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Cell Death & Disease Jun 2023Chemotherapy is a common strategy to treat cancer. However, acquired resistance and metastasis are the major obstacles to successful treatment. Anastasis is a process by...
Chemotherapy is a common strategy to treat cancer. However, acquired resistance and metastasis are the major obstacles to successful treatment. Anastasis is a process by which cells survive executioner caspase activation when facing apoptotic stress. Here we demonstrate that colorectal cancer cells can undergo anastasis after transient exposure to chemotherapeutic drugs. Using a lineage tracing system to label and isolate cells that have experienced executioner caspase activation in response to drug treatment, we show that anastasis grants colorectal cancer cells enhanced migration, metastasis, and chemoresistance. Mechanistically, treatment with chemotherapeutic drugs induces upregulated expression of cIAP2 and activation of NFκB, which are required for cells to survive executioner caspase activation. The elevated cIAP2/NFκB signaling persists in anastatic cancer cells to promote migration and chemoresistance. Our study unveils that cIAP2/NFκB-dependent anastasis promotes acquired resistance and metastasis after chemotherapy.
Topics: Humans; Cell Death Reversal; Drug Resistance, Neoplasm; NF-kappa B; Colorectal Neoplasms; Caspases
PubMed: 37391410
DOI: 10.1038/s41419-023-05916-8 -
Nature Immunology Sep 2019Understanding resistance to antibody to programmed cell death protein 1 (PD-1; anti-PD-1) is crucial for the development of reversal strategies. In anti-PD-1-resistant...
Understanding resistance to antibody to programmed cell death protein 1 (PD-1; anti-PD-1) is crucial for the development of reversal strategies. In anti-PD-1-resistant models, simultaneous anti-PD-1 and vaccine therapy reversed resistance, while PD-1 blockade before antigen priming abolished therapeutic outcomes. This was due to induction of dysfunctional PD-1CD38 CD8 cells by PD-1 blockade in suboptimally primed CD8 cell conditions induced by tumors. This results in erroneous T cell receptor signaling and unresponsiveness to antigenic restimulation. On the other hand, PD-1 blockade of optimally primed CD8 cells prevented the induction of dysfunctional CD8 cells, reversing resistance. Depleting PD-1CD38 CD8 cells enhanced therapeutic outcomes. Furthermore, non-responding patients showed more PD-1CD38CD8 cells in tumor and blood than responders. In conclusion, the status of CD8 T cell priming is a major contributor to anti-PD-1 therapeutic resistance. PD-1 blockade in unprimed or suboptimally primed CD8 cells induces resistance through the induction of PD-1CD38 CD8 cells that is reversed by optimal priming. PD-1CD38 CD8 cells serve as a predictive and therapeutic biomarker for anti-PD-1 treatment. Sequencing of anti-PD-1 and vaccine is crucial for successful therapy.
Topics: ADP-ribosyl Cyclase 1; Animals; Antibodies; CD8-Positive T-Lymphocytes; Cancer Vaccines; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Humans; Immunotherapy; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Neoplasms; Programmed Cell Death 1 Receptor; Tumor Microenvironment
PubMed: 31358999
DOI: 10.1038/s41590-019-0441-y -
The Journal of Neuroscience : the... Mar 2022Anastasis is a recently described process in which cells recover after late-stage apoptosis activation. The functional consequences of anastasis for cells and tissues...
Anastasis is a recently described process in which cells recover after late-stage apoptosis activation. The functional consequences of anastasis for cells and tissues are not clearly understood. Using , rat and human cells and tissues, including analyses of both males and females, we present evidence that glia undergoing anastasis in the primary astrogliopathy Alexander disease subsequently express hallmarks of senescence. These senescent glia promote non-cell autonomous death of neurons by secreting interleukin family cytokines. Our findings demonstrate that anastasis can be dysfunctional in neurologic disease by inducing a toxic senescent population of astroglia. Under some conditions cells otherwise destined to die can be rescued just before death in a process called anastasis, or "rising from the dead." The fate and function of cells undergoing a near death experience is not well understood. Here, we find that in models and patient cells from Alexander disease, an important brain disorder in which glial cells promote neuronal dysfunction and death, anastasis of astrocytic glia leads to secretion of toxic signaling molecules and neurodegeneration. These studies demonstrate a previously unexpected deleterious consequence of rescuing cells on the brink of death and suggest therapeutic strategies for Alexander disease and related disorders of glia.
Topics: Alexander Disease; Animals; Apoptosis; Cell Death Reversal; Drosophila; Female; Humans; Male; Neuroglia; Neurons; Rats
PubMed: 35105675
DOI: 10.1523/JNEUROSCI.1659-21.2021 -
Medicina 2020
Topics: Apoptosis; Cell Survival; HeLa Cells; Humans
PubMed: 32282324
DOI: No ID Found -
Royal Society Open Science Sep 2018Anastasis is a natural cell recovery phenomenon that rescues cells from the brink of death. Programmed cell death such as apoptosis has been traditionally assumed to be... (Review)
Review
Anastasis is a natural cell recovery phenomenon that rescues cells from the brink of death. Programmed cell death such as apoptosis has been traditionally assumed to be an intrinsically irreversible cascade that commits cells to a rapid and massive demolition. Interestingly, recent studies have demonstrated recovery of dying cells even at the late stages generally considered immutable. Here, we examine the evidence for anastasis in cultured cells and in animals, review findings illuminating the potential mechanisms of action, discuss the challenges of studying anastasis and explore new strategies to uncover the function and regulation of anastasis, the identification of which has wide-ranging physiological, pathological and therapeutic implications.
PubMed: 30839720
DOI: 10.1098/rsos.180442 -
Cancers Jul 2021For over 20 years, it has been a dogma that once the integrity of mitochondria is disrupted and proapoptotic proteins that are normally located in the intermembrane... (Review)
Review
For over 20 years, it has been a dogma that once the integrity of mitochondria is disrupted and proapoptotic proteins that are normally located in the intermembrane space of mitochondria appeared in the cytoplasm, the process of cell death becomes inevitable. However, it has been recently shown that upon removal of the death signal, even at the stage of disturbance in the mitochondria, cells can recover and continue to grow. This phenomenon was named anastasis. Here, we will critically discuss the present knowledge concerning the mechanisms of cell death reversal, or development of anastasis, methods for its detection, and what role signaling from different intracellular compartments plays in anastasis stimulation.
PubMed: 34359573
DOI: 10.3390/cancers13153671 -
Human Genetics Aug 2023Aging is a progressive multifaceted functional decline of a biological system. Chronic age-related conditions such as neurodegenerative diseases are leading causes of...
Aging is a progressive multifaceted functional decline of a biological system. Chronic age-related conditions such as neurodegenerative diseases are leading causes of death worldwide, and they are becoming a pressing problem for our society. To address this global challenge, there is a need for novel, safe, and effective rejuvenation therapies aimed at reversing age-related phenotypes and improving human health. With gene expression being a key determinant of cell identity and function, and in light of recent studies reporting rejuvenation effects through genetic perturbations, we propose an age reversal strategy focused on reprogramming the cell transcriptome to a youthful state. To this end, we suggest using transcriptomic data from primary human cells to predict rejuvenation targets and develop high-throughput aging assays, which can be used in large perturbation screens. We propose neural cells as particularly relevant targets for rejuvenation due to substantial impact of neurodegeneration on human frailty. Of all cell types in the brain, we argue that glutamatergic neurons, neuronal stem cells, and oligodendrocytes represent the most impactful and tractable targets. Lastly, we provide experimental designs for anti-aging reprogramming screens that will likely enable the development of neuronal age reversal therapies, which hold promise for dramatically improving human health.
Topics: Humans; Cellular Reprogramming; Transcriptome; Aging; Stem Cells; Neurons
PubMed: 37004545
DOI: 10.1007/s00439-023-02529-1 -
ALTEX 2015Cellular resilience describes the ability of a cell to cope with environmental changes such as toxicant exposure. If cellular metabolism does not collapse directly after...
Cellular resilience describes the ability of a cell to cope with environmental changes such as toxicant exposure. If cellular metabolism does not collapse directly after the hit or end in programmed cell death, the ensuing stress responses promote a new homeostasis under stress. The processes of reverting "back to normal" and reversal of apoptosis ("anastasis") have been studied little at the cellular level. Cell types show astonishingly similar vulnerability to most toxicants, except for those that require a very specific target, metabolism or mechanism present only in specific cell types. The majority of chemicals triggers "general cytotoxicity" in any cell at similar concentrations. We hypothesize that cells differ less in their vulnerability to a given toxicant than in their resilience (coping with the "hit"). In many cases, cells do not return to the naive state after a toxic insult. The phenomena of "pre-conditioning", "tolerance" and "hormesis" describe this for low-dose exposures to toxicants that render the cell more resistant to subsequent hits. The defense and resilience programs include epigenetic changes that leave a "memory/scar" - an alteration as a consequence of the stress the cell has experienced. These memories might have long-term consequences, both positive (resistance) and negative, that contribute to chronic and delayed manifestations of hazard and, ultimately, disease. This article calls for more systematic analyses of how cells cope with toxic perturbations in the long-term after stressor withdrawal. A technical prerequisite for these are stable (organotypic) cultures and a characterization of stress response molecular networks.
Topics: Adaptation, Physiological; Animal Testing Alternatives; Animals; Cell Death; Cell Physiological Phenomena; Humans; Stress, Physiological
PubMed: 26536287
DOI: 10.14573/altex.1509271 -
Trends in Biochemical Sciences Jan 2018Despite its name, signalling induced by the tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is versatile. Besides eliciting cell death by both... (Review)
Review
Despite its name, signalling induced by the tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is versatile. Besides eliciting cell death by both apoptosis and necroptosis, TRAIL can also induce migration, proliferation, and cytokine production in cancerous and non-cancerous cells. Unravelling the mechanisms regulating the intricate balance between these different outputs could therefore facilitate our understanding of the role of TRAIL in tissue homeostasis, immunity, and cancer. Ubiquitination and its reversal, deubiquitination, are crucial modulators of immune receptor signalling. This review discusses recent progress on the orchestration of TRAIL signalling outcomes by ubiquitination of various components of the signalling complexes, our understanding of the molecular switches that decide between cell death and gene activation, and what remains to be discovered.
Topics: Animals; Apoptosis; Humans; Neoplasms; TNF-Related Apoptosis-Inducing Ligand; Ubiquitin
PubMed: 29195774
DOI: 10.1016/j.tibs.2017.11.002 -
Oncogenesis Jun 2023Cancer relapse and metastasis are major obstacles for effective treatment. One important mechanism to eliminate cancer cells is to induce apoptosis. Activation of...
Cancer relapse and metastasis are major obstacles for effective treatment. One important mechanism to eliminate cancer cells is to induce apoptosis. Activation of executioner caspases is the key step in apoptosis and was considered "a point of no return". However, in recent years, accumulating evidence has demonstrated that cells can survive executioner caspase activation in response to apoptotic stimuli through a process named anastasis. Here we show that breast cancer cells that have survived through anastasis (anastatic cells) after exposure to chemotherapeutic drugs acquire enhanced proliferation and migration. Mechanistically, cadherin 12 (CDH12) is persistently upregulated in anastatic cells and promotes breast cancer malignancy via activation of ERK and CREB. Moreover, we demonstrate that executioner caspase activation induced by chemotherapeutic drugs results in loss of DNA methylation and repressive histone modifications in the CDH12 promoter region, leading to increased CDH12 expression. Our work unveils the mechanism underlying anastasis-induced enhancement in breast cancer malignancy, offering new therapeutic targets for preventing post-chemotherapy cancer relapse and metastasis.
PubMed: 37355711
DOI: 10.1038/s41389-023-00479-x