Micronuclei Frequency in Tumors Is a Predictive Biomarker for Genetic Instability and Sensitivity to the DNA Repair Inhibitor AsiDNA

Jdey, Wael; Thierry, Sylvain; Popova, Tatiana; Stern, Marc‐Henri; Dutreix, Marie

doi:10.1158/0008-5472.can-16-2693

Cited by 28 publications

(23 citation statements)

References 44 publications

(59 reference statements)

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“…Moreover, this defect accounted as the only irreversible event upon doxycycline removal. Observed at elevated frequencies in cancer cell lines, micronuclei frequency is a predictive biomarker for genetic instability and for rapid karyotype evolution [ 105 ], as their few chromosomes, unprotected from DNA damage, may undergo chromothripsis and chromoanasynthesis [ 106 ] and then get incorporated into the genome of the host cell within just 1–2 mitoses [ 107 ].…”

Section: Discussionmentioning

confidence: 99%

Nuclear Isoforms of Neurofibromin Are Required for Proper Spindle Organization and Chromosome Segregation

Peta

Tsirimonaki

Samouil

et al. 2020

Cells

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Mitotic spindles are highly organized, microtubule (MT)-based, transient structures that serve the fundamental function of unerring chromosome segregation during cell division and thus of genomic stability during tissue morphogenesis and homeostasis. Hence, a multitude of MT-associated proteins (MAPs) regulates the dynamic assembly of MTs in preparation for mitosis. Some tumor suppressors, normally functioning to prevent tumor development, have now emerged as significant MAPs. Among those, neurofibromin, the product of the Neurofibromatosis-1 gene (NF1), a major Ras GTPase activating protein (RasGAP) in neural cells, controls also the critical function of chromosome congression in astrocytic cellular contexts. Cell type- and development-regulated splicings may lead to the inclusion or exclusion of NF1exon51, which bears a nuclear localization sequence (NLS) for nuclear import at G2; yet the functions of the produced NLS and ΔNLS neurofibromin isoforms have not been previously addressed. By using a lentiviral shRNA system, we have generated glioblastoma SF268 cell lines with conditional knockdown of NLS or ΔNLS transcripts. In dissecting the roles of NLS or ΔNLS neurofibromins, we found that NLS-neurofibromin knockdown led to increased density of cytosolic MTs but loss of MT intersections, anastral spindles featuring large hollows and abnormal chromosome positioning, and finally abnormal chromosome segregation and increased micronuclei frequency. Therefore, we propose that NLS neurofibromin isoforms exert prominent mitotic functions.

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Section: Discussionmentioning

confidence: 99%

Nuclear Isoforms of Neurofibromin Are Required for Proper Spindle Organization and Chromosome Segregation

Peta

Tsirimonaki

Samouil

et al. 2020

Cells

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“…In tumour cells, increased genomic instability results in the formation of micronuclei, because DNA is mis-segregated during cell division. 166,167 Breakdown of the micronuclear envelope associated with chromothripsis exposes the self-DNA to the cytosol, leading to rapid accumulation of cGAS, 168 which binds to and is activated by the exposed nucleic acids, 169 resulting in STING phosphorylation and interferon induction. 169,170 Alternatively, tumour-derived DNA can activate cGAS-STING in host APCs after tumour cell phagocytosis.…”

Section: Cgas-sting Pathwaymentioning

confidence: 99%

Phagocytosis checkpoints as new targets for cancer immunotherapy

et al. 2019

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Cancer immunotherapies that target adaptive immune checkpoints have significantly improved patient outcomes for multiple metastatic and treatment-refractory cancers. Recent studies, however, have demonstrated that innate immune checkpoints, which interfere with the detection and clearance of malignant cells and suppress innate sensing, also play a critical role in tumourmediated immune escape and may be potential targets for cancer immunotherapy. In this review, we highlight the current understanding of how cancer cells evade the immune system by disrupting phagocytic clearance and the implications of phagocytosis checkpoint blockade on the activation of antitumour immune responses. A better understanding of the tumour-intrinsic processes that inhibit essential immune surveillance processes such as phagocytosis and innate sensing could pave the way for developing more effective combination immunotherapy strategies that incorporate both innate and adaptive immune responses to treat patients with cancer.

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“…The unique mechanism of action of AsiDNA, which activates two independent target enzymes and inhibits several repair pathways, differs from other DNA repair inhibitors. Indeed, intrinsic resistance of tumor cells to a single exposure of AsiDNA has been shown to be associated with multiple parameters such as high mRNA expression level; copy number gains; and mutations in processes involved in cell proliferation, cell survival, epithelial-mesenchymal transition, and cell motility [10]. In this study, the potential of AsiDNA, in comparison with other anticancer treatments such as PARP inhibitors, to promote acquired resistance was evaluated by performing repeated cyclic treatments.…”

Section: Introductionmentioning

confidence: 99%

AsiDNA Treatment Induces Cumulative Antitumor Efficacy with a Low Probability of Acquired Resistance

et al. 2019

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The Achilles heel of anticancer treatments is intrinsic or acquired resistance. Among many targeted therapies, the DNA repair inhibitors show limited efficacy due to rapid emergence of resistance. We examined evolution of cancer cells and tumors treated with AsiDNA, a new DNA repair inhibitor targeting all DNA break repair pathways. Effects of AsiDNA or Olaparib were analyzed in various cell lines. Frequency of AsiDNA- and olaparib-resistant clones was measured after 2 weeks of continuous treatment in KBM7 haploid cells. Cell survivals were also measured after one to six cycles of 1-week treatment and 1-week recovery in MDA-MB-231 and NCI-H446. Transcriptomes of cell populations recovering from cyclic treatments or mock treatment were compared. MDA-MB-231 xenografted models were treated with three cycles of AsiDNA to monitor the effects of treatment on tumor growth and transcriptional modifications. No resistant clones were selected after AsiDNA treatment (frequency < 3x10 −8 ) in treatment conditions that generate resistance to olaparib at a frequency of 7.2x10 −7 resistant clones per treated cell. Cyclic treatments promote cumulative sensitivity characterized by a higher mortality of cells having undergone previous treatment cycles. This sensitization was stable, and transcriptome analysis revealed a major gene downregulation with a specific overrepresentation of genes coding for targets of DNA-PK. Such changes were also detected in tumor models which showed impaired growth after cycles of AsiDNA treatment.

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Micronuclei Frequency in Tumors Is a Predictive Biomarker for Genetic Instability and Sensitivity to the DNA Repair Inhibitor AsiDNA

Cited by 28 publications

References 44 publications

Nuclear Isoforms of Neurofibromin Are Required for Proper Spindle Organization and Chromosome Segregation

Nuclear Isoforms of Neurofibromin Are Required for Proper Spindle Organization and Chromosome Segregation

Phagocytosis checkpoints as new targets for cancer immunotherapy

AsiDNA Treatment Induces Cumulative Antitumor Efficacy with a Low Probability of Acquired Resistance

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