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Cell Jan 2021Cancer cells enter a reversible drug-tolerant persister (DTP) state to evade death from chemotherapy and targeted agents. It is increasingly appreciated that DTPs are...
Cancer cells enter a reversible drug-tolerant persister (DTP) state to evade death from chemotherapy and targeted agents. It is increasingly appreciated that DTPs are important drivers of therapy failure and tumor relapse. We combined cellular barcoding and mathematical modeling in patient-derived colorectal cancer models to identify and characterize DTPs in response to chemotherapy. Barcode analysis revealed no loss of clonal complexity of tumors that entered the DTP state and recurred following treatment cessation. Our data fit a mathematical model where all cancer cells, and not a small subpopulation, possess an equipotent capacity to become DTPs. Mechanistically, we determined that DTPs display remarkable transcriptional and functional similarities to diapause, a reversible state of suspended embryonic development triggered by unfavorable environmental conditions. Our study provides insight into how cancer cells use a developmentally conserved mechanism to drive the DTP state, pointing to novel therapeutic opportunities to target DTPs.
Topics: Animals; Antineoplastic Agents; Autophagy; Cell Line, Tumor; Clone Cells; Colorectal Neoplasms; Diapause; Drug Resistance, Neoplasm; Embryo, Mammalian; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genetic Heterogeneity; Humans; Irinotecan; Mice, Inbred NOD; Mice, SCID; Models, Biological; Signal Transduction; Up-Regulation; Xenograft Model Antitumor Assays; Mice
PubMed: 33417860
DOI: 10.1016/j.cell.2020.11.018 -
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 -
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 -
Challenges during diapause and anhydrobiosis: Mitochondrial bioenergetics and desiccation tolerance.IUBMB Life Dec 2018In preparation for the onset of environmental challenges like overwintering, food limitation, anoxia, or water stress, many invertebrates and certain killifish enter... (Review)
Review
In preparation for the onset of environmental challenges like overwintering, food limitation, anoxia, or water stress, many invertebrates and certain killifish enter diapause. Diapause is a developmentally-programed dormancy characterized by suppression of development and metabolism. For embryos of Artemia franciscana (brine shrimp), the metabolic arrest is profound. These gastrula-stage embryos depress oxidative metabolism by ~99% during diapause and survive years of severe desiccation in a state termed anhydrobiosis. Trehalose is the sole fuel source for this developmental stage. Mitochondrial function during diapause is downregulated primarily by restricting substrate supply, as a result of inhibiting key enzymes of carbohydrate metabolism. Because proton conductance across the inner membrane is not decreased during diapause, the inference is that membrane potential must be compromised. In the absence of any intervention, the possibility exists that the F F ATP synthase and the adenine nucleotide translocator may reverse, leading to wholesale hydrolysis of cellular ATP. Studies with anhydrobiotes like A. franciscana are revealing multiple traits useful for improving desiccation tolerance that include the expression and accumulation late embryogenesis abundant (LEA) proteins and trehalose. LEA proteins are intrinsically disordered in aqueous solution but gain secondary structure (predominantly α-helix) as water is removed. These protective agents stabilize biological structures including lipid bilayers and mitochondria during severe water stress. © 2018 IUBMB Life, 70(12):1251-1259, 2018.
Topics: Adaptation, Physiological; Animals; Artemia; Dehydration; Diapause; Embryo, Nonmammalian; Embryonic Development; Energy Metabolism; Fundulidae; Mitochondria; Trehalose
PubMed: 30369011
DOI: 10.1002/iub.1953 -
Frontiers in Physiology 2022The swallowtail butterfly, Gray, is endemic to East Asia, has high ornamental value but faces an increased risk of extinction. To understand the overwintering...
The swallowtail butterfly, Gray, is endemic to East Asia, has high ornamental value but faces an increased risk of extinction. To understand the overwintering strategies of this species, the dynamic changes in supercooling point (SCP) and water and biochemical contents of diapause-destined and non-diapause pupae were investigated. The SCP of laboratory-reared diapause pupae was as low as -26°C compared to -24°C in diapause pupae in the field. Although there was no significant difference in total water content between diapause-destined and non-diapause pupae, the free water of diapause-destined pupae was significantly lower, and the bound water was significantly higher, than that of non-diapause pupae. Lipid, glycogen, and protein contents of diapause-destined pupae showed a downward trend, whereas the total sugar content showed the opposite trend after pupation. The glycogen content decreased rapidly during the initial stage of pupation, whereas the lipid content decreased significantly after 30 days of pupation, suggesting that diapause-destined pupae deplete glycogen stores during the pre-diapause period and then switch to using lipids during the diapause maintenance phase. Trehalose levels in diapause-destined pupae increased significantly and remained high after pupation. Meanwhile, the trehalose content of overwintering pupae during the diapause maintenance period was significantly higher than that of diapause termination pupae in the field. These results suggest that trehalose is the main cryoprotectant for overwintering pupae. Thus, diapausing pupae appear to be freeze avoidant, accumulate trehalose as a cryoprotectant, and reduce the free water content to decrease the SCP, enhancing their cold tolerance.
PubMed: 36406979
DOI: 10.3389/fphys.2022.1031654 -
Frontiers in Physiology 2022Diapause is a physiological adaptation to conditions that are unfavorable for growth or reproduction. During diapause, animals become long-lived, stress-resistant,... (Review)
Review
Diapause is a physiological adaptation to conditions that are unfavorable for growth or reproduction. During diapause, animals become long-lived, stress-resistant, developmentally static, and non-reproductive, in the case of diapausing adults. Diapause has been observed at all developmental stages in both vertebrates and invertebrates. In adults, diapause traits weaken into adaptations such as hibernation, estivation, dormancy, or torpor, which represent evolutionarily diverse versions of the traditional diapause traits. These traits are regulated through modifications of the endocrine program guiding development. In insects, this typically includes changes in molting hormones, as well as metabolic signals that limit growth while skewing the organism's energetic demands toward conservation. While much work has been done to characterize these modifications, the interactions between hormones and their downstream consequences are incompletely understood. The current state of diapause endocrinology is reviewed here to highlight the relevance of diapause beyond its use as a model to study seasonality and development. Specifically, insect diapause is an emerging model to study mechanisms that determine lifespan. The induction of diapause represents a dramatic change in the normal progression of age. Hormones such as juvenile hormone, 20-hydroxyecdysone, and prothoracicotropic hormone are well-known to modulate this plasticity. The induction of diapause-and by extension, the cessation of normal aging-is coordinated by interactions between these pathways. However, research directly connecting diapause endocrinology to the biology of aging is lacking. This review explores connections between diapause and aging through the perspective of endocrine signaling. The current state of research in both fields suggests appreciable overlap that will greatly contribute to our understanding of diapause and lifespan determination.
PubMed: 35242054
DOI: 10.3389/fphys.2022.825057 -
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 -
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