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Summary: 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.

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.

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]

We at Cell Reports discuss with Xianjue Ma his work on mechanisms of tumor progression, particularly his lab's recent work on tumor-suppressive cell competition., Competing Interests: Declaration of interests The author declares no competing interests., (Copyright © 2023.)

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]

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 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]

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]

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]

Cell competition in the thymus is a homeostatic process that drives turnover. If the process is impaired, thymopoiesis can be autonomously maintained for several weeks, but this causes leukemia. We aimed to understand the effect of cell competition on thymopoiesis, identify the cells involved, and determine how the process is regulated. Using thymus transplantation experiments, we found that cell competition occurs within the double-negative 2 (DN2) and 3 early (DN3e) thymocytes and inhibits thymus autonomy. Furthermore, the expansion of DN2b is regulated by a negative feedback loop that is imposed by double-positive thymocytes and determines the kinetics of thymopoiesis. This feedback loop affects the cell cycle duration of DN2b, in a response controlled by interleukin 7 availability. Altogether, we show that thymocytes do not merely follow a pre-determined path if provided with the correct signals. Instead, thymopoiesis dynamically integrates cell-autonomous and non-cell-autonomous aspects that fine-tune normal thymus function., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Calorie restriction (CR) extends lifespan through several intracellular mechanisms, including increased DNA repair, leading to fewer DNA mutations that cause age-related pathologies. However, it remains unknown how CR acts on mutation retention at the tissue level. Here, we use Cre-mediated DNA recombination of the confetti reporter as proxy for neutral mutations and follow these mutations by intravital microscopy to identify how CR affects retention of mutations in the intestine. We find that CR leads to increased numbers of functional Lgr5 + stem cells that compete for niche occupancy, resulting in slower but stronger stem cell competition. Consequently, stem cells carrying neutral or Apc mutations encounter more wild-type competitors, thus increasing the chance that they get displaced from the niche to get lost over time. Thus, our data show that CR not only affects the acquisition of mutations but also leads to lower retention of mutations in the intestine., Competing Interests: Declaration of Interests The authors declare no competing interests., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

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]