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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 -
EvoDevo Dec 2020Annual fishes of the genus Nothobranchius inhabit ephemeral habitats in Eastern and Southeastern Africa. Their life cycle is characterized by very rapid maturation, a... (Review)
Review
Annual fishes of the genus Nothobranchius inhabit ephemeral habitats in Eastern and Southeastern Africa. Their life cycle is characterized by very rapid maturation, a posthatch lifespan of a few weeks to months and embryonic diapause to survive the dry season. The species N. furzeri holds the record of the fastest-maturing vertebrate and of the vertebrate with the shortest captive lifespan and is emerging as model organism in biomedical research, evolutionary biology, and developmental biology. Extensive characterization of age-related phenotypes in the laboratory and of ecology, distribution, and demography in the wild are available. Species/populations from habitats differing in precipitation intensity show parallel evolution of lifespan and age-related traits that conform to the classical theories on aging. Genome sequencing and the establishment of CRISPR/Cas9 techniques made this species particularly attractive to investigate the effects genetic and non-genetic intervention on lifespan and aging-related phenotypes. At the same time, annual fishes are a very interesting subject for comparative approaches, including genomics, transcriptomics, and proteomics. The N. furzeri community is highly diverse and rapidly expanding and organizes a biannual meeting.
PubMed: 33323125
DOI: 10.1186/s13227-020-00170-x -
Insects Jun 2021The biodiversity of useful organisms, e.g., insects, decreases due to many environmental factors and increasing anthropopressure. Multifunctional tissues, such as the... (Review)
Review
The biodiversity of useful organisms, e.g., insects, decreases due to many environmental factors and increasing anthropopressure. Multifunctional tissues, such as the fat body, are key elements in the proper functioning of invertebrate organisms and resistance factors. The fat body is the center of metabolism, integrating signals, controlling molting and metamorphosis, and synthesizing hormones that control the functioning of the whole body and the synthesis of immune system proteins. In fat body cells, lipids, carbohydrates and proteins are the substrates and products of many pathways that can be used for energy production, accumulate as reserves, and mobilize at the appropriate stage of life (diapause, metamorphosis, flight), determining the survival of an individual. The fat body is the main tissue responsible for innate and acquired humoral immunity. The tissue produces bactericidal proteins and polypeptides, i.e., lysozyme. The fat body is also important in the early stages of an insect's life due to the production of vitellogenin, the yolk protein needed for the development of oocytes. Although a lot of information is available on its structure and biochemistry, the fat body is an interesting research topic on which much is still to be discovered.
PubMed: 34208190
DOI: 10.3390/insects12060547 -
Developmental Cell Jan 2020Embryonic diapause is the reversible arrest in development of mammalian embryos at the blastocyst stage. In this issue of Developmental Cell, Hussein et al. (2020)... (Review)
Review
Embryonic diapause is the reversible arrest in development of mammalian embryos at the blastocyst stage. In this issue of Developmental Cell, Hussein et al. (2020) reveal that alternative splicing of Lkb1 is essential for diapause to persist and find the elevation of glycolytic and lipolytic pathways that were previously considered dormant.
Topics: AMP-Activated Protein Kinase Kinases; Alternative Splicing; Blastocyst; Embryo Implantation, Delayed; Embryo, Mammalian; Embryonic Development; Gene Expression Regulation, Developmental; Humans; Protein Serine-Threonine Kinases
PubMed: 31991103
DOI: 10.1016/j.devcel.2020.01.002 -
Philosophical Transactions of the Royal... Dec 2020Variability in the environment defines the structure and dynamics of all living systems, from organisms to ecosystems. Species have evolved traits and strategies that... (Review)
Review
Variability in the environment defines the structure and dynamics of all living systems, from organisms to ecosystems. Species have evolved traits and strategies that allow them to detect, exploit and predict the changing environment. These traits allow organisms to maintain steady internal conditions required for physiological functioning through feedback mechanisms that allow internal conditions to remain at or near a set-point despite a fluctuating environment. In addition to feedback, many organisms have evolved feedforward processes, which allow them to adjust in anticipation of an expected future state of the environment. Here we provide a framework describing how feedback and feedforward mechanisms operating within organisms can generate effects across scales of organization, and how they allow living systems to persist in fluctuating environments. Daily, seasonal and multi-year cycles provide cues that organisms use to anticipate changes in physiologically relevant environmental conditions. Using feedforward mechanisms, organisms can exploit correlations in environmental variables to prepare for anticipated future changes. Strategies to obtain, store and act on information about the conditional nature of future events are advantageous and are evidenced in widespread phenotypes such as circadian clocks, social behaviour, diapause and migrations. Humans are altering the ways in which the environment fluctuates, causing correlations between environmental variables to become decoupled, decreasing the reliability of cues. Human-induced environmental change is also altering sensory environments and the ability of organisms to detect cues. Recognizing that living systems combine feedback and feedforward processes is essential to understanding their responses to current and future regimes of environmental fluctuations. This article is part of the theme issue 'Integrative research perspectives on marine conservation'.
Topics: Adaptation, Biological; Animals; Climate Change; Ecosystem; Environment; Plants
PubMed: 33131443
DOI: 10.1098/rstb.2019.0454 -
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 -
Annual Review of Entomology Jan 2023Winter provides many challenges for insects, including direct injury to tissues and energy drain due to low food availability. As a result, the geographic distribution... (Review)
Review
Winter provides many challenges for insects, including direct injury to tissues and energy drain due to low food availability. As a result, the geographic distribution of many species is tightly coupled to their ability to survive winter. In this review, we summarize molecular processes associated with winter survival, with a particular focus on coping with cold injury and energetic challenges. Anticipatory processes such as cold acclimation and diapause cause wholesale transcriptional reorganization that increases cold resistance and promotes cryoprotectant production and energy storage. Molecular responses to low temperature are also dynamic and include signaling events during and after a cold stressor to prevent and repair cold injury. In addition, we highlight mechanisms that are subject to selection as insects evolve to variable winter conditions. Based on current knowledge, despite common threads, molecular mechanisms of winter survival vary considerably across species, and taxonomic biases must be addressed to fully appreciate the mechanistic basis of winter survival across the insect phylogeny.
Topics: Animals; Seasons; Insecta; Cold Temperature; Cold Injury
PubMed: 36206770
DOI: 10.1146/annurev-ento-120120-095233 -
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