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In this review, we introduce the concept of cell competition, which occurs between heterogeneous neighboring cell populations. Cells with higher relative fitness become "winners" that outcompete cells of lower relative fitness ("losers"). We discuss the idea of super-competitors, mutant cells that expand at the expense of wild-type cells. Work on adult stem cells (ASCs) has revealed principles of neutral competition, wherein ASCs can be stochastically lost and replaced, and of biased competition, in which a winning ASC with a competitive advantage replaces its neighbors. Germline stem cells (GSCs) are ASCs that are uniquely endowed with the ability to produce gametes and, therefore, impact the next generation. Mechanisms of GSC competition have been elucidated by studies in Drosophila gonads, tunicates, and the mammalian testis. Competition between ASCs is thought to underlie various forms of cancer, including spermatocytic tumors in the human testis. Paternal age effect (PAE) disorders are caused by de novo mutations in human GSCs that increase their competitive ability and make them more likely to be inherited, leading to skeletal and craniofacial abnormalities in offspring. Given its widespread effects on human health, it is important to study GSC competition to elucidate how cells can become winners or losers. [ABSTRACT FROM AUTHOR]

The earliest metazoans probably evolved from single-celled organisms which found the colonial system to be a beneficial organization. Over the course of their evolution, these primary colonial organisms increased in size, and division of labour among the cells became a remarkable feature, leading to a higher level of organization: the biological organs. Primitive metazoans were the first organisms in evolution to show organ-type structures, which set the grounds for complex organs to evolve. Throughout evolution, and concomitant with organogenesis, is the appearance of tissue-specific stem cells. Tissue-specific stem cells gave rise to multicellular living systems with distinct organs which perform specific physiological functions. This setting is a constructive role of evolution; however, rebel cells can take over the molecular mechanisms for other purposes: nowadays we know that cancer stem cells, which generate aberrant organ-like structures, are at the top of a hierarchy. Furthermore, cancer stem cells are the root of metastasis, therapy resistance, and relapse. At present, most therapeutic drugs are unable to target cancer stem cells and therefore, treatment becomes a challenging issue. We expect that future research will uncover the mechanistic "forces" driving organ growth, paving the way to the implementation of new strategies to impair human tumorigenesis. [ABSTRACT FROM AUTHOR]

Mathematical and computational models are used to describe biomechanical processes in multicellular systems. Here, we develop a model to analyse how two types of epithelial cell layers interact during tissue invasion depending on their cellular properties, i.e., simulating cancer cells expanding into a region of normal cells. We model the tissue invasion process using the cellular Potts model and implement our two-dimensional computational simulations in the software package CompuCell3D. The model predicts that differences in mechanical properties of cells can lead to tissue invasion, even if the division rates and death rates of the two cell types are the same. We also show how the invasion speed varies depending on the cell division and death rates and the mechanical properties of the cells. [ABSTRACT FROM AUTHOR]

Simple Summary: NRF2-activated or NRF2-addicted cancers show high incidence, especially in esophageal squamous cell carcinoma (ESCC). ESCC with high NRF2 expression is largely resistant to the current major treatments for ESCC and therefore shows a very poor prognosis. In order to develop effective treatments for NRF2-addicted esophageal cancers, the elucidation and understanding of the mechanistic basis of NRF2 function in NRF2-addicted cancer cells are critically important. This review summarizes the current knowledge of the KEAP1-NRF2 system and proposes three distinct approaches for the treatment of NRF2-addicted ESCC. NRF2 (nuclear factor erythroid 2-related factor 2) is a transcription factor that regulates the expression of many cytoprotective genes. NRF2 activation is mainly regulated by KEAP1 (kelch-like ECH-associated protein 1) through ubiquitination and proteasome degradation. Esophageal cancer is classified histologically into two major types: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCC harbors more genetic alterations in the KEAP-NRF2 system than EAC does, which results in NRF2 activation in these cancers. NRF2-addicted ESCC exhibits increased malignancy and acquisition of resistance to chemoradiotherapy. Therefore, it has been recognized that the development of drugs targeting the KEAP1-NRF2 system based on the molecular dissection of NRF2 function is important and urgent for the treatment of ESCC, along with efficient clinical screening for NRF2-addicted ESCC patients. Recently, the fate of NRF2-activated cells in esophageal tissues, which was under the influence of strong cell competition, and its relationship to the pathogenesis of ESCC, was clarified. In this review, we will summarize the current knowledge of the KEAP1-NRF2 system and the treatment of ESCC. We propose three main strategies for the treatment of NRF2-addicted cancer: (1) NRF2 inhibitors, (2) synthetic lethal drugs for NRF2-addicted cancers, and (3) NRF2 inducers of the host defense system. [ABSTRACT FROM AUTHOR]

Deregulation of MYC family proteins in cancer is associated with a global reprogramming of gene expression, ultimately promoting glycolytic pathways, cell growth and proliferation. It is well known that MYC upregulation triggers cell-autonomous apoptosis in normal tissues, while frankly malignant cells develop resistance to apoptotic stimuli, partly resulting from MYC addiction. As well as inducing cell-autonomous apoptosis, MYC upregulation is able to trigger non cell-autonomous apoptotic death through an evolutionarily conserved mechanism known as "cell competition". With regard to this intimate and dual relationship between MYC and cell death, recent evidence obtained in Drosophila models of cancer has revealed that, in early tumourigenesis, MYC upregulation guides the clonal expansion of mutant cells, while the surrounding tissue undergoes non-cell autonomous death. Apoptosis inhibition in this context was shown to restrain tumour growth and to restore a wild-type phenotype. This suggests that cell-autonomous and non cell-autonomous apoptosis dependent on MYC upregulation may shape tumour growth in different ways, soliciting the need to reconsider the role of cell death in cancer in the light of this new level of complexity. Here we review recent literature about MYC and cell competition obtained in Drosophila, with a particular emphasis on the relevance of cell death to cell competition and, more generally, to cancer. Possible implications of these findings for the understanding of mammalian cancers are also discussed. [ABSTRACT FROM AUTHOR]

Tissue homeostasis via the elimination of aberrant cells is fundamental for organism survival. Cell competition is a key homeostatic mechanism, contributing to the recognition and elimination of aberrant cells, preventing their malignant progression and the development of tumors. Here, using Drosophila as a model organism, we have defined a role for protein tyrosine phosphatase 61F (PTP61F) (orthologue of mammalian PTP1B and TCPTP) in the initiation and progression of epithelial cancers. We demonstrate that a Ptp61F null mutation confers cells with a competitive advantage relative to neighbouring wild-type cells, while elevating PTP61F levels has the opposite effect. Furthermore, we show that knockdown of Ptp61F affects the survival of clones with impaired cell polarity, and that this occurs through regulation of the JAK–STAT signalling pathway. Importantly, PTP61F plays a robust non-cell-autonomous role in influencing the elimination of adjacent polarity-impaired mutant cells. Moreover, in a neoplastic RAS-driven polarity-impaired tumor model, we show that PTP61F levels determine the aggressiveness of tumors, with Ptp61F knockdown or overexpression, respectively, increasing or reducing tumor size. These effects correlate with the regulation of the RAS–MAPK and JAK–STAT signalling by PTP61F. Thus, PTP61F acts as a tumor suppressor that can function in an autonomous and non-cell-autonomous manner to ensure cellular fitness and attenuate tumorigenesis. [ABSTRACT FROM AUTHOR]

Simple Summary: The NUP98-HOXD13 (NHD13) mouse is a model of T-cell leukaemia (T-ALL) featuring a pre-leukemic phase, in which T-cell progenitors from the thymus of an NHD13 mouse can engraft into the thymus of a recipient mouse—an ability that normal T-cell progenitors do not possess. However, loss of this engraftment ability (by deletion of the Lyl1 gene) did not result in any loss of leukemogenesis activity, indicating the activity of redundant oncogenic pathways in this model. Having observed an overexpression of the EphA3 protein in the NHD13 thymocytes, we hypothesized that this gene might be involved in a redundant leukaemogenic pathway. Deletion of EphA3 did not affect the engraftment ability of the thymocytes, but did reduce the incidence of T-ALL. We thus uncovered a distinct mechanism of leukaemogenesis, which we believe operates in parallel to that mediated by Lyl1. We recently characterised the NUP98-HOXD13 (NHD13) mouse as a model of T-cell pre-leukaemia, featuring thymocytes that can engraft in recipient animals and progress to T-cell acute lymphoblastic leukaemia (T-ALL). However, loss of this engraftment ability by deletion of Lyl1 did not result in any loss of leukemogenesis activity. In the present study, we observe that NHD13 thymocytes overexpress EPHA3, and we characterise thymocyte behaviour in NHD13 mice with deletion of EphA3, which show a markedly reduced incidence of T-ALL. Deletion of EphA3 from the NHD13 mice does not prevent the abnormal accumulation or transplantation ability of these thymocytes. However, upon transplantation, these cells are unable to block the normal progression of recipient wild type (WT) progenitor cells through the normal developmental pathway. This is in contrast to the EphA3+/+ NHD13 thymocytes, which block the progression of incoming WT progenitors past the DN1 stage. Therefore, EphA3 is not critical for classical self-renewal, but is essential for mediating an interaction between the abnormally self-renewing cells and healthy progenitors—an interaction that results in a failure of the healthy cells to differentiate normally. We speculate that this may orchestrate a loss of healthy cell competition, which in itself has been demonstrated to be oncogenic, and that this may explain the decrease in T-ALL incidence in the absence of EphA3. We suggest that pre-leukaemic self-renewal in this model is a complex interplay of cell-intrinsic and -extrinsic factors, and that multiple redundant pathways to leukaemogenesis are active. [ABSTRACT FROM AUTHOR]

The wound healing response of fibroblasts critically depends on the primary cilium, a sensory organelle protruding into the environment and comprising a stable axonemal structure. A characteristic marker for primary cilia is acetylation of axonemal tubulin. Although formation of primary cilia is under cell cycle control, the environmental cues affecting ciliation are not fully understood. Our purpose was, therefore, to study the impact of culture conditions on cilia formation in NIH3T3 fibroblasts. We quantified ciliation in different NIH3T3 sub-cell lines and culture conditions by immunodetection of primary cilia and counting. Quantitative Western blotting, qRT-PCR, and proliferation assays completed our investigation. We observed large differences between NIH3T3 sub-cell lines in their ability to generate acetylated primary cilia that correlated with cytoplasmic tubulin acetylation. We found no increased activity of the major tubulin deacetylase, HDAC6, but instead reduced expression of the α-tubulin acetyltransferase 1 (Atat1) as being causative. Our observations demonstrate that cells with reduced expression of Atat1 and tubulin acetylation proliferate faster, eventually displacing all other cells in the population. Expression of Atat1 and tubulin acetylation are therefore selective forces in cell competition. [ABSTRACT FROM AUTHOR]

Cell competition (CC) is a feature that allows tumor cells to outcompete and eliminate adjacent cells that are deemed less fit. Studies of CC, first described in Drosophila melanogaster, reveal a diversity of underlying mechanisms. In this review, we will discuss three recent studies that expand our understanding of the molecular features governing CC. In particular, we will focus on a molecular fitness fingerprint, oncogenic pathways, and the importance of cell junction stability. A fitness fingerprint, mediated by flower (hFWE) protein isoforms, dictates that cells expressing the flower-win isoforms will outcompete adjacent flower-loss-expressing cells. The impact of the flower protein isoforms is seen in cancer progression and may have diagnostic potential. The yes-associated protein (YAP) and TAZ transcription factors, central mediators of the oncogenic Hippo pathway, elevate peritumoral fitness thereby protecting against tumor progression and provide a suppressive barrier. Similarly, COL17A1 is a key component in hemidesmosome stability, and its expression in epidermal stem cells contributes to fitness competition and aging characteristics. The contributions of these pathways to disease development and progression will help define how CC is hijacked to favor cancer growth. Understanding these features will also help frame the diagnostic and therapeutic possibilities that may place CC in the crosshairs of cancer therapeutics. [ABSTRACT FROM AUTHOR]

The biogenesis of ribosomes is a finely regulated multistep process linked to cell proliferation and growth—processes which require a high rate of protein synthesis. One of the master regulators of ribosome biogenesis is Myc, a well-known proto-oncogene that has an important role in ribosomal function and in the regulation of protein synthesis. The relationship between Myc and the ribosomes was first highlighted in Drosophila, where Myc's role in controlling Pol-I, II and III was evidenced by both microarrays data, and by the ability of Myc to control growth (mass), and cellular and animal size. Moreover, Myc can induce cell competition, a physiological mechanism through which cells with greater fitness grow better and thereby prevail over less competitive cells, which are actively eliminated by apoptosis. Myc-induced cell competition was shown to regulate both vertebrate development and tumor promotion; however, how these functions are linked to Myc's control of ribosome biogenesis, protein synthesis and growth is not clear yet. In this review, we will discuss the major pathways that link Myc to ribosomal biogenesis, also in light of its function in cell competition, and how these mechanisms may reflect its role in favoring tumor promotion. [ABSTRACT FROM AUTHOR]

Measuring Förster-resonance-energy-transfer (FRET) efficiency allows the investigation of protein-protein interactions (PPI), but extracting quantitative measures of affinity necessitates highly advanced technical equipment or isolated proteins. We demonstrate the validity of a recently suggested novel approach to quantitatively analyze FRET-based experiments in living mammalian cells using standard equipment using the interaction between different type-1 peroxisomal targeting signals (PTS1) and their soluble receptor peroxin 5 (PEX5) as a model system. Large data sets were obtained by flow cytometry coupled FRET measurements of cells expressing PTS1-tagged EGFP together with mCherry fused to the PTS1-binding domain of PEX5, and were subjected to a fitting algorithm extracting a quantitative measure of the interaction strength. This measure correlates with results obtained by in vitro techniques and a two-hybrid assay, but is unaffected by the distance between the fluorophores. Moreover, we introduce a live cell competition assay based on this approach, capable of depicting dose- and affinity-dependent modulation of the PPI. Using this system, we demonstrate the relevance of a sequence element next to the core tripeptide in PTS1 motifs for the interaction strength between PTS1 and PEX5, which is supported by a structure-based computational prediction of the binding energy indicating a direct involvement of this sequence in the interaction.