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Cell competition is an evolutionarily conserved quality control process that eliminates suboptimal or potentially dangerous cells. Although differential metabolic states act as direct drivers of competition, how these are measured across tissues is not understood. Here, we demonstrate that vesicular glutamate transporter (VGlut) and autocrine glutamate signaling are required for cell competition and Myc -driven super-competition in the Drosophila epithelia. We find that the loss of glutamate-stimulated VGlut>NMDAR>CaMKII>CrebB signaling triggers loser status and cell death under competitive settings via the autocrine induction of TNF. This in turn drives TNFR>JNK activation, triggering loser cell elimination and PDK/LDH-dependent metabolic reprogramming. Inhibiting caspases or preventing loser cells from transferring lactate to their neighbors nullifies cell competition. Further, in a Drosophila model for premalignancy, Myc -overexpressing clones co-opt this signaling circuit to acquire super-competitor status. Targeting glutamate signaling converts Myc "super-competitor" clones into "losers," highlighting new therapeutic opportunities to restrict the evolution of fitter clones. [Display omitted] • Glutamate signaling surveys epithelial fitness through cell competition • Loss of glutamate signaling results in autocrine TNF-induced loser elimination • Loser cells undergo metabolic reprogramming and transfer lactate to winners • Mychigh cells promote and depend on glutamate signaling to outcompete neighbors Soares et al. show that differential levels of VGlut>NMDAR>CaMKII-mediated glutamate signaling regulate epithelial fitness, in which loser cells undergo TNF-induced elimination and donate their carbon fuel to winners. Targeting this signaling axis converts Myc super-competitors into losers. [ABSTRACT FROM AUTHOR]

p53 was discovered 45 years ago as an SV40 large T antigen binding protein, coded by the most frequently mutated TP53 gene in human cancers. As a transcription factor, p53 is tightly regulated by a rich network of post-translational modifications to execute its diverse functions in tumor suppression. Although early studies established p53-mediated cell-cycle arrest, apoptosis, and senescence as the classic barriers in cancer development, a growing number of new functions of p53 have been discovered and the scope of p53-mediated anti-tumor activity is largely expanded. Here, we review the complexity of different layers of p53 regulation, and the recent advance of the p53 pathway in metabolism, ferroptosis, immunity, and others that contribute to tumor suppression. We also discuss the challenge regarding how to activate p53 function specifically effective in inhibiting tumor growth without harming normal homeostasis for cancer therapy. p53 plays a central role in suppressing tumorigenesis. In this issue, Liu et al. review the complexity of different layers of p53 regulation, and the recent advance of the p53 pathway in metabolism, ferroptosis, immunity, and others that largely expand the scope of its anti-tumor activity. [ABSTRACT FROM AUTHOR]

Complex multicellular organisms require quantitative and qualitative assessments on each of their constitutive cell types to ensure coordinated and cooperative behavior towards overall functional proficiency. Cell competition represents one of the operating arms of such quality control mechanisms and relies on fitness comparison among individual cells. However, what is exactly included in the fitness equation for each cell type is still uncertain. Evidence will be discussed to suggest that the ability of the cell to integrate and collaborate within the organismal community represents an integral part of the best fitness phenotype. Thus, under normal conditions, cell competition will select against the emergence of altered cells with disruptive behavior towards tissue integrity and/or tissue pattern formation. On the other hand, the winner phenotype prevailing as a result of cell competition does not entail, by itself, any degree of growth autonomy. While cell competition per se should not be considered as a biological driving force towards the emergence of the neoplastic phenotype, it is possible that the molecular machinery involved in the winner/loser interaction could be hijacked by evolving cancer cell populations. [ABSTRACT FROM AUTHOR]

Collective behaviour emerges from interacting units within communities, such as migrating herds, swimming fish schools, and cells within tissues. At the microscopic level, collective behaviours include collective cell migration in development and cancer invasion, rhythmic gene expression in pattern formation, cell competition in homeostasis and cancer, force generation and mechano-sensing in morphogenesis. Studying the initiation and the maintenance of collective cell behaviours is key to understand the principles of development, regeneration and disease. However, the manifold influences of contributing factors in in vivo environments challenge the dissection of causalities in animal models. As an alternative model that has emerged to overcome this difficulty, in vitro three-dimensional organoid cultures provide a reductionist approach yet retain similarities with the in vivo tissue in cellular composition and tissue organisation. Here, we focus on recent progresses in studying collective behaviours in different organoid systems and discuss their advantages and the possibility of improvement for future applications. [ABSTRACT FROM AUTHOR]

How tumors arise or the cause of precancerous lesions is a fundamental question in cancer biology. It is generally accepted that tumors originate from normal cells that undergo uncontrolled proliferation owing to genetic alterations. At the onset of adenoma formation, cancer driver mutations confer clonal growth advantage, enabling mutant cells to outcompete and eliminate the surrounding healthy cells. Hence, the development of precancerous lesions is not only attributed to the expansion of pre-malignant clones, but also relies on the relative fitness of mutated cells compared to the neighboring cells. Colorectal cancer (CRC) is an excellent model to investigate cancer origin as it follows a stereotypical process from mutant cell hyperplasia to adenoma formation and progression. Here, we review the evolving understanding of colonic tumor development, focusing on how cell intrinsic and extrinsic factors impact cell competition and the "clone war" between cancer-initiating cells and normal stem cells. We also discuss the promises and limitations of targeting cell competitiveness in cancer prevention and early intervention. The field of tumor initiation is currently in its infancy, elucidating the adenoma origin is crucial for designing effective prevention strategies and early treatments before cancer becomes incurable. • We review cell intrinsic and extrinsic factors that impact cell competition and adenoma onset. • We review cancer stem cells and cancer niche. • We review cancer metabolism and tumor initiation. • We discuss the current state and future directions of colon cancer prevention and early intervention. [ABSTRACT FROM AUTHOR]

The comparison of fitness between cells leads to the elimination of less competent cells in the presence of more competent neighbors via cell competition (CC). This phenomenon has been linked with several cancer-related genes and thus may play an important role in cancer. Various processes are involved in the regulation of tumor initiation and growth, including tumor hypoxia, clonal stem cell selection, and immune cell response, all of which have been recently shown to have a potential connection with the mechanisms involved in CC. This review aims to unravel the relation between these processes and competitive cell interactions and how this affects disease progression. Various pathways are involved in cell competition (CC), which tumor cells rely on to acquire a competitive advantage leading to growth and metastasis. Hypoxia is characterized by low oxygen levels; CC and hypoxia have been associated, as the expression of some CC-related genes is influenced by hypoxia-inducible factors and influences cancer outcome. Clonal stem cell selection contributes to tumor heterogeneity since the development of mutations in a fraction of stem cells in a niche can lead to their selection. This heterogeneity contributes to competition, which ultimately affects cancer detection, targeting, and prognosis. CC maintains immune homeostasis, function, and development, which prevents immune malignancies. [ABSTRACT FROM AUTHOR]

Cell competition is a short-range intercellular communication, in which cells compare their fitness with that of their neighbors and eliminate the cells with relatively lower fitness. It is considered important for the formation and maintenance of healthy tissues; however, its exact role during development, especially in mammals, has been obscure. Recent studies in mouse embryonic epiblast and skin tissues revealed that cell differentiation in early embryos and stem cell proliferation tends to produce suboptimal cells, especially during early developmental stages. Cell competition occurs at multiple stages and via multiple mechanisms during development to ensure elimination of such low-quality cells. Thus, quality control via cell competition supports correct development by overcoming the heterogeneity produced during cell differentiation and stem cell proliferation. [ABSTRACT FROM AUTHOR]

The process of embryonic development involves remarkable cellular plasticity, which governs the coordination between cells necessary to build an organism. One role of this plasticity is to ensure that when aberrant cells are eliminated, growth adjustment occurs so that the size of the tissue is maintained. An important regulator of cellular plasticity that ensures cellular cooperation is a fitness-sensing mechanism termed cell competition. During cell competition, cells with defects that lower fitness but do not affect viability, such as those that cause impaired signal transduction, slower cellular growth, mitochondrial dysregulation or impaired protein homeostasis, are killed when surrounded by fitter cells. This is accompanied by the compensatory proliferation of the surviving cells. The underlying factors and mechanisms that demarcate certain cells as less fit than their neighbouring cells and losers of cell competition are still relatively unknown. Recent evidence has pointed to mitochondrial defects and proteotoxic stress as important hallmarks of these loser cells. Here, we review recent advances in this area, focussing on the role of mitochondrial activity and protein homeostasis as major mechanisms determining competitive cell fitness during development and the importance of cell proteostasis in determining cell fitness. [ABSTRACT FROM AUTHOR]

In the Drosophila testis, a group of stromal cells termed hub provides multiple niche signals for the surrounding germline and somatic stem cells. Stem cells of both populations compete for physical retention in the niche, and clones unable to transduce any one niche signal are rapidly eliminated from the stem cell pool by differentiation. We have mapped the transcriptomes of isolated somatic cyst stem cells and differentiated cyst cells, and found that the stem cells but not their differentiated progeny exhibit the signature of an innate immune response including the NF-κB transcription factor Relish (Rel). Related signalling pathways had previously implicated in cell competition in larval epithelia, prompting the question of whether NF-κB signalling was, despite the clear differences between the two competition scenarios, also involved in stem cell competition in the testis. Here we show i) that in the testis Rel is dispensable for stemness, ii) that loss of Rel or the upstream receptor Toll suppresses loser elimination following a variety of different triggers used to induce loser fate, and iii) that clonal Rel activation is sufficient for the displacement of neutral or winner cells from the niche, even if these cells otherwise retain stem cell properties. • Somatic stem cells in the Drosophila testis niche are subject to intense cell competition. • Loser cells are eliminated from the stem cell pool by differentiation. • Activation of NF-κB / Rel signalling is both necessary and sufficient for the eviction of loser cells from the niche. • Rel is activated in loser cells by an unusual competitive signalling module downstream of Toll. • Rel activation only influences cell competition in the narrow sense, but does not affect neutral competition. • Participation in cell competition should be considered a distinct aspect of stemness as a compound physiological state. [ABSTRACT FROM AUTHOR]

Though burgeoning research manifests that cell competition, an essential selection and quality control mechanism for maintaining tissue or organ growth and homeostasis in multicellular organisms, is closely related to tumorigenesis and development, the mechanism of cell competition associated with tumor drug resistance remains elusive. In the study, we uncovered that oxaliplatin-resistant hepatocellular carcinoma (HCC) cells exhibit a pronounced competitive advantage against their sensitive counterparts, which is related to lipid takeover of resistant cells from sensitive cells. Of note, such lipid takeover is dependent on the existence of isocitrate dehydrogenase 1 (IDH1) in resistant HCC cells. Mechanistically, IDH1 activity is regulated by heat shock protein 90 alpha (HSP90α) through binding with each other, which orchestrates the expressions of lipid metabolic enzymes and lipid accumulation in resistant HCC cells. Our results suggest that HCC cell competition-driven chemoresistance can be regulated by HSP90α/IDH1-mediated lipid metabolism, which may serve as a promising target for overcoming drug resistance in HCC. • Oxaliplatin-resistant HCC cells eliminate sensitive HCC cells through cell competition. • Active lipid metabolism maintains the competitive dominance of oxaliplatin-resistant HCC in cell competition. • IDH1 upregulation promotes lipid takeover of oxaliplatin-resistant HCC cells from sensitive HCC cells. • HSP90α boosts oxaliplatin resistance via regulating IDH1-modulated lipid takeover in HCC. [ABSTRACT FROM AUTHOR]

Tumor-suppressive cell competition (TSCC) is a conserved surveillance mechanism in which neighboring cells actively eliminate oncogenic cells. Despite overwhelming studies showing that the unfolded protein response (UPR) is dysregulated in various tumors, it remains debatable whether the UPR restrains or promotes tumorigenesis. Here, using Drosophila eye epithelium as a model, we uncover a surprising decisive role of the Ire1 branch of the UPR in regulating cell polarity gene scribble (scrib) loss-induced TSCC. Both mutation and hyperactivation of Ire1 accelerate elimination of scrib clones via inducing apoptosis and autophagy, respectively. Unexpectedly, relative Ire1 activity is also crucial for determining loser cell fate, as dysregulating Ire1 signaling in the surrounding healthy cells reversed the "loser" status of scrib clones by decreasing their apoptosis. Furthermore, we show that Ire1 is required for cell competition in mammalian cells. Together, these findings provide molecular insights into scrib -mediated TSCC and highlight Ire1 as a key determinant of loser cell fate. [Display omitted] • Ire1 depletion promotes tumor-suppressive cell competition by inducing apoptosis • Ire1 overexpression cooperates with JNK to induce autophagy-dependent removal of scrib clone • Relative Ire1 activity between different cells is crucial to determine the loser cell fate • Ire1/ENR1 is required for cell competition in mammalian cells Zheng et al. investigate the role of the Ire1 branch of the UPR in regulating tumor-suppressive cell competition in Drosophila. They find that Ire1 activity is crucial for determining the fate of loser cells. Either downregulation or overexpression of Ire1 facilitates the elimination of loser cells via inducing apoptosis and autophagy, respectively. [ABSTRACT FROM AUTHOR]

Summary p53 is a tumor suppressor protein, and its missense mutations are frequently found in human cancers. During the multi-step progression of cancer, p53 mutations generally accumulate at the mid or late stage, but not in the early stage, and the underlying mechanism is still unclear. In this study, using mammalian cell culture and mouse ex vivo systems, we demonstrate that when p53R273H- or p53R175H-expressing cells are surrounded by normal epithelial cells, mutant p53 cells undergo necroptosis and are basally extruded from the epithelial monolayer. When mutant p53 cells alone are present, cell death does not occur, indicating that necroptosis results from cell competition with the surrounding normal cells. Furthermore, when p53R273H mutation occurs within RasV12-transformed epithelia, cell death is strongly suppressed and most of the p53R273H-expressing cells remain intact. These results suggest that the order of oncogenic mutations in cancer development could be dictated by cell competition. [ABSTRACT FROM AUTHOR]

Summary Recent studies have revealed that newly emerging transformed cells are often eliminated from epithelial tissues via cell competition with the surrounding normal epithelial cells. This cancer preventive phenomenon is termed epithelial defense against cancer (EDAC). However, it remains largely unknown whether and how EDAC is diminished during carcinogenesis. In this study, using a cell competition mouse model, we show that high-fat diet (HFD) feeding substantially attenuates the frequency of apical elimination of RasV12-transformed cells from intestinal and pancreatic epithelia. This process involves both lipid metabolism and chronic inflammation. Furthermore, aspirin treatment significantly facilitates eradication of transformed cells from the epithelial tissues in HFD-fed mice. Thus, our work demonstrates that obesity can profoundly influence competitive interaction between normal and transformed cells, providing insights into cell competition and cancer preventive medicine. [ABSTRACT FROM AUTHOR]

The RNA-binding protein Musashi-1 (MSI1) regulates the proliferation and differentiation of adult stem cells. However, its role in embryonic stem cells (ESCs) and early embryonic development remains poorly understood. Here, we report the presence of short C-terminal MSI1 (MSI1-C) proteins in early mouse embryos and mouse ESCs, but not in human ESCs, under conventional culture conditions. In mouse embryos and mESCs, deletion of MSI1-C together with full-length MSI1 causes early embryonic developmental arrest and pluripotency dissolution. MSI1-C is induced upon naive induction and facilitates hESC naive pluripotency acquisition, elevating the pluripotency of primed hESCs toward a formative-like state. MSI1-C proteins are nuclear localized and bind to RNAs involved in DNA-damage repair (including MLH1 , BRCA1 , and MSH2), conferring on hESCs better survival in human-mouse interspecies cell competition and prolonged ability to form blastoids. This study identifies MSI1-C as an essential regulator in ESC pluripotency states and early embryonic development. [Display omitted] • MSI1 is localized in the nucleus of naive ESCs but in the cytoplasm of primed ESCs • Short MSI1-C in naive pluripotency state regulates mRNA stability of pluripotency genes • MSI1-C facilitates primed-to-naive state transition of primed hESCs • MSI1-C binds to RNAs and regulates DNA-damage repair and stress resistance Chen et al. report the presence of short Musashi-1 protein (MSI1-C) that regulates the naive pluripotency of embryonic stem cells and early development. MSI1-C promotes the acquisition of naive pluripotency in human embryonic cells by regulating mRNA stability and DNA-damage repair and increasing stress resistance. [ABSTRACT FROM AUTHOR]

Comparative studies of primordial germ cell (PGC) development across organisms in many phyla reveal surprising diversity in the route of migration, timing and underlying molecular mechanisms, suggesting that the process of migration itself is conserved. However, beyond the perfunctory transport of cellular precursors to their later arising home of the gonads, does PGC migration serve a function? Here we propose that the process of migration plays an additional role in quality control, by eliminating PGCs incapable of completing migration as well as through mechanisms that favor PGCs capable of responding appropriately to migration cues. Focusing on PGCs in mice, we explore evidence for a selective capacity of migration, considering the tandem regulation of proliferation and migration, cell-intrinsic and extrinsic control, the potential for tumors derived from failed PGC migrants, the potential mechanisms by which migratory PGCs vary in their cellular behaviors, and corresponding effects on development. We discuss the implications of a selective role of PGC migration for in vitro gametogenesis. [ABSTRACT FROM AUTHOR]

Summary Primordial germ cells (PGCs) are vital for inheritance and evolution. Their transcriptional program has been extensively studied and is assumed to be well known. We report here a remarkable global upregulation of the transcriptome of mouse PGCs compared to somatic cells. Using cell-number-normalized genome-wide analyses, we uncover significant transcriptional amplification in PGCs, including mRNAs, rRNA, and transposable elements. Hypertranscription preserves tissue-specific gene expression patterns, correlates with cell size, and can still be detected in E15.5 male germ cells when proliferation has ceased. PGC hypertranscription occurs at the level of nascent transcription, is accompanied by increased translation rates, and is driven by Myc factors n-Myc and l-Myc (but not c-Myc) and by P-TEFb. This study provides a paradigm for transcriptional analyses during development and reveals a major global hyperactivity of the germline transcriptome. [ABSTRACT FROM AUTHOR]

Cell competition acts as a quality-control mechanism that eliminates cells less fit than their neighbors to optimize organ development. Whether and how competitive interactions occur between neural progenitor cells (NPCs) in the developing brain remains unknown. Here, we show that endogenous cell competition occurs and intrinsically correlates with the Axin2 expression level during normal brain development. Induction of genetic mosaicism predisposes Axin2-deficient NPCs to behave as "losers" in mice and undergo apoptotic elimination, but homogeneous ablation of Axin2 does not promote cell death. Mechanistically, Axin2 suppresses the p53 signaling pathway at the post-transcriptional level to maintain cell fitness, and Axin2-deficient cell elimination requires p53-dependent signaling. Furthermore, mosaic Trp53 deletion confers a "winner" status to p53-deficient cells that outcompete their neighbors. Conditional loss of both Axin2 and Trp53 increases cortical area and thickness, suggesting that the Axin2-p53 axis may coordinate to survey cell fitness, regulate natural cell competition, and optimize brain size during neurodevelopment. [Display omitted] • Endogenous cell competition occurs between neural progenitor cells (NPCs) • Genetic mosaics of Axin2 and Trp53 provoke cell competition between NPCs • Stabilization of p53 confers loser status to NPCs with mosaic Axin2 deficiency • Stem cell competition regulates brain size Sun et al. identify the presence of cell competition between neural progenitor cells in the early-developing mouse brain, defining regulation by Axin2 and Trp53. They also explore its potential role in brain size control. [ABSTRACT FROM AUTHOR]

Cells can globally upregulate their transcriptome during specific transitions, a phenomenon called hypertranscription. Evidence for hypertranscription dates back over 70 years but has gone largely ignored in the genomics era until recently. We discuss data supporting the notion that hypertranscription is a unifying theme in embryonic development, stem cell biology, regeneration, and cell competition. We review the history, methods for analysis, underlying mechanisms, and biological significance of hypertranscription. [ABSTRACT FROM AUTHOR]

Summary Cells dynamically interact throughout animal development to coordinate growth and deter disease. For example, cell-cell competition weeds out aberrant cells to enforce homeostasis. In Drosophila , tumorigenic cells mutant for the cell polarity gene scribble ( scrib ) are actively eliminated from epithelia when surrounded by wild-type cells. While scrib cell elimination depends critically on JNK signaling, JNK-dependent cell death cannot sufficiently explain scrib cell extirpation. Thus, how JNK executed cell elimination remained elusive. Here, we show that repulsive Slit-Robo2-Ena signaling exerts an extrusive force downstream of JNK to eliminate scrib cells from epithelia by disrupting E-cadherin. While loss of Slit-Robo2-Ena in scrib cells potentiates scrib tumor formation within the epithelium, Robo2-Ena hyperactivation surprisingly triggers luminal scrib tumor growth following excess extrusion. This extrusive signaling is amplified by a positive feedback loop between Slit-Robo2-Ena and JNK. Our observations provide a potential causal mechanism for Slit-Robo dysregulation in numerous human cancers. [ABSTRACT FROM AUTHOR]

Multicellular organisms evolved to resolve conflicts between individual cells, protecting the internal organization of the individual. This is illustrated by cell competition, a process that eliminates suboptimal cells from growing tissues by apoptosis. Since its early characterization in Drosophila an increasing number of conditions have been associated with competition, and mounting evidence demonstrates conservation of this process. We describe here the broad range of contexts that utilize cell competition, including tissue health, aging, and tumor development. We then delineate different models for the processes underlying the recognition and elimination of outcompeted cells. [ABSTRACT FROM AUTHOR]

While it is a relatively rare disease, glioblastoma multiform (GBM) is one of the more deadly adult cancers. Following current interventions, the tumor is never eliminated whatever the treatment performed; whether it is radiotherapy, chemotherapy, or surgery. One hypothesis to explain this poor outcome is the “cancer stem cell” hypothesis. This concept proposes that a minority of cells within the tumor mass share many of the properties of adult neural stem cells and it is these that are responsible for the growth of the tumor and its resistance to existing therapies. Accumulating evidence suggests that Ca 2 + might also be an important positive regulator of tumorigenesis in GBM, in processes involving quiescence, maintenance, proliferation, or migration. Glioblastoma tumors are generally thought to develop by co-opting pathways that are involved in the formation of an organ. We propose that the cells initiating the tumor, and subsequently the cells of the tumor mass, must hijack the different checkpoints that evolution has selected in order to prevent the pathological development of an organ. In this article, two main points are discussed. (i) The first is the establishment of a so-called “cellular society,” which is required to create a favorable microenvironment. (ii) The second is that GBM can be considered to be an organism, which fights to survive and develop. Since GBM evolves in a limited space, its only chance of development is to overcome the evolutionary checkpoints. For example, the deregulation of the normal Ca 2 + signaling elements contributes to the progression of the disease. Thus, by manipulating the Ca 2 + signaling, the GBM cells might not be killed, but might be reprogrammed toward a new fate that is either easy to cure or that has no aberrant functioning. This article is part of a Special Issue entitled: Calcium and Cell Fate . Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen. [ABSTRACT FROM AUTHOR]

Background & Aims The regenerative potential of the liver declines with age, this might be dependent on a decrease in the intensity of the stimulus and/or an increased refractoriness of the target. In the present study, we compared the in vivo growth capacity of young and old hepatocytes transplanted into the same host. Methods We utilized the retrorsine (RS)-based model for liver repopulation, which provides a specific and effective stimulus for transplanted hepatocytes. Rats of the dipeptidyl-peptidase type IV (DPP-IV)-deficient strain were given RS and were injected with a mix of hepatocytes isolated from either a 2-month old or an 18-month old donor. To follow the fate of transplanted cells, they were each identified through a specific tag: young hepatocytes expressed the green fluorescent protein (GFP + ), while those from old donors were DPP-IV-positive. Results At 1 month post-transplantation, DPP-IV-positive clusters (derived from old donor) were consistently smaller than those GFP + (young donor); the cross sectional area of clusters was decreased by 50%, while the mean volume was reduced to 1/3. Furthermore, when 2/3 partial hepatectomy (PH) was performed, the S-phase response of old hepatocyte-derived clusters was only 30–40% compared to that observed in cluster originating from young hepatocytes. No markers of cell senescence were expressed in clusters of transplanted hepatocytes. Conclusions This is the first direct evidence in vivo that hepatocytes in the aged liver express a cell-autonomous decline in their replicative capacity and in their regenerative response to PH compared to those from a young animal. [ABSTRACT FROM AUTHOR]

The identification of the Drosophila homolog of the human MYC oncogene has fostered a series of studies aimed to address its functions in development and cancer biology. Due to its essential roles in many fundamental biological processes it is hard to imagine a molecular mechanism in which MYC function is not required. For this reason, the easily manipulated Drosophila system has greatly helped in the dissection of the genetic and molecular pathways that regulate and are regulated by MYC function. In this review, we focus on studies of MYC in the fruitfly with particular emphasis on metabolism and cell competition, highlighting the contributions of this model system in the last decade to our understanding of MYC's complex biological nature. This article is part of a Special Issue entitled: Myc proteins in cell biology and pathology. [ABSTRACT FROM AUTHOR]

Cell competition is a process by which unwanted cells are eliminated from tissues. Apical extrusion is one mode whereby normal epithelial cells remove transformed cells, but it remains unclear how this process is mechanically effected. In this study, we show that autophagic and endocytic fluxes are attenuated in RasV12-transformed cells surrounded by normal cells due to lysosomal dysfunction, and that chemical manipulation of lysosomal activity compromises apical extrusion. We further find that RasV12 cells deficient in autophagy initiation machinery are resistant to elimination pressure exerted by normal cells, suggesting that non-degradable autophagic vacuoles are required for cell competition. Moreover, in vivo analysis revealed that autophagy-ablated RasV12 cells are less readily eliminated by cell competition, and remaining transformed cells destroy ductal integrity, leading to chronic pancreatitis. Collectively, our findings illuminate a positive role for autophagy in cell competition and reveal a homeostasis-preserving function of autophagy upon emergence of transformed cells. [Display omitted] • Autophagic flux is impaired in RasV12-transformed cells surrounded by normal cells • Reduced lysosomal activity perturbs autophagic activity • Non-degradable autophagosomes facilitate apical elimination of RasV12 cells • Defective autophagy inhibits cell competition and causes chronic pancreatitis in mice Akter et al. demonstrate that non-degradable autophagic vacuoles that result from reduced lysosomal activity are required for RasV12-transformed cells to be apically extruded by cell competition. [ABSTRACT FROM AUTHOR]

Highlights: [•] Compensatory cellular hypertrophy (CCH) as a conserved tissue repair system. [•] CCH during cell competition in postmitotic tissues. [•] CCH during wound healing in postmitotic tissues. [•] Loss of local tissue volume triggers CCH in postmitotic tissues. [Copyright &y& Elsevier]

In vertebrates, newly emerging transformed cells are often apically extruded from epithelial layers through cell competition with surrounding normal epithelial cells. However, the underlying molecular mechanism remains elusive. Here, using phospho-SILAC screening, we show that phosphorylation of AHNAK2 is elevated in normal cells neighboring RasV12 cells soon after the induction of RasV12 expression, which is mediated by calcium-dependent protein kinase C. In addition, transient upsurges of intracellular calcium, which we call calcium sparks, frequently occur in normal cells neighboring RasV12 cells, which are mediated by mechanosensitive calcium channel TRPC1 upon membrane stretching. Calcium sparks then enhance cell movements of both normal and RasV12 cells through phosphorylation of AHNAK2 and promote apical extrusion. Moreover, comparable calcium sparks positively regulate apical extrusion of RasV12-transformed cells in zebrafish larvae as well. Hence, calcium sparks play a crucial role in the elimination of transformed cells at the early phase of cell competition. [Display omitted] • Phosphorylation of AHNAK2 is elevated in normal cells neighboring transformed cells • TRPC1-mediated calcium sparks in normal cells mediate the AHNAK2 phosphorylation • Calcium sparks promote tissue fluidity and apical extrusion of transformed cells • Comparable calcium sparks regulate apical extrusion in cultured cells and zebrafish Kuromiya et al. use mammalian cell culture and zebrafish systems to show that calcium sparks frequently occur in normal epithelial cells neighboring RasV12-transformed cells at the early phase of cell competition. Calcium sparks then promote epithelial tissue fluidity and apical extrusion of transformed cells through the phosphorylation of AHNAK2. [ABSTRACT FROM AUTHOR]

Tumor-suppressive cell competition is an evolutionarily conserved process that selectively removes precancerous cells to maintain tissue homeostasis. Using the polarity-deficiency-induced cell competition model in Drosophila , we identify Toll-6, a Toll-like receptor family member, as a driver of tension-mediated cell competition through α-Spectrin (α-Spec)-Yorkie (Yki) cascade. Toll-6 aggregates along the boundary between wild-type and polarity-deficient clones, where Toll-6 physically interacts with the cytoskeleton network protein α-Spec to increase mechanical tension, resulting in actomyosin-dependent Hippo pathway activation and the elimination of scrib mutant cells. Furthermore, we show that Spz5 secreted from fat body, the key innate organ in fly, facilitates the elimination of scrib clones by binding to Toll-6. These findings uncover mechanisms by which fat bodies remotely regulate tumor-suppressive cell competition of polarity-deficient tumors through inter-organ crosstalk and identified the Toll-6-α-Spec axis as an essential guardian that prevents tumorigenesis via tension-mediated cell elimination. [Display omitted] • Loss of Toll-6 prevents the elimination of scrib mutant clones • Toll-6 acts through α-Spec to regulate Hippo pathway-dependent cell competition • Fat body-derived Spz5 remotely promotes elimination of precancerous clones Using a polarity-deficiency-induced cell competition model, Kong et al. show how loser clones are eliminated by actomyosin-dependent Hippo pathway activation. The authors uncover Toll-6 as an essential membrane receptor that actively removes losers through the cytoskeletal network and demonstrate that fat body-derived Spz5 boosts the loser clones' elimination. [ABSTRACT FROM AUTHOR]

Within tissues, cells sense differences in fitness levels and this can lead to fitter cells eliminating less fit, albeit viable, cells via competitive cell interactions. The involvement of several cancer-related genes in this phenomenon has drawn attention to a potential connection between competitive cell interactions and cancer. Indeed, initial studies found that tumor-promoting genes can turn cells into ‘supercompetitors’, able to kill normal cells around them. However, more recently it has been observed that cells harboring certain cancer-promoting mutations can be eliminated by surrounding normal cells, suggesting that competitive cell interactions could also have a tumor-suppressive role. These findings suggest a new view whereby tumor and host cells engage in a bidirectional tug of war, the outcome of which may have a profound impact on disease progression. [Copyright &y& Elsevier]

Abstract: During the initial stages of carcinogenesis, neoplastic transformation occurs in single epithelial cells and the transformed cells proliferate while being surrounded by normal epithelia. In Drosophila, normal and transformed epithelial cells compete with each other for survival, a process called cell competition. However, it was not known whether comparable phenomena also occur in mammals. Recently, several reports have shown that the interaction between normal and transformed epithelial cells causes various phenomena in mammals. For example, with elaborate cell culture systems that express oncoproteins or knockdown tumour suppressor proteins in an inducible manner, certain types of transformed cells have been shown to be apically eliminated from normal epithelial layers in an apoptosis-dependent or -independent manner. During the process of apical extrusion, various signalling pathways are modulated in transformed cells located within the normal epithelium, indicating that the presence of surrounding normal epithelial cells affects the behaviour and fate of transformed cells. Recent studies in mice have also shown that normal and transformed cells can compete with each other for survival during several processes such as liver regeneration. In this review, we will introduce these recent publications on interactions between normal and transformed mammalian epithelial cells. Furthermore, we will discuss how these studies can potentially lead to identification of biomarkers for precancerous cells and to invention of novel types of cancer prevention and treatment. [Copyright &y& Elsevier]

The transcription factor Myc drives cell growth across animal phyla and is activated in most forms of human cancer. However, it is unclear which Myc target genes need to be regulated to induce growth and whether multiple targets act additively or if induction of each target is individually necessary. Here, we identified Myc target genes whose regulation is conserved between humans and flies and deleted Myc-binding sites (E-boxes) in the promoters of fourteen of these genes in Drosophila. E-box mutants of essential genes were homozygous viable, indicating that the E-boxes are not required for basal expression. Eight E-box mutations led to Myc-like phenotypes; the strongest mutant, ppan Ebox−/− , also made the flies resistant to Myc-induced cell growth without affecting Myc-induced apoptosis. The ppan Ebox −/− flies are healthy and display only a minor developmental delay, suggesting that it may be possible to treat or prevent tumorigenesis by targeting individual downstream targets of Myc. [Display omitted] • Identification of Myc targets whose regulation is conserved between humans and flies • Deletion of canonical E-boxes of ribosome biogenesis genes has no effect on viability • E-box deletion at the rRNA processing factor Ppan results in a Minute -like phenotype • E-box deleted Ppan prevents Myc-dependent growth but not apoptosis Zielke et al. demonstrate that, despite the complexity of the Myc-regulated network, it is possible to prevent Myc's growth-promoting effect by deletion of a single binding motif at a single target gene. These results indicate that Myc downstream targets may be candidates for the development of cancer therapies. [ABSTRACT FROM AUTHOR]

Abstract: Segmentation of multiple objects with irregular contours and surrounding sporadic spots is a common practice in ultrasound image analysis. A new region-based approach, called cell-competition algorithm, is proposed for simultaneous segmentation of multiple objects in a sonogram. The algorithm is composed of two essential ideas. One is simultaneous cell-based deformation of regions and the other is cell competition. The cells are generated by two-pass watershed transformations. The cell-competition algorithm has been validated with 13 synthetic images of different contrast-to-noise ratios and 71 breast sonograms. Three assessments have been carried out and the results show that the boundaries derived by the cell-competition algorithm are reasonably comparable to those delineated manually. Moreover, the cell-competition algorithm is robust to the variation of regions-of-interest and a range of thresholds required for the second-pass watershed transformation. The proposed algorithm is also shown to be superior to the region-competition algorithm for both types of images. (E-mail: chung@ntu.edu.tw) [Copyright &y& Elsevier]

The appearance of genetic changes in human pluripotent stem cells (hPSCs) presents a concern for their use in research and regenerative medicine. Variant hPSCs that harbor recurrent culture-acquired aneuploidies display growth advantages over wild-type diploid cells, but the mechanisms that yield a drift from predominantly wild-type to variant cell populations remain poorly understood. Here, we show that the dominance of variant clones in mosaic cultures is enhanced through competitive interactions that result in the elimination of wild-type cells. This elimination occurs through corralling and mechanical compression by faster-growing variants, causing a redistribution of F-actin and sequestration of yes-associated protein (YAP) in the cytoplasm that induces apoptosis in wild-type cells. YAP overexpression or promotion of YAP nuclear localization in wild-type cells alleviates their "loser" phenotype. Our results demonstrate that hPSC fate is coupled to mechanical cues imposed by neighboring cells and reveal that hijacking this mechanism allows variants to achieve clonal dominance in cultures. [Display omitted] • Genetically variant human pluripotent stem cells (hPSCs) eliminate wild-type cells • Mechanical cues mediate competitive interactions of wild-type and variant hPSCs • Mechanotransducer YAP is a key mediator of cell competition in hPSC cultures • Cell competition allows the fast overtake of cultures by variant hPSCs Price et al. identify competitive interactions that enhance selective advantage of genetically variant human pluripotent stem cells (hPSCs). In the presence of faster-growing variant hPSCs, wild-type cells sequester yes-associated protein (YAP) in the cytoplasm and undergo apoptosis. Neighboring variant cells retain nuclear YAP, remaining proliferative. Modifying culture conditions reduces competitive advantage of variant hPSCs. [ABSTRACT FROM AUTHOR]

Competitive cell interactions play a crucial role in quality control during development and homeostasis. Here, we show that cancer cells use such interactions to actively eliminate wild-type intestine cells in enteroid monolayers and organoids. This apoptosis-dependent process boosts proliferation of intestinal cancer cells. The remaining wild-type population activates markers of primitive epithelia and transits to a fetal-like state. Prevention of this cell-state transition avoids elimination of wild-type cells and, importantly, limits the proliferation of cancer cells. Jun N-terminal kinase (JNK) signaling is activated in competing cells and is required for cell-state change and elimination of wild-type cells. Thus, cell competition drives growth of cancer cells by active out-competition of wild-type cells through forced cell death and cell-state change in a JNK-dependent manner. [Display omitted] • In organoids, wild-type intestine cells are actively eliminated by cancer cells • Cell competition boosts proliferation of intestinal cancer cells • Remaining wild-type cells adopt a fetal-like state • JNK signaling in wild-type cells drives cell competition Interactions between cells helps coordinated decision making in tissues. Krotenberg Garcia et al. show that intestinal cancer cells use competitive cell interactions to actively eliminate surrounding wild-type cells. These interactions drive oncogenic growth in organoids. [ABSTRACT FROM AUTHOR]

T lymphocyte differentiation in the steady state is characterized by high cellular turnover whereby thymocytes do not self-renew. However, if deprived of competent progenitors, the thymus can temporarily maintain thymopoiesis autonomously. This bears a heavy cost, because prolongation of thymus autonomy causes leukemia. Here, we show that, at an early stage, thymus autonomy relies on double-negative 3 early (DN3e) thymocytes that acquire stem-cell-like properties. Following competent progenitor deprivation, DN3e thymocytes become long lived, are required for thymus autonomy, differentiate in vivo , and include DNA-label-retaining cells. At the single-cell level, the transcriptional programs of thymopoiesis in autonomy and the steady state are similar. However, a new cell population emerges in autonomy that expresses an aberrant Notch target gene signature and bypasses the β-selection checkpoint. In summary, DN3e thymocytes have the potential to self-renew and differentiate in vivo if cell competition is impaired, but this generates atypical cells, probably the precursors of leukemia. [Display omitted] • Thymus autonomy depends on DN3e thymocytes that secure T cell differentiation • DN3e in autonomy self-renew, retain DNA label, and have enhanced proliferation • Thymus autonomy preserves the hallmarks of thymopoiesis at the single-cell level • Aberrant cells with active notch that bypassed β-selection emerge in autonomy Thymus autonomy is the capacity to produce T cells without bone marrow contribution, which has a high risk for leukemia. Paiva et al. show that thymus autonomy depends on self-renewing DN3e thymocytes. This property generates aberrant cells that are likely the predecessors of leukemia. Hence, conditions causing thymus autonomy should be avoided. [ABSTRACT FROM AUTHOR]

Metabolic diseases such as type 2 diabetes are associated with increased cancer incidence. Here, we show that hyperinsulinemia promotes epithelial tumorigenesis by abrogating cell competition. In Drosophila eye imaginal epithelium, oncogenic scribble (scrib) mutant cells are eliminated by cell competition when surrounded by wild-type cells. Through a genetic screen, we find that flies heterozygous for the insulin receptor substrate chico allow scrib cells to evade cell competition and develop into tumors. Intriguingly, chico is required in the brain's insulin-producing cells (IPCs) to execute cell competition remotely. Mechanistically, chico downregulation in IPCs causes hyperinsulinemia by upregulating a Drosophila insulin Dilp2, which activates insulin-mTOR signaling and thus boosts protein synthesis in scrib cells. A diet-induced increase in insulin levels also triggers scrib tumorigenesis, and pharmacological repression of protein synthesis prevents hyperinsulinemia-induced scrib overgrowth. Our findings provide an in vivo mechanistic link between metabolic disease and cancer risk via systemic regulation of cell competition. • scrib cells evade cell competition and overgrow in chico heterozygous flies • chico downregulation in insulin-producing cells causes hyperinsulinemia • Hyperinsulinemia boosts insulin/mTOR-mediated protein synthesis in scrib cells • Anti-diabetic drug metformin represses scrib tumorigenesis under hyperinsulinemia Oncogenic scrib mutant cells are eliminated by cell competition when surrounded by wild-type cells. Sanaki et al. show that scrib cells normally have lower insulin signaling than wild-type neighbors do, but hyperinsulinemia boosts insulin/mTOR-mediated protein synthesis in scrib cells, leading to abrogation of cell competition and scrib tumorigenesis. [ABSTRACT FROM AUTHOR]

Cell competition is a quality control process that selectively eliminates unfit cells from the growing tissue via cell-cell interaction. Despite extensive mechanistic studies, the mechanism by which cell elimination is triggered has been elusive. Here, through a genetic screen in Drosophila , we discover that V-ATPase, an essential factor for autophagy, is required for triggering cell competition. Strikingly, autophagy is specifically elevated in prospective "loser" cells nearby wild-type "winner" cells, and blocking autophagy in loser cells abolishes their elimination. Mechanistically, elevated autophagy upregulates a proapoptotic gene hid through NFκB, and the elevated hid cooperates with JNK signaling to effectively induce loser's death. Crucially, this mechanism generally applies to cell competition caused by differences in protein synthesis between cells. Our findings establish a common mechanism of cell competition whereby cells with higher protein synthesis induce autophagy in their neighboring cells, leading to elimination of unfit cells. • Autophagy is required for losers of cell competition to be eliminated • Autophagy is elevated in prospective loser cells nearby winner cells • Elevated autophagy induces hid expression via NFκB • Hid cooperates with JNK signaling in loser cells to induce cell death Cells with compromised protein synthesis in the epithelial tissue are eliminated as "losers" of cell competition. Nagata et al. show that prospective loser cells emerging adjacent to wild-type "winner" cells elevate autophagy, which induces NFκB-dependent hid expression and leads to cell death via cooperation between hid and JNK. [ABSTRACT FROM AUTHOR]

The epiblast is a pluripotent cell population first formed in preimplantation embryos, and its quality is important for proper development. Here, we examined the mechanisms of epiblast formation and found that the Hippo pathway transcription factor TEAD and its coactivator YAP regulate expression of pluripotency factors. After specification of the inner cell mass, YAP accumulates in the nuclei and activates TEAD. TEAD activity is required for strong expression of pluripotency factors and is variable in the forming epiblast. Cells showing low TEAD activity are eliminated from the epiblast through cell competition. Pluripotency factor expression and MYC control cell competition downstream of TEAD activity. Cell competition eliminates unspecified cells and is required for proper organization of the epiblast. These results suggest that induction of pluripotency factors by TEAD activity and elimination of unspecified cells via cell competition ensure the production of an epiblast with naive pluripotency. • TEAD-YAP is activated in the forming epiblast of preimplantation embryos • TEAD activity is required for strong expression of pluripotency factors • TEAD activity and pluripotency factors are variable in the forming epiblast • Cell competition eliminates unspecified cells to produce a high-quality epiblast Pluripotent epiblast is formed during preimplantation development. Hashimoto and Sasaki show that TEAD-YAP is activated and induces pluripotency factors in the forming epiblast cells. TEAD activity and pluripotency factor expression are highly variable, and cell competition eliminates unspecified cells to ensure the production of a high-quality epiblast. [ABSTRACT FROM AUTHOR]

Summary Alzheimer's disease (AD) is the most common form of dementia, impairing cognitive and motor functions. One of the pathological hallmarks of AD is neuronal loss, which is not reflected in mouse models of AD. Therefore, the role of neuronal death is still uncertain. Here, we used a Drosophila AD model expressing a secreted form of human amyloid-β42 peptide and showed that it recapitulates key aspects of AD pathology, including neuronal death and impaired long-term memory. We found that neuronal apoptosis is mediated by cell fitness-driven neuronal culling, which selectively eliminates impaired neurons from brain circuits. We demonstrated that removal of less fit neurons delays β-amyloid-induced brain damage and protects against cognitive and motor decline, suggesting that contrary to common knowledge, neuronal death may have a beneficial effect in AD. Graphical Abstract Highlights • Peptides linked to neurodegenerative diseases reduce neuronal fitness in Drosophila • β-amyloid-induced neuronal death is mediated by fitness regulators flower and azot • Suppression of fitness-based neuronal culling aggravates cognitive and motor decline • Neuronal death related to fitness-based selection has a beneficial net effect Multicellular organisms eliminate abnormal but viable cells based on their fitness status through cell competition to maintain tissue integrity. Here, Coelho et al. report that fitness-based neuronal selection occurs in the course of neurodegeneration. Death of unfit neurons is beneficial, protecting against disease progression by restoring motor and cognitive functions. [ABSTRACT FROM AUTHOR]

Summary Cell competition employs comparisons of fitness to selectively eliminate cells sensed as less healthy. In Drosophila , apoptotic elimination of the weaker “loser” cells from growing wing discs is induced by a signaling module consisting of the Toll ligand Spätzle (Spz), several Toll-related receptors, and NF-κB factors. How this module is activated and restricted to competing disc cells is unknown. Here, we use Myc-induced cell competition to demonstrate that loser cell elimination requires local wing disc synthesis of Spz. We identify Spz processing enzyme (SPE) and modular serine protease (ModSP) as activators of Spz-regulated competitive signaling and show that “winner” cells trigger elimination of nearby WT cells by boosting SPE production. Moreover, Spz requires both Toll and Toll-8 to induce apoptosis of wing disc cells. Thus, during cell competition, Spz-mediated signaling is strictly confined to the imaginal disc, allowing errors in tissue fitness to be corrected without compromising organismal physiology. Graphical Abstract Highlights • In Myc super-competition, Spz signals via Toll and Toll-8 to kill loser cells • Spz is activated for competitive signaling by the proteases SPE and ModSP • Regulation of protease production and receptor expression by Myc allows “cheating” • Wing disc-restricted Spz keeps competitive signaling isolated from immune tissues Low levels of the Toll ligand Spätzle and its activating proteases are synthesized continuously by wing disc cells, but signaling is unproductive. Alpar et al. show that Myc super-competitor cells boost production of the proteases, thereby triggering Spätzle activation and inducing a killing signal that selectively eliminates nearby wild-type cells. [ABSTRACT FROM AUTHOR]

Summary Ribosomes perform protein synthesis but are also involved in signaling processes, the full extent of which are still being uncovered. We report that phenotypes of mutating ribosomal proteins (Rps) are largely due to signaling. Using Drosophila , we discovered that a bZip-domain protein, Xrp1, becomes elevated in Rp mutant cells. Xrp1 reduces translation and growth, delays development, is responsible for gene expression changes, and causes the cell competition of Rp heterozygous cells from genetic mosaics. Without Xrp1, even cells homozygously deleted for Rp genes persist and grow. Xrp1 induction in Rp mutant cells depends on a particular Rp with regulatory effects, RpS12, and precedes overall changes in translation. Thus, effects of Rp mutations, even the reductions in translation and growth, depend on signaling through the Xrp1 pathway and are not simply consequences of reduced ribosome production limiting protein synthesis. One benefit of this system may be to eliminate Rp-mutant cells by cell competition. [ABSTRACT FROM AUTHOR]

Summary The mammalian epiblast is formed by pluripotent cells able to differentiate into all tissues of the new individual. In their progression to differentiation, epiblast cells and their in vitro counterparts, embryonic stem cells (ESCs), transit from naive pluripotency through a differentiation-primed pluripotent state. During these events, epiblast cells and ESCs are prone to death, driven by competition between Myc-high cells (winners) and Myc-low cells (losers). Using live tracking of Myc levels, we show that Myc-high ESCs approach the naive pluripotency state, whereas Myc-low ESCs are closer to the differentiation-primed state. In ESC colonies, naive cells eliminate differentiating cells by cell competition, which is determined by a limitation in the time losers are able to survive persistent contact with winners. In the mouse embryo, cell competition promotes pluripotency maintenance by elimination of primed lineages before gastrulation. The mechanism described here is relevant to mammalian embryo development and induced pluripotency. [ABSTRACT FROM AUTHOR]