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Published in final edited form as: Trends Genet. 2020 May 14;36(7):490–498. doi: 10.1016/j.tig.2020.04.003

Picking winners and losers: Cell competition in tissue development and homeostasis

Wonho Kim 1, Rajan Jain 1,2
PMCID: PMC7299791  NIHMSID: NIHMS1585885  PMID: 32418713

Abstract

Viable cells with reduced fitness are often eliminated by neighboring cells with greater fitness. This phenomenon, called cell competition, is an important mechanism for maintaining a high quality population of cells in tissues. Foundational studies characterizing cellular competition and its molecular underpinnings were first carried out utilizing Drosophila as a model system. More recently, competitive behavior studies have extended into mammalian cell types. In this review, we highlight recent advances in the field, focusing on new insights into the molecular mechanisms regulating competitive behavior in various cellular contexts and in cancer. Throughout the review, we highlight new avenues to expand our understanding of the molecular underpinnings of cell competition and its role in tissue development and homeostasis.

Cell competition: more than simple survival

Competitive behavior between cells with different levels of fitness is an important regulatory mechanism for tissue development and homeostasis. Cell competition occurs when cells with lower fitness are eliminated by neighboring cells with higher levels of fitness, a process that has been investigated extensively in Drosophila [1–3]. Ribosomal proteins are essential for cell viability, and homozygous loss of ribosomal proteins results in cell death. Drosophila with mutations in ribosomal proteins have collectively been termed Minute mutants [4–6]. Examination of Minute mutants in the Drosophila wing imaginal disc, an epithelial precursor tissue, revealed the first example of cell competition [6]. Heterozygous Minute flies where all cells in the tissue are mutant develop into adults, albeit at a slower growth rate. However, mosaic induction of a Minute heterozygous mutation in an otherwise wild type imaginal disc results in specific loss of the mutant cells and preferential expansion of wild type cells (Figure 1). These experiments suggested that wild type cells (“winner cells”) induce death of Minute mutant cells (“loser cells”) when the cells are mixed within a developing tissue. These landmark studies launched a series of experiments focused on cell competition [7, 8]. Another important regulator of competitive behavior which was subsequently identified is the oncogenic transcription factor Myc [9, 10]. Two independent groups demonstrated that cells harboring mutation in the Myc gene, resulting in reduced Myc expression, selectively apoptosed only when they were mixed with wild type cells in the imaginal disc [10, 11] (Figure 1). Conversely, wild type cells were eliminated when they were adjacent to Myc-overexpressing cells. These results were not impacted by biases in proliferation rates as wild type cells were only eliminated when adjacent to Myc-overexpressing cells (Figure 1). Intriguingly, the groups observed that cells expressing four copies of Myc outcompeted cells expressing two copies of Myc. These findings suggested that gene dosage, through variation in Myc expression, contributes to competitive behavior [10].

Figure 1. Cell competition overview.

Figure 1.

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When cells of different fitness are mixed, cells with greater fitness induce the elimination of less fit cells. For example, the Minute+/− or Myc hypomorph mutant cells have reduced fitness and grow slowly, but they are viable. When mutant cells are mixed with wild type cells, which have relatively higher fitness than mutant cells, the mutant cells are eliminated and replaced by wild type cells. Myc-overexpressing cells which have higher fitness than wild type cells induce the elimination of wild type cells in a mixed population, which makes Myc-overexpressing cells a “super competitor”.

These foundational experiments led to the overarching hypothesis that cells with higher fitness levels sense neighboring cells with reduced fitness and actively eliminate them. Since that work, it has been found that many of the guiding principles of cell competition discovered in Drosophila are conserved in murine development. For example, cells heterozygous for ribosomal protein L24 are selectively removed during mouse embryogenesis [12]. In addition, clonal overexpression of Myc induces cell death of wild type cells while Myc-overexpressing clones outcompete wild type cells in murine epiblast development [13]. Complementary to these results, it has been determined that cells expressing decreased levels of Myc expression are specifically removed during murine epidermis development through competitive behavior [14]. These studies suggest that cell competition is an actively regulated and an evolutionarily conserved mechanism of tissue development. In addition, newer studies in higher organisms have demonstrated that competitive behavior can result in multiple outcomes in addition to cell death of loser cells and expansion of winner cells. These will be highlighted below.

Mechanisms governing cell competition

A variety of mechanistic pathways have been implicated in cell competition. Here, we summarize recent experimental results from Drosophila and mammals which provide unique insights into how cells sense other cells during cell competition (Figure 2).

Figure 2. Mechanisms underlying Myc-induced cell competition in Drosophila.

Figure 2.

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In Myc-induced cell competition, an increase in protein synthesis is required for loser cells death and it is enhanced by increased glycolysis. Downregulation of oxidative phosphorylation (OXPHOS) induces loser cell apoptosis. Moreover, loser cell-specific expression of Flower and azot induces cell death.

Protein synthesis in cell competition

The molecular mechanisms through which winner cells sense loser cells, and vice versa, is an intense area of research. As discussed above, two factors involved in cell competition are ribosomal proteins, essential for growth, and Myc, an evolutionarily conserved activator of cell growth. An implication of these observations is that differential cell size or growth activity may be a cell-sensing cue. However, differential cell size or growth is not sufficient to drive cell competition. For example, clonal overexpression of Phosphoinositide 3-kinase (PI3K) or Cyclin-dependent kinase 4 (CDK4)/Cyclin D, regulators of cell growth in Drosophila [15, 16], results in the expansion of PI3K or CDK4/cyclin D-expressing clones but not cell death of neighboring wild type cells [9]. Others have proposed that mRNA translation and protein synthesis could be the driver of cell competition. In accord, it has been demonstrated that cell competition which is induced by Myc overexpression can be suppressed by lowering the expression of ribosomal protein L19 in Myc-overexpressing cells [10], while elimination of Minute mutant cells is rescued upon elevation of protein synthesis rates [17]. This data indicate that decreased or increased protein synthesis in winner and loser cells, respectively, suppresses cell competition. Additionally, loser cells have lower expression of ribosomal proteins and rates of protein synthesis compared to winner cells in the murine epidermis and mouse epiblast, two locations where competitive behavior between cells has been observed [13, 14]. Taken together, these data raise the possibility that winner and loser cells have differential protein synthesis rates and that these differences regulate cell competition in an evolutionarily conserved manner. It will be interesting to determine whether winner and loser cells specifically sense differences in rates of protein synthesis between them, and if so, how this sensing mechanism triggers cell competition.

The role of energy metabolism in competitive behavior

Energy metabolism has also been implicated in governing competitive behavior. Myc overexpression increases rates of glycolysis in the Drosophila wing disc. Glycolysis rates are further increased when Myc-overexpressing cells surround wild type cells, resulting in the selective elimination of wild type cells [18]. Specific changes in metabolic enzyme function has also been observed in loser cells in mammals. Cells expressing an oncogenic mutant form of RasG12V (glycine is replaced by valine at position 12 and results in constitutively active Ras signaling) are removed by surrounding wild type cells in Madin-Darby Canine Kidney cell culture. RasG12V-expressing cells exhibit diminished mitochondrial oxidative phosphorylation capacity which is inhibited by Pyruvate Dehydrogenase Kinase 4 (PDK4) [19]. Knockdown of PDK4 in the RasG12V cells reduces their rate of elimination, indicating that oxidative phosphorylation can modulate cell competition. It will be important to determine if specific metabolic pathways are directly orchestrating cell competition or whether metabolic health, in general, mediates fitness. Moreover, it will be exciting to apply emerging technologies enabling measurement of individual metabolites at single cell resolution to the study of cell competition. This will provide researchers the tools to understand if and how a range of metabolic fitness might direct the overall health of a tissue.

Transcriptional control of winner and loser cells

As described above, wild type cells are eliminated when surrounded by Myc-overexpressing cells [9, 10]. Hence, it is likely that cell competition induces differential gene expression. To explore this, the Moreno group performed transcriptome analysis of loser cells and identified genes specifically induced during cell competition [20–22]. Among them, Flower is required for cell competition-induced elimination. In Drosophila, Flower is encoded by three major isoforms: Fweubi, FweLose-A, and FweLose-B. Fweubi is ubiquitously expressed in normal tissue. In contrast, FweLose-A and FweLose-B are specifically expressed in loser cells during cell competition, but not expressed in the absence of competitive behavior. Interestingly, mosaic ectopic expression of the loser-specific FweLose-A and FweLose-B isoforms is sufficient to induce cell death in a cell autonomous fashion even in the absence of cell competition. In contrast, ectopic expression of FweLose-A or FweLose-B in all cells of the wing imaginal disc does not induce cell death. Moreover, deletion of Flower in both winner and loser cells blocks cell competition-induced apoptosis. These results indicate that differential Flower isoform expression in winner and loser cells (FweUbi in winner cells and FweLose-A or FweLose-B in loser cells) is required for cell competition. Importantly, expression of loser-specific Flower isoforms is induced by heterozygous mutation of genes encoding ribosomal protein (Minute+/−) as well as during Myc-mediated cell competition. This suggests that the change in expression of Flower isoforms may be a general mechanism of sensing differential cell fitness. Flower is a putative calcium channel, but the downstream action of Flower is unknown, nor is it understood whether calcium flux is required for cell competition. It is of great interest to elucidate these functions and reveal additional regulators of cell competition.

Examples of cell competition and the biological consequences

Since the initial studies of cell competition in Drosophila, similar phenomena have been characterized in a number of other cell types across multiple organisms, such as pluripotent stem cells, neurons, and cardiomyocytes [23–25]. Moreover, there is an increasing effort towards understanding the biological impact of cell competition on tissue health and how mis-regulation of cell competition contributes to disease. In this section, we specifically discuss the role of cell competition in progenitor cells, tumorigenesis, tissue homeostasis and aging.

a. Competition in progenitor populations

Recently, the Fuchs laboratory demonstrated that Myc heterozygous mutant clones are eliminated by cell competition during mouse epidermis development [14]. They first clonally deleted a single copy of Myc during embryogenesis by injecting low-titer lentiviruses harboring the Cre recombinase into Mycflox/+ mice. During early murine gestation, Myc+− cells had a growth disadvantage compared to wild type cells, and died when they contacted wild type cells. However, in late embryogenesis, Myc+/− cells were not eliminated by apoptosis, but instead, differentiated and were thus eliminated from the epidermal stem cell pool. This important result indicated that a powerful mechanism of stem cell homeostasis is elimination of loser stem cells via differentiation. Concordant with this result, another study performed in the murine adult epidermis demonstrated that lower fitness stem cells, labeled by low expression of the hemidesmosome component Collagen XVII (COL17A1), more frequently differentiate than stem cells with greater fitness, labeled by high expression of COL17A1 [26]. COL17A1 expression is downregulated during aging and when cells are exposed to genotoxic stress such as ultraviolet light, and COL17A1 overexpression prevents aging-associated epidermal dysfunction, indicating that the fitness of stem cells correlates with COL17A1 expression level. Taken together, these results suggest that progenitor pools in the mammalian epidermis can maintain the health of the progenitor pool by eliminating reduced fitness cells via differentiation induced by competition.

Reduced fitness heterozygous Minute mutant intestinal stem cells are eliminated by both cell competition and induced proliferation of adjacent wild type stem cells in Drosophila [27]. This is likely due to reciprocal cytokine signaling between the wild type and mutant cells. These results further indicate that multiple outcomes can result from cell competition, including death, differentiation, and proliferation. It will be important to determine if secreted molecules governing bidirectional communication between cell types are conserved across different tissues and organisms.

Clonal dynamics and cell competition have recently been investigated during induced pluripotent stem cell (iPSC) generation from mouse embryonic fibroblasts (MEFs) [28]. Previous studies in the field have demonstrated that cell competition regulates pluripotency in vitro [25, 29, 30]. More recently, Shakiba, Fahmy, and colleagues employed a creative DNA barcoding strategy, labeling thousands of MEFs in a seemingly homogenous population, to determine whether all cells are equally capable of reprogramming or if some cells are more likely to undergo reprogramming. If all cells have an equal potential to reprogram into iPSCs, then the expectation would be representation of thousands of unique bar codes in the iPSC clones (clonal equipotency). If an “elite” group of cells drives the majority of the reprogramming process, then only a subset of bar codes would be represented in the iPSC clones. Strikingly, their results demonstrated the latter; only a handful of barcodes were represented in iPSC colonies. The authors discovered that even though individual MEF cells can undergo reprogramming, the dynamics are skewed in population-based assays. These results are all consistent with cell competition regulating iPSC reprograming in a population. Intriguingly, by using a fluorescent reporter, the authors also demonstrated that Wnt1-expressing MEFs harbor a competitive advantage. It is important to determine if Wnt1 expression is a stable property of a subset of MEFs, or a transient property which can be acquired. If it is the case that Wnt1 expression is acquired, it will be critical to elucidate the determinants of its expression in this model system. In addition, real time imaging will greatly advance our understanding of how Wnt1+ MEFs interact with adjacent Wnt1- MEFs during reprogramming.

b. Cell competition in cancer: tumor-promotion vs tumor-suppression

Aspects of oncogenic transformation and cancer growth provide a natural example of mis-regulated cell competition. Unbalanced cell growth can be a result of cell competition as cells which undergo oncogenic transformation often have a competitive growth advantage compared to surrounding cells. Work from the Moreno group supports a role for cell competition in oncogenic transformation and cancer growth. As described above, certain isoforms of Flower are specifically expressed in loser cells in Drosophila. Mammalian cells express four isoforms of Flower (FWE1–4), and cells expressing FWE2 or FWE4 induce apoptosis of cells expressing FWE1 or FWE3 upon co-culture. These results indicate that FWE2 or FWE4 expression correlates with winner cell characteristics and FWE1 or FWE3 expression correlates with loser cell characteristics [31]. Human breast and colon cancer cells highly express a winner form of FWE, whereas neighboring stromal cells express loser forms of FWE at high levels. Loss of winner FWE isoforms in the cancer cells reduces tumor growth when injected into a host mouse as part of a xenograft model. These results suggest that FWE-mediated cell competition can modulate tumorigenesis, and additional in vivo models will yield new insights into FWE function.

Components of the Notch signaling pathway are also frequently mutated in multiple types of cancer [32–34]. Mastermind like 1 (MAML1) is required for Notch intracellular domain transactivation [35], and decreasing Notch signaling by clonally expressing a dominant-negative form of MAML1 in esophageal progenitor cells results in expansion of mutant cells in vivo [36]. The mutant progenitor cells eliminate neighboring wild type stem cells by inducing their differentiation. In addition, Adenomatous polyposis coli (APC) has been known to be tumor suppressor and frequently mutated in colon cancer [37]. Loss of APC results in precocious Wnt signaling. In the Drosophila intestine, APC mutants induce apoptosis of neighboring wild type cells. However, expression of the anti-apoptotic protein Drosophila Inhibitor of Apoptosis 1 (DIAP1) in the wild type cells limits APC mutant cell expansion. These results indicate that apoptosis-mediated cell competition is required for tumorigenesis [38]. Collectively, these genetic studies indicate that cell competition mechanisms might be hijacked by tumor cells to preferentially promote growth of oncogenic cells as compared to wild type cells.

Conversely, tumor cells can also be eliminated by neighboring cells through cell competition. Genetic screens in Drosophila identified a group of tumor suppressor genes, scribble, discs large, and lethal (2) giant larvae, that are essential for maintenance of cell polarity [39–41]. Loss of any of these genes in all cells of a tissue results in overgrowth of the tissue [42]. However, when mutant and wild type cells coexist together in a mosaic fashion, mutant cells are preferentially removed via competition [43, 44]. Again, these experiments suggest that wild type cells sense tumor cells and can eliminate them through cell competition. Similar paradigms have been observed in mammalian cells. Cells that express RasG12V are eliminated upon contact wild type cells both in vitro and in the murine intestine [19, 45]. Presumably, tumor cells can evolve mechanisms to evade this elimination, as RAS mutations are often found in intestinal tumors [46]. More recently, this paradigm has been extended to the hair follicle niche [47]. Live imaging demonstrated that wild type cells will surround cells which have been induced to activate β-catenin, and Wnt-High cells are eliminated. This elimination of mutant cells is significantly impaired upon abrogation of Wnt signaling in neighboring wild type cells, indicating that wild type cells actively sense and remove oncogenic mutant cells. Elucidating the molecular players which instruct sensing will be critical as it might inform how such mutant cells can bypass these mechanisms and expand.

Additional, non-genetic, physiologic stimuli likely impact cell competition in the context of cancer. For example, low dose ionizing radiation results in p53-mutant cells to outcompete normal cells in the mouse esophagus [48]. Moreover, various clinical studies have also demonstrated that obesity is a risk factor for cancer [49, 50]. There are likely multiple explanations for these observations, but intriguingly, mice fed a high-fat diet demonstrate a reduced ability to eliminate tumor cells overexpressing RasG12V [51], suggesting that non-genetic factors might impact cell competition mechanisms in tumorigenesis.

c. Cell competition in tissue homeostasis and aging

Somatic cells will accumulate mutations over time, and multiple mechanisms operate to eliminate cells that have become unfit. The Moreno group identified azot, a protein related to calmodulin, and showed that it is specifically expressed in loser cells in the imaginal disc [22]. Their experiments indicated that azot expression labels loser cells destined to be eliminated and is required for elimination of loser cells. Azot-null Drosophila have a shorter lifespan compared to control flies and demonstrate precocious aging-related changes, including neurodegenerative vacuoles. The group extended these observations by knocking out azot and simultaneously driving expression of the pro-apoptotic factor hid from the azot promoter, which rescued the azot knockout lifespan phenotype. Collectively, these observations strongly suggest that azot-mediated cell death in cells with reduced fitness is required for normal lifespan and health span.

In mammals, a variety of epidemiologic data also support a role for clonal expansion cell competition in a variety of aging diseases. For example, it has been well-established in humans that clonal hematopoiesis, the expansion of blood cell clones derived from a somatically mutated stem cell, is an aging-related process. Clones are infrequently detected in individuals under age 40, but the chances of detecting a clone increase in a nearly stepwise manner with age thereafter [52, 53]. Whereas malignant clonal hematopoiesis can result in myelodysplastic syndrome and acute myeloid leukemia, non-malignant clonal hematopoiesis which harbor oncogenic mutation (clonal hematopoiesis of indeterminate potential, CHIP) has been linked to worse cardiovascular outcomes and accelerated atherosclerotic burden [54]. Many individuals with CHIP have been found to carry mutations in Tet Methylcytosine Dioxygenase 2 (Tet2), Tumor Protein P53 (TP53) and protein phosphatase, Mg2+/Mn2+ dependent 1D (PPM1D) [55–57], and models better recapitulating the human condition are needed to delineate how clonal hematopoiesis contributes to cardiac disease. As many of the mutations associated with clonal hematopoiesis encompass a diverse group of epigenetic factors, it is possible they converge on a final common pathway resulting in epigenetic dysregulation of vulnerable cell types. Alternatively, clonal hematopoiesis itself might be sensed by numerous cell types, resulting in worsening outcomes. Reconciling these two, non-mutually exclusive possibilities, will require a deeper understanding of the pathobiology underlying clonal hematopoiesis. The expansion of clones which carry somatic mutations has been also observed in other tissues, skin and esophagus [58–60]. The authors sequenced the genomes of biopsy specimens from multiple individuals. They found that the mutant clones carrying somatic mutations in cancer-related genes, such as NOTCH and TP53, are expanded in aging, and it is possible that these mutant clones eventually compromise tissue function and/or develop into cancer. Finally, in a pioneering series of assays, multiple groups have demonstrated the ability to infer clonality from mitochondrial DNA mutations. Mitochondria DNA is readily available from current single cell expression and accessibility assays, and by comparing the pattern of mutation in mitochondria DNA across thousands of cells, clonal relationships can be inferred [61, 62]. It will be exciting to apply these technologies to banked tissues from both control and diseased specimens to understand how clonal expansion, and potentially cell competition, instructs development and disease in various solid organs.

Concluding remarks

Since cell competition was first observed in Drosophila, experiments utilizing fly models have identified molecular regulators of cell competition and highlighted the importance of cell competition in tissue development and homeostasis. In addition, we have begun to understand how competitive behavior is regulated in higher organisms. Despite these findings, many important questions remain to be answered (See Outstanding Questions). One of the most important questions focuses on defining the molecular basis of “cellular fitness” and how different levels of fitness can be actively sensed by winner and loser cells. Although protein synthesis rates have been proposed as one such mechanism, it seems unlikely that only a single cellular pathway can govern this dynamic process. Hence, identifying the molecular and cellular cues which mediate communication between cells of differing fitness is also of intense interest. Transcriptomic analysis by the Moreno group reported that Flower and azot are specifically expressed in loser cells in Drosophila. However, the molecular mechanisms upstream and downstream of Flower and azot expression are still unclear. Secreted molecules or metabolites generated in winner cells could induce loser cell elimination. It will be exciting to address these mechanistic questions in a variety of contexts and model systems. Unbiased genome-wide screening using CRISPR (clustered regularly interspaced short palindromic repeats) technologies might be helpful in answering these questions, especially if assays reporting cell competition activity can be developed. Such experiments will allow the field to decipher cell-type specific mechanisms guiding cell competition versus those employed more broadly. Moreover, it will be exciting to manipulate molecular determinants of cell competition to induce “winner” cells to “loser” in mammalian cell types, and vice versa. This will allow us to decipher whether winner and loser status is a stable property of specific cells, or a transient property of cells that can be acquired and lost.

Outstanding Questions Box.

  • How do cells sense the fitness levels of adjacent cells and what is the molecular determinants of sensing?

  • How does cell competition orchestrate physiologic tissue development and homeostasis?

  • Which human tissues exhibit cell competition, and does disruption of competitive behavior affect disease progression other than cancer?

Most studies in cell competition have been conducted using genetic models which induce an artificial mutation. Though these studies have been incredibly insightful, it will be important to determine if the same mechanisms elucidated in these models regulate cell competition during physiologic growth. Moreover, uncovering natural triggers of cell competition, as opposed to inducing mutations in genes, such as mechanical stress caused by overcrowding, will likely prove to be an intriguing avenue of study [63, 64]. In addition, the studies discussed above highlight how outcomes of cell competition can have multiple consequences, including cell death, differentiation and even proliferation. These highlight how the result of competitive behavior can be context specific, and hence it will be important to understand how these outcomes differ in a lineage-specific manner both during development and disease pathogenesis. Recent advances in single cell expression and epigenetic assays will undoubtedly aid in understanding competitive behavior, a field not easily amenable to study using population-based studies. As next generation sequencing methods, depths and throughputs improve, these advances will allow the field to correlate transcriptional and epigenetic characteristics to winner and loser cells status in various cell types in development and disease. Finally, combining single-cell lineage tracing methods using mitochondrial DNA mutations [61, 62] or evolving barcoding technologies [65] and real time imaging will certainly provide new insights into how cell competition is utilized by various tissues and the molecular mechanisms that guide competition.

Highlights.

  • Cell competition has emerged as critical regulator of tissue development and homeostasis across species.

  • Competitive behavior can result in multiple outcomes, including cell survival, differentiation, and proliferation.

  • Defects in cell competition likely contribute to multiple diseases.

Acknowledgments

We thank the Jain laboratory, especially Parisha P. Shah, Ashley Karney, Ricardo Linares and Arjun Raj for critical feedback and thoughtful discussions. The Jain laboratory is supported by the NIH (New Innovator Award DP2 HL147123, R01 HL139783, and Transformative Research Award R01 GM137425), the Burroughs Wellcome Foundation (Career Award for Medical Scientists), NSF 15-48571, and funds from the American Heart Association and Allen Foundation.

Footnotes

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