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Cell Metabolism Sep 2023In response to adverse environmental conditions, embryonic development may reversibly cease, a process termed diapause. Recent reports connect this phenomenon with the...
In response to adverse environmental conditions, embryonic development may reversibly cease, a process termed diapause. Recent reports connect this phenomenon with the non-genetic responses of tumors to chemotherapy, but the mechanisms involved are poorly understood. Here, we establish a multifarious role for SMC4 in the switching of colorectal cancer cells to a diapause-like state. SMC4 attenuation promotes the expression of three investment phase glycolysis enzymes increasing lactate production while also suppressing PGAM1. Resultant high lactate levels increase ABC transporter expression via histone lactylation, rendering tumor cells insensitive to chemotherapy. SMC4 acts as co-activator of PGAM1 transcription, and the coordinate loss of SMC4 and PGAM1 affects F-actin assembly, inducing cytokinesis failure and polyploidy, thereby inhibiting cell proliferation. These insights into the mechanisms underlying non-genetic chemotherapy resistance may have significant implications for the field, advancing our understanding of aerobic glycolysis functions in tumor and potentially informing future therapeutic strategies.
Topics: Humans; Animals; Histones; Glycolysis; Cell Proliferation; Colorectal Neoplasms; Lactates; Diapause; Adenosine Triphosphatases; Chromosomal Proteins, Non-Histone
PubMed: 37543034
DOI: 10.1016/j.cmet.2023.07.005 -
Cancer Cell Feb 2021Treatment-persistent residual tumors impede curative cancer therapy. To understand this cancer cell state we generated models of treatment persistence that simulate the...
Treatment-persistent residual tumors impede curative cancer therapy. To understand this cancer cell state we generated models of treatment persistence that simulate the residual tumors. We observe that treatment-persistent tumor cells in organoids, xenografts, and cancer patients adopt a distinct and reversible transcriptional program resembling that of embryonic diapause, a dormant stage of suspended development triggered by stress and associated with suppressed Myc activity and overall biosynthesis. In cancer cells, depleting Myc or inhibiting Brd4, a Myc transcriptional co-activator, attenuates drug cytotoxicity through a dormant diapause-like adaptation with reduced apoptotic priming. Conversely, inducible Myc upregulation enhances acute chemotherapeutic activity. Maintaining residual cells in dormancy after chemotherapy by inhibiting Myc activity or interfering with the diapause-like adaptation by inhibiting cyclin-dependent kinase 9 represent potential therapeutic strategies against chemotherapy-persistent tumor cells. Our study demonstrates that cancer co-opts a mechanism similar to diapause with adaptive inactivation of Myc to persist during treatment.
Topics: Adaptation, Physiological; Animals; Antineoplastic Agents; Apoptosis; Cell Line; Cell Line, Tumor; Cyclin-Dependent Kinase 9; Diapause; Embryo, Mammalian; Female; HEK293 Cells; Humans; MCF-7 Cells; Mice; Proto-Oncogene Proteins c-myc; Transcription Factors; Transcription, Genetic; Up-Regulation
PubMed: 33417832
DOI: 10.1016/j.ccell.2020.12.002 -
Nature Communications Sep 2022The silkworm Bombyx mori is an important economic insect for producing silk, the "queen of fabrics". The currently available genomes limit the understanding of its...
The silkworm Bombyx mori is an important economic insect for producing silk, the "queen of fabrics". The currently available genomes limit the understanding of its genetic diversity and the discovery of valuable alleles for breeding. Here, we deeply re-sequence 1,078 silkworms and assemble long-read genomes for 545 representatives. We construct a high-resolution pan-genome dataset representing almost the entire genomic content in the silkworm. We find that the silkworm population harbors a high density of genomic variants and identify 7308 new genes, 4260 (22%) core genes, and 3,432,266 non-redundant structure variations (SVs). We reveal hundreds of genes and SVs that may contribute to the artificial selection (domestication and breeding) of silkworm. Further, we focus on four genes responsible, respectively, for two economic (silk yield and silk fineness) and two ecologically adaptive traits (egg diapause and aposematic coloration). Taken together, our population-scale genomic resources will promote functional genomics studies and breeding improvement for silkworm.
Topics: Animals; Bombyx; Diapause; Domestication; Genomics; Silk
PubMed: 36153338
DOI: 10.1038/s41467-022-33366-x -
Nature Cell Biology Aug 2023Cellular reprogramming by only small molecules holds enormous potentials for regenerative medicine. However, chemical reprogramming remains a slow process and labour...
Cellular reprogramming by only small molecules holds enormous potentials for regenerative medicine. However, chemical reprogramming remains a slow process and labour intensive, hindering its broad applications and the investigation of underlying molecular mechanisms. Here, through screening of over 21,000 conditions, we develop a fast chemical reprogramming (FCR) system, which significantly improves the kinetics of cell identity rewiring. We find that FCR rapidly goes through an interesting route for pluripotent reprogramming, uniquely transitioning through a developmentally diapause-like state. Furthermore, FCR critically enables comprehensive characterizations using multi-omics technologies, and has revealed unexpected important features including key regulatory factors and epigenetic dynamics. Particularly, activation of pluripotency-related endogenous retroviruses via inhibition of heterochromatin significantly enhances reprogramming. Our studies provide critical insights into how only environmental cues are sufficient to rapidly reinstate pluripotency in somatic cells, and make notable technical and conceptual advances for solving the puzzle of regeneration.
Topics: Animals; Pluripotent Stem Cells; Cellular Reprogramming; Cellular Reprogramming Techniques; Regenerative Medicine; Diapause; Induced Pluripotent Stem Cells
PubMed: 37550515
DOI: 10.1038/s41556-023-01193-x -
Bulletin of Entomological Research Dec 2022Tools that could be used to subvert the insect diapause response offer potential for insect pest management as well as for the experimental manipulation of insects and... (Review)
Review
Tools that could be used to subvert the insect diapause response offer potential for insect pest management as well as for the experimental manipulation of insects and the facilitation of mass rearing procedures. In some cases, it is desirable to break diapause on demand and in other cases, it may be attractive to exploit diapause for long-term storage of biocontrol agents or valuable experimental lines. This review highlights some of the diapause disruptors reported in the literature, as well as chemical and physical manipulations that can be used to extend diapause or even induce diapause in an insect not programmed for diapause. The insect hormones are quite effective agents for breaking diapause and in some cases for extending the duration of diapause, but a collection of other chemical agents can also act as potent diapause disruptors, e.g. organic solvents, weak acids and bases, carbon dioxide, imidazole compounds, LSD, deuterium oxide, DMSO, ouabain, cholera toxin, cyclic GMP, heavy metals, and hydrogen peroxide. Physical manipulations such as artificial light at night, anoxia, shaking and heat shock are also known diapause disruptors. Some of these documented manipulations prevent diapause, others terminate diapause immediately, others alter the duration of diapause, and a few compounds can induce a diapause-like state in insects that are not programmed for diapause. The diversity of tools noted in the literature offers promise for the development of new tools or manipulations that possibly could be used to disrupt diapause or manage diapause in controlled laboratory experiments and in mass-rearing facilities.
Topics: Animals; Diapause, Insect; Insect Hormones; Diapause; Insecta; Heat-Shock Response
PubMed: 36200451
DOI: 10.1017/S000748532100016X -
Cells Sep 2022Embryonic diapause is an enigmatic state of dormancy that interrupts the normally tight connection between developmental stages and time. This reproductive strategy and... (Review)
Review
Embryonic diapause is an enigmatic state of dormancy that interrupts the normally tight connection between developmental stages and time. This reproductive strategy and state of suspended development occurs in mice, bears, roe deer, and over 130 other mammals and favors the survival of newborns. Diapause arrests the embryo at the blastocyst stage, delaying the post-implantation development of the embryo. This months-long quiescence is reversible, in contrast to senescence that occurs in aging stem cells. Recent studies have revealed critical regulators of diapause. These findings are important since defects in the diapause state can cause a lack of regeneration and control of normal growth. Controlling this state may also have therapeutic applications since recent findings suggest that radiation and chemotherapy may lead some cancer cells to a protective diapause-like, reversible state. Interestingly, recent studies have shown the metabolic regulation of epigenetic modifications and the role of microRNAs in embryonic diapause. In this review, we discuss the molecular mechanism of diapause induction.
Topics: Animals; Blastocyst; Deer; Diapause; Embryonic Development; Mice; MicroRNAs; Neoplasms
PubMed: 36230891
DOI: 10.3390/cells11192929 -
Biochemical Society Transactions Oct 2023Diapause is a protective mechanism that many organisms deploy to overcome environmental adversities. Diapause extends lifespan and fertility to enhance the reproductive... (Review)
Review
Diapause is a protective mechanism that many organisms deploy to overcome environmental adversities. Diapause extends lifespan and fertility to enhance the reproductive success and survival of the species. Although diapause states have been known and employed for commercial purposes, for example in the silk industry, detailed molecular and cell biological studies are an exciting frontier. Understanding diapause-like protective mechanisms will shed light on pathways that steer organisms through adverse conditions. One hope is that an understanding of the mechanisms that support diapause might be leveraged to extend the lifespan and/or health span of humans as well as species threatened by climate change. In addition, recent findings suggest that cancer cells that persist after treatment mimic diapause-like states, implying that these programs may facilitate cancer cell survival from chemotherapy and cause relapse. Here, we review the molecular mechanisms underlying diapause programs in a variety of organisms, and we discuss pathways supporting diapause-like states in tumor persister cells.
Topics: Animals; Humans; Diapause; Reproduction; Longevity
PubMed: 37800560
DOI: 10.1042/BST20221431 -
Advances in Genetics 2015Food availability determines developmental rate, behavior, and survival of animals. Animals that enter diapause or hibernate in response to lack of food have a double... (Review)
Review
Food availability determines developmental rate, behavior, and survival of animals. Animals that enter diapause or hibernate in response to lack of food have a double advantage: they are able to adapt to environmental and cellular challenges and survive to these challenges for a prolonged time. The metabolic and physiological adaptations that make possible diapause and hibernation also provide a favorable cellular environment for tissue protection. This review highlights the benefits of dormancy on neuronal protection in the model organism Caenorhabditis elegans and small mammals such as squirrels. Additionally, I discuss the link between metabolic restructuring occurring in diapause and changes in gene expression with the increased capacity of diapausing animals to protect neurons from degeneration and potentially foster their regeneration.
Topics: Animals; Caenorhabditis elegans; Diapause, Insect; Hibernation; Mammals; Neurons; Neuroprotection; Starvation
PubMed: 26639915
DOI: 10.1016/bs.adgen.2015.09.004 -
Biomolecules May 2021The mechanistic target of rapamycin (mTOR) is a central regulator of cellular homeostasis that integrates environmental and nutrient signals to control cell growth and... (Review)
Review
The mechanistic target of rapamycin (mTOR) is a central regulator of cellular homeostasis that integrates environmental and nutrient signals to control cell growth and survival. Over the past two decades, extensive studies of mTOR have implicated the importance of this protein complex in regulating a broad range of metabolic functions, as well as its role in the progression of various human diseases. Recently, mTOR has emerged as a key signaling molecule in regulating animal entry into a hypometabolic state as a survival strategy in response to environmental stress. Here, we review current knowledge of the role that mTOR plays in contributing to natural hypometabolic states such as hibernation, estivation, hypoxia/anoxia tolerance, and dauer diapause. Studies across a diverse range of animal species reveal that mTOR exhibits unique regulatory patterns in an environmental stressor-dependent manner. We discuss how key signaling proteins within the mTOR signaling pathways are regulated in different animal models of stress, and describe how each of these regulations uniquely contribute to promoting animal survival in a hypometabolic state.
Topics: Adaptation, Physiological; Animals; Cell Cycle; Cell Proliferation; Diapause; Estivation; Hibernation; Humans; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Signal Transduction; Stress, Physiological; TOR Serine-Threonine Kinases
PubMed: 34062764
DOI: 10.3390/biom11050681 -
Annual Review of Entomology Jan 2023Although it is generally more adaptive for insects to produce additional generations than to have longer life cycles, some insects produce one or fewer generations per... (Review)
Review
Although it is generally more adaptive for insects to produce additional generations than to have longer life cycles, some insects produce one or fewer generations per year (univoltine or semivoltine life cycles, respectively). Some insects with the potential to produce multiple generations per year produce a univoltine life cycle in response to environmental conditions. Obligatory univoltine insects have a single long diapause or multiple diapauses in different seasons. Semivoltine insects have multiple diapauses in different years, a prolonged diapause for more than a year, or diapause controlled by a circannual rhythm. Diapause in these insects greatly varies among species both in the physiological mechanism and in the evolutionary background, and there is no general rule defining it. In this review, we survey the physiological control of univoltine and semivoltine insects' diapause and discuss the adaptive significance of the long life cycles. Although constraints such as slow development are sometimes responsible for these life cycles, the benefits of these life cycles can be explained by bet-hedging in many cases. We also discuss the effect of climate warming on these life cycles as a future area of research.
Topics: Animals; Diapause, Insect; Diapause; Life Cycle Stages; Insecta; Seasons
PubMed: 36198404
DOI: 10.1146/annurev-ento-120220-101047