and both intrinsic and extrinsic cues contribute to organ size. The molecular nature of organ-size determinants has been the subject of intense study, and major pathways, which underlie cell interactions controlling cell compartment size, have been identified. In this work, we review these data as well as the future perspectives of research in this important area of study.

Cell competition in vertebrate organ size regulation.

The study of animal organ size determination has provided evidence of the existence of organ-intrinsic mechanisms that 'sense' and adjust organ growth. Cell competition, a form of cell interaction that equalizes cell population growth, has been proposed to play a role in organ size regulation. Cell competition involves a cell-context dependent response triggered by perceived differences in cell growth and/or proliferation rates, resulting in apoptosis in growth-disadvantaged cells and compensatory expansion of the more 'fit' cells. The mechanisms that allow cells to compare growth are not yet understood, but a number of genes and pathways have been implicated in cell competition. These include Myc, the members of the Hippo, JAK/STAT and WNT signaling pathways, and the Dlg/Lgl/Scrib and the Crb/Std/PatJ membrane protein complexes. Cell competition was initially characterized in the Drosophila imaginal disc, but several recent studies have shown that cell competition occurs in mouse embryonic stem cells and in the embryonic epiblast, where it plays a role in the regulation of early embryo size. In addition, competition-like behavior has been described in the adult mouse liver and the hematopoietic stem cell compartment. These data indicate that cell competition plays a more universal role in organ size regulation. In addition, as some authors have suggested that similar types of competitive behavior may operate in during tumorigenesis, there may be additional practical reasons for understanding this fundamental process of intercellular communication.

Critical roles for SoxC transcription factors in development and cancer.

Sox4, Sox11 and Sox12 constitute the group C of Sry-related HMG box proteins. They are co-expressed in embryonic neuronal progenitors and in mesenchymal cells in many developing organs. More closely related to each other than to any other proteins, they nevertheless bind DNA and activate transcription in vitro with different efficiencies. Sox4-null embryos and Sox11-null newborns die from heart malformations and the latter display widespread defects, while Sox12-null mice are viable and do not show obvious malformations. Sox4 facilitates differentiation of lymphocytes, pancreatic beta cells, osteoblasts and acts in redundancy with Sox11 to promote neuronal differentiation. Sox4 and Sox11 are upregulated in many tumor types in humans, where their roles in cell survival, proliferation, and metastasis remain controversial. Together, these data hint that Sox4 and Sox11 regulate cell differentiation, proliferation and survival in multiple essential processes, and suggest that they may act in redundancy to control many more developmental, physiological and pathological processes than currently known.