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1.
Nat Immunol ; 23(9): 1379-1392, 2022 09.
Article in English | MEDLINE | ID: mdl-36002648

ABSTRACT

Cancer stem cells (CSCs) are a subpopulation of cancer cells endowed with high tumorigenic, chemoresistant and metastatic potential. Nongenetic mechanisms of acquired resistance are increasingly being discovered, but molecular insights into the evolutionary process of CSCs are limited. Here, we show that type I interferons (IFNs-I) function as molecular hubs of resistance during immunogenic chemotherapy, triggering the epigenetic regulator demethylase 1B (KDM1B) to promote an adaptive, yet reversible, transcriptional rewiring of cancer cells towards stemness and immune escape. Accordingly, KDM1B inhibition prevents the appearance of IFN-I-induced CSCs, both in vitro and in vivo. Notably, IFN-I-induced CSCs are heterogeneous in terms of multidrug resistance, plasticity, invasiveness and immunogenicity. Moreover, in breast cancer (BC) patients receiving anthracycline-based chemotherapy, KDM1B positively correlated with CSC signatures. Our study identifies an IFN-I → KDM1B axis as a potent engine of cancer cell reprogramming, supporting KDM1B targeting as an attractive adjunctive to immunogenic drugs to prevent CSC expansion and increase the long-term benefit of therapy.


Subject(s)
Breast Neoplasms , Epigenesis, Genetic , Histone Demethylases , Interferon Type I , Anthracyclines/metabolism , Anthracyclines/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Female , Histone Demethylases/metabolism , Humans , Interferon Type I/metabolism , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology
2.
Nat Immunol ; 21(2): 120-134, 2020 02.
Article in English | MEDLINE | ID: mdl-31873291

ABSTRACT

Therapeutic irradiation of the tumor microenvironment causes differential activation of pro-survival and pro-death pathways in malignant, stromal, endothelial and immune cells, hence causing a profound cellular and biological reconfiguration via multiple, non-redundant mechanisms. Such mechanisms include the selective elimination of particularly radiosensitive cell types and consequent loss of specific cellular functions, the local release of cytokines and danger signals by dying radiosensitive cells, and altered cytokine secretion by surviving radioresistant cells. Altogether, these processes create chemotactic and immunomodulatory cues for incoming and resident immune cells. Here we discuss how cytoprotective and cytotoxic signaling modules activated by radiation in specific cell populations reshape the immunological tumor microenvironment.


Subject(s)
Cell Death/radiation effects , Signal Transduction/immunology , Signal Transduction/radiation effects , Tumor Microenvironment/immunology , Tumor Microenvironment/radiation effects , Animals , Humans
3.
Trends Genet ; 38(8): 787-788, 2022 08.
Article in English | MEDLINE | ID: mdl-35490031

ABSTRACT

Unscheduled tetraploidy is a metastable state that rapidly evolves into aneuploidy. Recent findings reported by Gemble et al. demonstrate that freshly formed tetraploid cells fail to accumulate the required amounts of DNA replication factors during the first G1 phase after whole-genome duplication (WGD), culminating in genetic instability in the subsequent S phase and extensive karyotypic alterations.


Subject(s)
DNA Replication , Tetraploidy , Aneuploidy , Cell Cycle Proteins/genetics , DNA Replication/genetics , Humans , Mitosis , S Phase
4.
Mol Cell ; 66(3): 306-319, 2017 May 04.
Article in English | MEDLINE | ID: mdl-28475867

ABSTRACT

Both embryonic and adult stem cells are endowed with a superior capacity to prevent the accumulation of genetic lesions, repair them, or avoid their propagation to daughter cells, which would be particularly detrimental to the whole organism. Inducible pluripotent stem cells also display a robust DNA damage response, but the stability of their genome is often conditioned by the mutational history of the cell population of origin, which constitutes an obstacle to clinical applications. Cancer stem cells are particularly tolerant to DNA damage and fail to undergo senescence or regulated cell death upon accumulation of genetic lesions. Such a resistance contributes to the genetic drift of evolving tumors as well as to their limited sensitivity to chemo- and radiotherapy. Here, we discuss the pathophysiological and therapeutic implications of the molecular pathways through which stem cells cope with DNA damage.


Subject(s)
Adult Stem Cells/pathology , DNA Damage , DNA Repair , Embryonic Stem Cells/pathology , Neoplasms/pathology , Neoplastic Stem Cells/pathology , Pluripotent Stem Cells/pathology , Adult Stem Cells/metabolism , Animals , Embryonic Stem Cells/metabolism , Genetic Drift , Genomic Instability , Humans , Mutation , Neoplasms/genetics , Neoplasms/metabolism , Neoplasms/radiotherapy , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/radiation effects , Pluripotent Stem Cells/metabolism , Radiation Tolerance/genetics
5.
Nat Rev Mol Cell Biol ; 12(6): 385-92, 2011 06.
Article in English | MEDLINE | ID: mdl-21527953

ABSTRACT

The improper distribution of chromosomes during mitosis compromises cellular functions and can reduce cellular fitness or contribute to malignant transformation. As a countermeasure, higher eukaryotes have developed strategies for eliminating mitosis-incompetent cells, one of which is mitotic catastrophe. Mitotic catastrophe is driven by a complex and poorly understood signalling cascade but, from a functional perspective, it can be defined as an oncosuppressive mechanism that precedes (and is distinct from) apoptosis, necrosis or senescence. Accordingly, the disruption of mitotic catastrophe precipitates tumorigenesis and cancer progression, and its induction constitutes a therapeutic endpoint.


Subject(s)
Aneuploidy , Chromosome Aberrations , Genomic Instability , Mitosis/genetics , Spindle Apparatus/metabolism , Animals , Apoptosis/genetics , Autophagy , Cell Cycle/genetics , Cell Division , Chromosomes , Humans , Mice , Necrosis/genetics
6.
Nucleic Acids Res ; 49(W1): W67-W71, 2021 07 02.
Article in English | MEDLINE | ID: mdl-34038531

ABSTRACT

The interaction between RNA and RNA-binding proteins (RBPs) has a key role in the regulation of gene expression, in RNA stability, and in many other biological processes. RBPs accomplish these functions by binding target RNA molecules through specific sequence and structure motifs. The identification of these binding motifs is therefore fundamental to improve our knowledge of the cellular processes and how they are regulated. Here, we present BRIO (BEAM RNA Interaction mOtifs), a new web server designed for the identification of sequence and structure RNA-binding motifs in one or more RNA molecules of interest. BRIO enables the user to scan over 2508 sequence motifs and 2296 secondary structure motifs identified in Homo sapiens and Mus musculus, in three different types of experiments (PAR-CLIP, eCLIP, HITS). The motifs are associated with the binding of 186 RBPs and 69 protein domains. The web server is freely available at http://brio.bio.uniroma2.it.


Subject(s)
RNA-Binding Proteins/metabolism , RNA/chemistry , Software , Animals , Base Sequence , Cell Line , Humans , Internet , Mice , Nucleotide Motifs , RNA/metabolism , RNA, Small Nuclear/metabolism , RNA, Viral/metabolism , Sequence Analysis, RNA
7.
Trends Genet ; 34(2): 85-87, 2018 02.
Article in English | MEDLINE | ID: mdl-29277455

ABSTRACT

Two recent genomic studies suggest that a large fraction of human tumors evolves in the presence of limited negative selection against somatic mutations. In this context, specific genetic defects enable the establishment of a hypermutant state that may constitute a target for immunotherapeutic interventions.


Subject(s)
Microsatellite Repeats , Neoplasms/genetics , DNA Repair , Humans
8.
Trends Genet ; 33(8): 491-492, 2017 08.
Article in English | MEDLINE | ID: mdl-28668385

ABSTRACT

Recent findings from a prospective clinical study involving multiregion whole-exome sequencing suggest that driver mutations in cancer-relevant genes including EGFR and TP53 are often clonal and precede whole-genome duplication events in early lung carcinogenesis. This paves an expressway to extensive subclonal diversification, elevated intratumoral heterogeneity, and dismal disease outcome.


Subject(s)
Lung Neoplasms/genetics , ErbB Receptors/genetics , Humans , Mitosis , Polyploidy , Tumor Suppressor Protein p53/genetics , Exome Sequencing
9.
Semin Cancer Biol ; 53: 31-41, 2018 12.
Article in English | MEDLINE | ID: mdl-30081229

ABSTRACT

Cancer stem cells (CSCs) are subpopulations of multipotent stem cells (SCs) responsible for the initiation, long-term clonal maintenance, growth and spreading of most human neoplasms. Reportedly, CSCs share a very robust DNA damage response (DDR) with embryonic and adult SCs, which allows them to survive endogenous and exogenous genotoxins. A range of experimental evidence indicates that CSCs have high but heterogeneous levels of replication stress (RS), arising from, and being boosted by, endogenous causes, such as specific genetic backgrounds (e.g., p53 deficiency) and/or aberrant karyotypes (e.g., supernumerary chromosomes). A multipronged RS response (RSR) is put in place by CSCs to limit and ensure tolerability to RS. The characteristics of such dedicated cascade have two opposite consequences, both relevant for cancer therapy. On the one hand, RSR efficiency often increases the reliance of CSCs on specific DDR components. On the other hand, the functional redundancy of pathways of the RSR can paradoxically promote the acquisition of resistance to RS- and/or DNA damage-inducing agents. Here, we provide an overview of the molecular mechanisms of the RSR in cancer cells and CSCs, focusing on the role of CHK1 and some emerging players, such as PARP1 and components of the homologous recombination repair, whose targeting can represent a long-term effective anti-CSC strategy.


Subject(s)
DNA Replication/genetics , Neoplasms/genetics , Neoplastic Stem Cells/metabolism , Signal Transduction/genetics , Animals , Antineoplastic Agents/therapeutic use , DNA Damage , DNA Repair , DNA Replication/drug effects , Humans , Neoplasms/drug therapy , Neoplasms/pathology , Neoplastic Stem Cells/drug effects , Signal Transduction/drug effects
10.
Gut ; 67(5): 903-917, 2018 05.
Article in English | MEDLINE | ID: mdl-28389531

ABSTRACT

OBJECTIVE: Cancer stem cells (CSCs) are responsible for tumour formation and spreading, and their targeting is required for tumour eradication. There are limited therapeutic options for advanced colorectal cancer (CRC), particularly for tumours carrying RAS-activating mutations. The aim of this study was to identify novel CSC-targeting strategies. DESIGN: To discover potential therapeutics to be clinically investigated as single agent, we performed a screening with a panel of FDA-approved or investigational drugs on primary CRC cells enriched for CSCs (CRC-SCs) isolated from 27 patients. Candidate predictive biomarkers of efficacy were identified by integrating genomic, reverse-phase protein microarray (RPPA) and cytogenetic analyses, and validated by immunostainings. DNA replication stress (RS) was increased by employing DNA replication-perturbing or polyploidising agents. RESULTS: The drug-library screening led to the identification of LY2606368 as a potent anti-CSC agent acting in vitro and in vivo in tumour cells from a considerable number of patients (∼36%). By inhibiting checkpoint kinase (CHK)1, LY2606368 affected DNA replication in most CRC-SCs, including RAS-mutated ones, forcing them into premature, lethal mitoses. Parallel genomic, RPPA and cytogenetic analyses indicated that CRC-SCs sensitive to LY2606368 displayed signs of ongoing RS response, including the phosphorylation of RPA32 and ataxia telangiectasia mutated serine/threonine kinase (ATM). This was associated with mutation(s) in TP53 and hyperdiploidy, and made these CRC-SCs exquisitely dependent on CHK1 function. Accordingly, experimental increase of RS sensitised resistant CRC-SCs to LY2606368. CONCLUSIONS: LY2606368 selectively eliminates replication-stressed, p53-deficient and hyperdiploid CRC-SCs independently of RAS mutational status. These results provide a strong rationale for biomarker-driven clinical trials with LY2606368 in patients with CRC.


Subject(s)
Antineoplastic Agents/pharmacology , Checkpoint Kinase 1/drug effects , Colorectal Neoplasms/drug therapy , Neoplastic Stem Cells/drug effects , Pyrazines/pharmacology , Pyrazoles/pharmacology , Cell Line, Tumor , Checkpoint Kinase 1/genetics , Colorectal Neoplasms/genetics , DNA Replication/drug effects , Humans , Immunohistochemistry , Mutation , Neoplastic Stem Cells/metabolism , Oligonucleotide Array Sequence Analysis , Tumor Suppressor Protein p53/genetics
11.
Int J Cancer ; 140(11): 2587-2595, 2017 06 01.
Article in English | MEDLINE | ID: mdl-28233295

ABSTRACT

The DNA damage response (DDR) network is exploited by cancer cells to withstand chemotherapy. Gastric cancer (GC) carries deregulation of the DDR and harbors genetic defects that fuel its activation. The ATM-Chk2 and ATR-Chk1-Wee1 axes are deputed to initiate DNA repair. Overactivation of these pathways in cancer cells may represent an adaptive response for compensating genetic defects deregulating G1 -S transition (e.g., TP53) and ATM/ATR-initiated DNA repair (e.g., ARID1A). We hypothesized that DDR-linked biomarkers may predict clinical outcomes in GC patients treated with chemotherapy. Immunohistochemical assessment of DDR kinases (pATM, pChk2, pChk1 and pWee1) and DNA damage markers (γ-H2AX and pRPA32) was performed in biological samples from 110 advanced GC patients treated with first-line chemotherapy, either in phase II trials or in routine clinical practice. In 90 patients, this characterization was integrated with targeted ultra-deep sequencing for evaluating the mutational status of TP53 and ARID1A. We recorded a positive association between the investigated biomarkers. The combination of two biomarkers (γ-H2AXhigh /pATMhigh ) was an adverse factor for both progression-free survival (multivariate Cox: HR 2.23, 95%CI: 1.47-3.40) and overall survival (multivariate Cox: HR: 2.07, 95%CI: 1.20-3.58). The relationship between the γ-H2AXhigh /pATMhigh model and progression-free survival was consistent across the different TP53 backgrounds and was maintained in the ARID1A wild-type setting. Conversely, this association was no longer observed in an ARID1A-mutated subgroup. The γ-H2AXhigh /pATMhigh model negatively impacted survival outcomes in GC patients treated with chemotherapy. The mutational status of ARID1A, but apparently not TP53 mutations, affects its predictive significance.


Subject(s)
Antineoplastic Agents/therapeutic use , DNA Damage/drug effects , DNA Repair/drug effects , Stomach Neoplasms/drug therapy , Aged , Ataxia Telangiectasia Mutated Proteins/metabolism , Biomarkers, Tumor/metabolism , Cell Cycle Proteins , DNA-Binding Proteins/metabolism , Disease-Free Survival , Female , Gastric Mucosa/metabolism , Histones/metabolism , Humans , Male , Middle Aged , Protein Kinases/metabolism , Signal Transduction/drug effects , Stomach/drug effects , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism
12.
BMC Cancer ; 17(1): 101, 2017 Feb 06.
Article in English | MEDLINE | ID: mdl-28166748

ABSTRACT

BACKGROUND: Body mass index (BMI) is largely investigated as a prognostic and predictive factor in triple-negative breast cancer (TNBC). Overweight and obesity are linked to a variety of pathways regulating tumor-promoting functions, including the DNA damage response (DDR). The DDR physiologically safeguards genome integrity but, in a neoplastic background, it is aberrantly engaged and protects cancer cells from chemotherapy. We herein verified the role of BMI on a previously assessed association between DDR biomarkers and pathological complete response (pCR) in TNBC patients treated with neoadjuvant chemotherapy (NACT). METHODS: In this retrospective analysis 54 TNBC patients treated with NACT were included. The relationship between DDR biomarkers, namely phosphorylated H2A Histone Family Member X (γ-H2AX) and phosphorylated checkpoint kinase 1 (pChk1), and pCR was reconsidered in light of BMI data. The Pearson's Chi-squared test of independence (2-tailed) and the Fisher Exact test were employed to assess the relationship between clinical-molecular variables and pCR. Uni- and multivariate logistic regression models were used to identify variables impacting pCR. Internal validation was carried out. RESULTS: We observed a significant association between elevated levels of the two DDR biomarkers and pCR in patients with BMI < 25 (p = 0.009 and p = 0.022 for γ-H2AX and pChk1, respectively), but not in their heavier counterpart. Results regarding γ-H2AX were confirmed in uni- and multivariate models and, again, for leaner patients only (γ-H2AXhigh vs γ-H2AXlow: OR 10.83, 95% CI: 1.79-65.55, p = 0.009). The consistency of this finding was confirmed upon internal validation. CONCLUSIONS: The predictive significance of γ-H2AX varies according to BMI status. Indeed, elevated levels of γ-H2AX seemed associated with lower pCR rate only in leaner patients, whereas differences in pCR rate according to γ-H2AX levels were not appreciable in heavier patients. Larger investigations are warranted concerning the potential role of BMI as effect modifier of the relationship between DDR-related biomarkers and clinical outcomes in TNBC.


Subject(s)
Body Mass Index , Checkpoint Kinase 1/analysis , DNA Damage , Histones/analysis , Neoadjuvant Therapy , Triple Negative Breast Neoplasms/pathology , Checkpoint Kinase 1/chemistry , Checkpoint Kinase 1/metabolism , Female , Histones/metabolism , Humans , Middle Aged , Obesity/complications , Phosphorylation , Retrospective Studies , Triple Negative Breast Neoplasms/complications , Triple Negative Breast Neoplasms/diagnosis , Triple Negative Breast Neoplasms/therapy
13.
Proc Natl Acad Sci U S A ; 111(8): 3020-5, 2014 Feb 25.
Article in English | MEDLINE | ID: mdl-24516128

ABSTRACT

Tetraploidy constitutes a genomically metastable state that can lead to aneuploidy and genomic instability. Tetraploid cells are frequently found in preneoplastic lesions, including intestinal cancers arising due to the inactivation of the tumor suppressor adenomatous polyposis coli (APC). Using a phenotypic screen, we identified resveratrol as an agent that selectively reduces the fitness of tetraploid cells by slowing down their cell cycle progression and by stimulating the intrinsic pathway of apoptosis. Selective killing of tetraploid cells was observed for a series of additional agents that indirectly or directly stimulate AMP-activated protein kinase (AMPK) including salicylate, whose chemopreventive action has been established by epidemiological studies and clinical trials. Both resveratrol and salicylate reduced the formation of tetraploid or higher-order polyploid cells resulting from the culture of human colon carcinoma cell lines or primary mouse epithelial cells lacking tumor protein p53 (TP53, best known as p53) in the presence of antimitotic agents, as determined by cytofluorometric and videomicroscopic assays. Moreover, oral treatment with either resveratrol or aspirin, the prodrug of salicylate, repressed the accumulation of tetraploid intestinal epithelial cells in the Apc(Min/+) mouse model of colon cancer. Collectively, our results suggest that the chemopreventive action of resveratrol and aspirin involves the elimination of tetraploid cancer cell precursors.


Subject(s)
Adenomatous Polyposis Coli/prevention & control , Aspirin/therapeutic use , Cell Death/drug effects , Epithelial Cells/drug effects , Stilbenes/therapeutic use , Tetraploidy , Animals , Aspirin/pharmacology , Cell Line, Tumor , Epithelial Cells/chemistry , Flow Cytometry , Image Processing, Computer-Assisted , In Situ Hybridization, Fluorescence , Mice , Mice, Inbred C57BL , Microscopy, Video , Resveratrol , Stilbenes/pharmacology
14.
Expert Rev Mol Med ; 17: e14, 2015 Jul 02.
Article in English | MEDLINE | ID: mdl-26136233

ABSTRACT

The Hippo signalling is emerging as a tumour suppressor pathway whose function is regulated by an intricate network of intracellular and extracellular cues. Defects in the signal cascade lead to the activation of the Hippo transducers TAZ and YAP. Compelling preclinical evidence showed that TAZ/YAP are often aberrantly engaged in breast cancer (BC), where their hyperactivation culminates into a variety of tumour-promoting functions such as epithelial-to-mesenchymal transition, cancer stem cell generation and therapeutic resistance. Having acquired a more thorough understanding in the biology of TAZ/YAP, and the molecular outputs they elicit, has prompted a first wave of exploratory, clinically-focused analyses aimed at providing initial hints on the prognostic/predictive significance of their expression. In this review, we discuss oncogenic activities linked with TAZ/YAP in BC, and we propose clinical strategies for investigating their role as biomarkers in the clinical setting. Finally, we address the therapeutic potential of TAZ/YAP targeting and the modalities that, in our opinion, should be pursued in order to further study the biological and clinical consequences of their inhibition.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Breast Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Intracellular Signaling Peptides and Proteins/genetics , Phosphoproteins/genetics , Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Adaptor Proteins, Signal Transducing/metabolism , Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Clinical Trials as Topic , Drug Resistance, Neoplasm/genetics , Epithelial-Mesenchymal Transition , Female , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/metabolism , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Phosphoproteins/antagonists & inhibitors , Phosphoproteins/metabolism , Phosphorylation , Signal Transduction , Trans-Activators , Transcription Factors , Transcriptional Coactivator with PDZ-Binding Motif Proteins , YAP-Signaling Proteins
15.
EMBO J ; 29(7): 1272-84, 2010 Apr 07.
Article in English | MEDLINE | ID: mdl-20186124

ABSTRACT

Tetraploidy can constitute a metastable intermediate between normal diploidy and oncogenic aneuploidy. Here, we show that the absence of p53 is not only permissive for the survival but also for multipolar asymmetric divisions of tetraploid cells, which lead to the generation of aneuploid cells with a near-to-diploid chromosome content. Multipolar mitoses (which reduce the tetraploid genome to a sub-tetraploid state) are more frequent when p53 is downregulated and the product of the Mos oncogene is upregulated. Mos inhibits the coalescence of supernumerary centrosomes that allow for normal bipolar mitoses of tetraploid cells. In the absence of p53, Mos knockdown prevents multipolar mitoses and exerts genome-stabilizing effects. These results elucidate the mechanisms through which asymmetric cell division drives chromosomal instability in tetraploid cells.


Subject(s)
Carcinoma/metabolism , Colonic Neoplasms/metabolism , Genes, mos , Mitosis , Polyploidy , Tumor Suppressor Protein p53/metabolism , Aneuploidy , Animals , Carcinoma/genetics , Cell Line, Tumor , Centrosome/metabolism , Chromosomal Instability , Colonic Neoplasms/genetics , Female , Gene Deletion , Gene Expression Regulation, Neoplastic , Humans , Mice , Mice, Nude , Tumor Suppressor Protein p53/genetics
16.
EMBO J ; 29(3): 619-31, 2010 Feb 03.
Article in English | MEDLINE | ID: mdl-19959994

ABSTRACT

In response to stress, cells start transcriptional and transcription-independent programs that can lead to adaptation or death. Here, we show that multiple inducers of autophagy, including nutrient depletion, trigger the activation of the IKK (IkappaB kinase) complex that is best known for its essential role in the activation of the transcription factor NF-kappaB by stress. Constitutively active IKK subunits stimulated autophagy and transduced multiple signals that operate in starvation-induced autophagy, including the phosphorylation of AMPK and JNK1. Genetic inhibition of the nuclear translocation of NF-kappaB or ablation of the p65/RelA NF-kappaB subunit failed to suppress IKK-induced autophagy, indicating that IKK can promote the autophagic pathway in an NF-kappaB-independent manner. In murine and human cells, knockout and/or knockdown of IKK subunits (but not that of p65) prevented the induction of autophagy in response to multiple stimuli. Moreover, the knockout of IKK-beta suppressed the activation of autophagy by food deprivation or rapamycin injections in vivo, in mice. Altogether, these results indicate that IKK has a cardinal role in the stimulation of autophagy by physiological and pharmacological stimuli.


Subject(s)
Autophagy/physiology , I-kappa B Kinase/physiology , Animals , Autophagy/genetics , Cells, Cultured , HeLa Cells , Humans , I-kappa B Kinase/genetics , I-kappa B Kinase/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Multiprotein Complexes/genetics , Multiprotein Complexes/metabolism , Multiprotein Complexes/physiology , NF-kappa B/genetics , NF-kappa B/metabolism , NIH 3T3 Cells , Signal Transduction/physiology
17.
Methods Cell Biol ; 181: 43-58, 2024.
Article in English | MEDLINE | ID: mdl-38302243

ABSTRACT

Senescence is a state of irreversible cell cycle arrest accompanied by the acquisition of the senescence-associated secretory phenotype (SASP), which is activated in response to a variety of damaging stimuli, including genotoxic therapy. Accumulating evidence indicates that mitotic stress also promotes entry into senescence. This occurs via a mechanism involving defective mitoses and mitotic arrest, followed by abortion of cell division and slippage in the G1 phase. In this process, mitotic slippage leads to the generation of senescent cells characterized by a large cell body and a multinucleated and/or enlarged nuclear size. Here, we provide a detailed protocol for the assessment of cell proliferation and mitotic slippage in colorectal cancer cells upon pharmacological inhibition of the mitotic kinesin KIF11, best known as EG5. This approach can be used for preliminary characterization of senescence induction by therapeutics, but requires validation with standard senescence assays.


Subject(s)
Apoptosis , Mitosis , Microscopy, Video , Mitosis/genetics , Cell Proliferation
18.
Cell Death Differ ; 30(5): 1097-1154, 2023 05.
Article in English | MEDLINE | ID: mdl-37100955

ABSTRACT

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.


Subject(s)
Apoptosis , Caspases , Animals , Humans , Apoptosis/genetics , Cell Death , Caspases/genetics , Caspases/metabolism , Carcinogenesis , Mammals/metabolism
19.
Cancer Cell ; 39(12): 1573-1575, 2021 12 13.
Article in English | MEDLINE | ID: mdl-34906316

ABSTRACT

Two recent reports in Nature highlight a novel mechanism of immunoevasion that relies on the SET domain bifurcated histone lysine methyltransferase 1 (SETDB1)-dependent epigenetic suppression of endogenous retroelements in melanoma cells. Because SETDB1 is highly expressed by the stem cell compartment, these findings delineate an innovative strategy for restoring cancer stem cell immunosurveillance.


Subject(s)
Neoplasms , Epigenesis, Genetic , Epigenomics , Humans , Neoplastic Stem Cells
20.
Nat Med ; 27(2): 212-224, 2021 02.
Article in English | MEDLINE | ID: mdl-33574607

ABSTRACT

Most (if not all) tumors emerge and progress under a strong evolutionary pressure imposed by trophic, metabolic, immunological, and therapeutic factors. The relative impact of these factors on tumor evolution changes over space and time, ultimately favoring the establishment of a neoplastic microenvironment that exhibits considerable genetic, phenotypic, and behavioral heterogeneity in all its components. Here, we discuss the main sources of intratumoral heterogeneity and its impact on the natural history of the disease, including sensitivity to treatment, as we delineate potential strategies to target such a detrimental feature of aggressive malignancies.


Subject(s)
Genetic Heterogeneity , Immunologic Factors/genetics , Neoplasms/genetics , Tumor Microenvironment/genetics , Disease Progression , Drug Resistance, Neoplasm/genetics , Humans , Immunotherapy , Neoplasms/immunology , Neoplasms/pathology , Tumor Microenvironment/immunology
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