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Cited by 1,638interferon and immune responsesMicrotubule and mitosis dynamicsDNA Repair Mechanisms

Chromosomal instability drives metastasis through a cytosolic DNA response

Open access
Bakhoum, Samuel F., Ngo, Bryan, Laughney, Ashley M., Cavallo, Julie-Ann, Murphy, Charles J., Ly, Peter, Shah, Pragya, Sriram, Roshan K. +25 more·2018·Nature
DOI 10.1038/nature25432PMC PMC5785464
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Abstract

Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling. Genetic suppression of chromosomal instability markedly delays metastasis even in highly aneuploid tumour models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs.

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Crossref · 10.1038/nature25432

Cites

60 of 60 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

24 of 29 cited sources checked · 10 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Chromosomally unstable cells exhibit evidence of chromosome missegregation during anaphase.

    “Chromosomally unstable cells exhibit evidence of chromosome missegregation during anaphase3,4”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [3] Thompson, S. L. & Compton, D. A. Examining the link between chromosomal instability and aneuploidy in human cells. J. Cell Biol. 180, 665–672 (2008) source
    • cites [4] Cimini, D. et al. Merotelic kinetochore orientation is a major mechanism of aneuploidy in mitotic mammalian tissue cells. J. Cell Biol. 153, 517–527 (2001) source

      The Results section reports lagging chromosomes and occasional sister-chromatid missegregation during anaphase in PtK1 cells. It does not establish that the cells studied were chromosomally unstable, so the claim’s population qualifier is not supported by this paper. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Findingown data

    Overexpression of Kif2a had no effect on CIN despite exhibiting microtubule-depolymerizing activity on interphase microtubules.

    “we overexpressed Kif2a, a third member of the kinesin-13 proteins that lacks kinetochore and centromere localization domains13, and observed no effect on CIN despite exhibiting microtubule-depolymerizing activity on interphase microtubules”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [13] Ems-McClung, S. C. & Walczak, C. E. Kinesin-13s in mitosis: key players in the spatial and temporal organization of spindle microtubules. Semin. Cell Dev. Biol. 21, 276–282 (2010) source

      The citation is attached to the description of Kif2A, not to the citing authors’ own overexpression and CIN results. Section 3.1 identifies Kif2A as a kinesin-13 found mainly at spindle poles, but also reports its association with centromeres; the copy does not establish that it lacks kinetochore and centromere localization domains. The cited review does not report the stated overexpression experiment. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
  • Premisecitation

    Overexpression of Kif2b or MCAK directly suppresses CIN in otherwise chromosomally unstable cells.

    “Destabilization of microtubule attachments to chromosomes at the kinetochores, through overexpression of the non-motile microtubule depolymerizing kinesin-13 proteins, Kif2b or MCAK/Kif2c, directly suppresses CIN in otherwise chromosomally unstable cells5–7.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [5] Bakhoum, S. F. et al. The mitotic origin of chromosomal instability. Curr. Biol. 24, R148–R149 (2014) source

      In the main text (page unavailable), GFP–Kif2b overexpression reduced karyotypic heterogeneity in two CIN+ cell lines, supporting suppression of CIN. The paper also reports earlier results for kinesin-13 overexpression in two other CIN+ lines, but our copy does not identify MCAK/Kif2c or establish its effect separately. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [6] Bakhoum, S. F. et al. Numerical chromosomal instability mediates susceptibility to radiation treatment. Nat. Commun. 6, 5990 (2015) source
    • cites [7] Bakhoum, S. F., Thompson, S. L., Manning, A. L. & Compton, D. A. Genome stability is ensured by temporal control of kinetochore–microtubule dynamics. Nat. Cell Biol. 11, 27–35 (2009) source
  • Findingcitation

    Overexpression of a dominant negative MCAK mutant led to a modest increase in chromosome missegregation in MDA-MB-231 cells.

    “whereas overexpression of a dominant negative MCAK mutant12 (dnMCAK) led to a modest increase in chromosome missegregation in MDA-MB-231 cells.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] Moore, A. T. et al. MCAK associates with the tips of polymerizing microtubules. J. Cell Biol. 169, 391–397 (2005) source
  • Premisecitation

    Cells overexpressing Kif2b or MCAK continue to propagate abnormal aneuploid karyotypes in a stable manner.

    “Cells overexpressing Kif2b or MCAK continue to propagate abnormal aneuploid karyotypes albeit in a stable manner7.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [7] Bakhoum, S. F., Thompson, S. L., Manning, A. L. & Compton, D. A. Genome stability is ensured by temporal control of kinetochore–microtubule dynamics. Nat. Cell Biol. 11, 27–35 (2009) source
  • May combine two claims. 32
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Findingcitation

    Overexpression of Mad2 in MCAK-expressing cells partially rescued chromosome missegregation and correspondingly augmented metastasis.

    “Overexpression of the spindle assembly checkpoint protein, Mad2 in MCAK-expressing cells partially rescued chromosome missegregation15, and correspondingly augmented metastasis”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [15] Sotillo, R. et al. Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell 11, 9–23 (2007) source

      The Summary (p. 1) and the chromosomal-instability results (p. 5) describe Mad2 overexpression in mice and fibroblasts, not in MCAK-expressing cells. Searches for MCAK, rescue of missegregation, and metastasis found no passage addressing those claimed outcomes. The reported increase in segregation defects without MCAK does not establish what happens when MCAK is expressed. (LLM, conf=0.75)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Suppressing micronuclear envelope rupture through mCherry-Lamin B2 overexpression reduced cytosolic dsDNA staining without influencing chromosome segregation errors.

    “Suppressing micronuclear envelope rupture through mCherry-Lamin B2 overexpression20 reduced cytosolic dsDNA staining without influencing chromosome segregation errors.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [20] Hatch, E. M., Fischer, A. H., Deerinck, T. J. & Hetzer, M. W. Catastrophic nuclear envelope collapse in cancer cell micronuclei. Cell 154, 47–60 (2013) source

      The Results section, “NE collapse is triggered by lamin disorganization” (page unavailable), reports that LmnB2 expression increased the proportion of intact micronuclei. It does not report reduced cytosolic dsDNA staining or test whether LmnB2 overexpression affects chromosome segregation errors. A separate Results passage finds no significant effect of micronuclear disruption on micronucleus formation after a second mitosis, but that is not the stated overexpression comparison. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    There was evidence for noncanonical NF-κB activation in CIN-high cells as revealed by lower levels of p100, a trend toward higher ratios of p52 and phosphorylated p100 relative to total p100, and lower levels of TRAF2.

    “We found evidence for noncanonical NF-κB activation in CIN-high cells as revealed by lower levels of the precursor protein, p100, a trend toward higher ratios of p52 and phosphorylated p100 relative to total p100, as well as lower levels of the noncanonical NF-κB pathway inhibitor, TRAF231”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [31] Sun, S.-C. Controlling the fate of NIK: a central stage in noncanonical NF-κB signaling. Sci. Signal. 3, pe18 (2010) source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    These findings are in line with reported roles for the noncanonical NF-κB pathway in EMT, cellular invasion, and metastasis.

    “These findings are in line with reported roles for the noncanonical NF-κB pathway in EMT, cellular invasion, and metastasis33–35.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [33] Wang, X. et al. Oestrogen signalling inhibits invasive phenotype by repressing RelB and its target BCL2. Nat. Cell Biol. 9, 470–478 (2007) source

      The Abstract reports that RelB promotes EMT and an invasive phenotype in breast cancer cells. It discusses metastasis through prior findings about NF-κB and Bcl-2, and calls for future studies of RelB in metastatic breast disease; it does not establish a role for the RelB pathway in metastasis. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [34] Wang, J., Yi, S., Zhou, J., Zhang, Y. & Guo, F. The NF-κB subunit RelB regulates the migration and invasion abilities and the radio-sensitivity of prostate cancer cells. Int. J. Oncol. 49, 381–392 (2016) source

      The Discussion (p. 10) reports a role for RelB, a noncanonical NF-κB subunit, in EMT in breast cancer cells and shows that RelB knockdown reduced invasion in prostate cancer cells. It discusses links to metastasis, but does not establish that RelB itself promotes metastasis; the authors say in vivo studies remain for future work (Discussion, p. 11). (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [35] Yang, C. et al. Antagonism of inhibitor of apoptosis proteins increases bone metastasis via unexpected osteoclast activation. Cancer Discov. 3, 212–223 (2013) source

      The Results section ('Osteoclast expression of constitutively active NIK promotes tumor growth in bone'; page unavailable) links activation of the alternative NF-κB pathway in osteoclasts to increased tumor burden in bone. The Discussion likewise describes promotion of metastatic growth through osteoclast activity. These passages support a role in bone metastatic growth, but do not establish roles in EMT or cellular invasion. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Kinesin-13 overexpression did not alter cellular proliferation or the number of centrosomes per cell.

    “Kinesin-13 overexpression did not alter cellular proliferation or the number of centrosomes per cell (Fig. 2a–b, Extended Data Figs. 1f–h and 3a).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    CIN-low cells maintained highly aneuploid karyotypes, yet faithfully propagated them in a stable manner.

    “Importantly, CIN-low cells maintained highly aneuploid karyotypes, yet they faithfully propagated them in a stable manner.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Metastases from CIN-high cells involved multiple organs and rapidly progressed leading to death.

    “whereas metastases from CIN-high cells involved multiple organs and rapidly progressed leading to death.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Depletion of STING, RelB, or p100 (NFKB2) in CIN-high cells reduced metastatic dissemination, extended lifespan, and reduced in vitro and in vivo invasion.

    “as evidenced by reduction in metastatic dissemination, lifespan extension, and reduction in in vitro and in vivo invasion in CIN-high cells depleted of STING, RelB, or p100 (NFKB2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Addition of cGAMP or overexpression of Mad2 increased nuclear RelB in MCAK-expressing cells.

    “whereas the addition of cGAMP or overexpression of Mad2 increased nuclear RelB in MCAK-expressing cells (Fig. 6d, Extended Data Figs. 4e and 9c–e).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The injected cell lines and most metastases had three copies of chromosome 1, whereas primary tumors consistently had 2 copies.

    “Karyotype analysis revealed that the injected cell lines and most metastases had three copies of chromosome 1, whereas primary tumors consistently had 2 copies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Induced missegregation of the Y chromosome led to the upregulation of OAS2 and increased interferon-β production by DLD-1 cells.

    “Indeed, induced missegregation of the Y chromosome led to the upregulation of OAS2, an ISG, and increased interferon-β production by DLD-1 cells (Extended Data Fig. 9f–g).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mice injected with CIN-low cells exhibited lower metastatic burden and a median survival of 207 days.

    “Conversely, mice injected with CIN-low cells exhibited lower metastatic burden and a median survival of 207 days.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    STING depletion reduced RelB nuclear localization and led to downregulation of EMT and inflammatory pathways.

    “STING depletion reduced RelB nuclear localization and led to downregulation of EMT and inflammatory pathways”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The dsDNA signal disappeared after treatment with double-strand-specific nuclease and after overexpression of Dnase2, confirming the specificity of the antibodies.

    “The dsDNA signal, which was distinct from mitochondrial staining, disappeared after treatment with double-strand-specific – but not single-strand-specific – nuclease and after overexpression of Dnase2, confirming the specificity of these antibodies”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Suppression of CIN had no effect on primary tumor implantation efficiency and even enhanced primary tumor growth in the 4T1 model.

    “Suppression of CIN had no effect on primary tumor implantation efficiency and even enhanced primary tumor growth in the 4T1 model.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Y chromosome-specific fragments were found dispersed within the cytosol 2-3 days after Dox/IAA addition, whereas the control autosome remained confined to the nucleus.

    “Strikingly, Y chromosome-specific fragments were found dispersed within the cytosol 2–3 days after Dox/IAA addition, whereas the control autosome remained confined to the nucleus (Fig. 5h), demonstrating that cytosolic DNA is generated from chromosomes undergoing high rates of missegregation”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In both orthotopic models, suppression of CIN significantly reduced spontaneous metastasis and prolonged survival.

    “Yet, in both models, suppression of CIN significantly reduced spontaneous metastasis and prolonged survival (Extended Data Fig. 3d–e).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Gene-gene Pearson correlation analysis using scRNA-seq data identified two large gene modules: module 1 characterized by proliferative and metabolic pathways, and module 2 comprising EMT and inflammation gene sets.

    “we performed a gene-gene Pearson correlation analysis using scRNA-seq data and identified two large gene modules: module 1 was characterized by proliferative and metabolic pathways, whereas module 2 comprised EMT and inflammation gene sets”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    RhoA and Rac1 pull-down assays revealed low basal levels of activity and no correlation with kinesin-13 overexpression.

    “We ruled out a direct role for kinesin-13-mediated microtubule depolymerization in activating small GTPases14 by performing RhoA and Rac1 pull-down assays, which revealed low basal levels of activity and no correlation with kinesin-13 overexpression”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Waterman-Storer, C. M., Worthylake, R. A., Liu, B. P., Burridge, K. & Salmon, E. D. Microtubule growth activates Rac1 to promote lamellipodial protrusion in fibroblasts. Nat. Cell Biol. 1, 45–50 (1999) source

  • May combine two claims.

    Findingown data

    PCA and unsupervised clustering accurately separated samples according to their CIN status.

    “Principle component analysis (PCA) and unsupervised clustering accurately separated samples according to their CIN status.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There was a robust correlation between the CIN signature, STING, and the CIN-responsive NC-NF-κB genes in scRNA-seq data, in contrast to a weaker correlation between CIN and type I interferon targets.

    “There was a robust correlation between the CIN signature, STING, and the CIN-responsive NC-NF-κB genes in scRNA-seq data, in contrast to a weaker correlation between CIN and type I interferon targets”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Increased canonical NF-κB or type I interferon regulatory factors were associated with an improved prognosis.

    “Conversely, increased canonical NF-κB or type I interferon regulatory factors were associated with an improved prognosis (Extended Data Fig. 10a).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    CIN-high cells had increased cytosolic dsDNA and single-stranded DNA.

    “we stained cells using two different anti-dsDNA antibodies after selective plasma membrane permeabilization and found increased cytosolic dsDNA and single-stranded DNA (ssDNA) in CIN-high cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CIN-high cells and those derived from metastases exhibited a higher preponderance of micronuclei compared with CIN-low or primary tumor-derived cells, respectively.

    “CIN-high cells and those derived from metastases exhibited a higher preponderance of micronuclei compared with CIN-low or primary tumor-derived cells, respectively”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CIN-high cells displayed evidence of actin cytoskeletal reorganization, diffuse vimentin staining, and increased cytoplasmic and nuclear localization of β-catenin.

    “and displayed evidence of actin cytoskeletal reorganization, diffuse vimentin staining, and increased cytoplasmic and nuclear localization of β-catenin (Extended Data Figs. 6c–d and 7a–d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Metastases contained a large number of differentially upregulated EMT and inflammation-related genes that were disproportionately clustered on chromosome 1, signifying chromosome 1-specific selection.

    “Yet, metastases contained a large number of differentially upregulated EMT and inflammation-related genes that were disproportionately clustered on chromosome 1, signifying chromosome 1-specific selection.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Changes in β-catenin are seen upon alteration of CIN; β-catenin is enriched at cell-to-cell junctions in MCAK expressing cells but cytoplasmic and nuclear in dnMCAK expressing cells.

    “Changes in β-catenin are seen upon alteration of CIN; enriched at cell-to-cell junctions in MCAK expressing cells but cytoplasmic and nuclear in dnMCAK expressing cells”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Cytosolic DNA leads to activation of the cGAS-STING cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signaling.

    “This leads to the activation of the cGAS-STING cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signaling.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    CIN generates micronuclei and cytosolic DNA.

    “CIN generates micronuclei and cytosolic DNA”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given

    There was no need to randomize animals.

    “There was no need to randomize animals.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Diploid controls were used to determine the false positive rate of the centromeric probes.

    “Diploid controls were used to determine false positive rate of the centromeric probes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Investigators were not blinded to group allocation.

    “Investigators were not blinded to group allocation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All cells tested negative for mycoplasma.

    “All cells tested negative for mycoplasma.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Ongoing chromosome missegregation is required to replenish cytosolic DNA pools and to maintain cells in a pro-metastatic state.

    “ongoing chromosome missegregation is required to replenish cytosolic DNA pools and to maintain cells in a pro-metastatic state.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    For each FISH probe, three normal peripheral blood samples were analyzed to derive cut-off values (false-positive).

    “For each probe, three normal peripheral blood samples (GM07535, GM06875 and GM00558), obtained from Coriell Institute (Camden, New Jersey) were also analyzed to derive cut-off values (false-positive).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    CIN promotes the formation and maintenance of metastasis.

    “CIN promotes formation and maintenance of metastasis”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    For each sample a minimum of 20 inverted DAPI-stained metaphases were fully karyotyped and analyzed according to ISCN 2013.

    “For each sample a minimum of 20 inverted DAPI-stained metaphases were fully karyotyped and analyzed according to the International System of Human Cytogenetic Nomenclature (ISCN) 2013.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The scRNA-seq analysis was robust to imputation, and similar results were obtained without imputed data.

    “Our analysis was robust to imputation and we obtained similar results without imputed data (not shown).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Power analysis indicated that 10 mice per group will be sufficient to detect a difference at relative hazard ratios of <0.25 or >4.0 with 80% power and 95% confidence in 4T1 experiments.

    “For the 4T1 experiments, Power analysis indicates that 10 mice per group will be sufficient to detect a difference at relative hazard ratios of <0.25 or >4.0 with 80% power and 95% confidence, given a median survival of 58 days in the control group and a total follow up period of 180 days.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Data was pre-processed to filter out cells with low total molecule counts, low complexity and high mitochondrial content, identified by a bimodal fit, to minimize the effects of experimental artifacts on the analysis.

    “Additionally, to minimize the effects of experimental artifacts on the analysis, data was pre-processed to filter out cells with low total molecule counts (library size), low complexity and high mitochondrial content, identified by a bimodal fit.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The evolutionary benefits of the noncanonical pathway would justify the scarcity of inactivating mutations in cGAS and STING among breast and lung cancers.

    “The evolutionary benefits of the noncanonical pathway would justify the scarcity of inactivating mutations in cGAS and STING among breast and lung cancers (Extended Data Fig. 10e).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Power analysis indicated that 10 mice per group will be sufficient to detect a difference at relative hazard ratios of <0.2 or >5 with 80% power and 95% confidence in MDA-MB-231 experiments.

    “For disease-specific survival in MDA-MB-231 experiments, power analysis indicated that 10 mice per group will be sufficient to detect a difference at relative hazard ratios of <0.2 or >5 with 80% power and 95% confidence, given a median disease-specific survival of 3 months in the control group and a total follow up period of 250 days.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Mitochondria were purified at 12,000xg to minimize their contamination in the cytosolic fraction.

    “Mitochondria were purified at 12,000xg to minimize their contamination in the cytosolic fraction.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    CIN promotes in vitro invasion and migration.

    “CIN promotes in vitro invasion and migration”
    Quote in the paperSubstantial claim
44 of 44

  • The paper relies on this without support.

    The role of CIN in metastasis has not been established.

    “its role in metastasis has not been established.”

  • The paper relies on this without support.

    The mouse xenograft and orthotopic models recapitulate human metastatic progression sufficiently to infer CIN's role in human metastasis.

    “We injected MDA-MB-231 cells into the left cardiac ventricles of athymic mice to enable systemic dissemination while tracking metastatic colonization using a bioluminescence reporter.”

  • The paper relies on this without support.

    The human tumor cohorts analyzed are representative of human metastatic disease generally.

    “we applied the weighted-genomic integrity index (wGII) as a proxy for CIN8 on 79 primary tumor-brain metastases matched pairs from a recently published cohort9.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • MN play a critical pathogenic role in cancer genome evolution and metastasis by driving genomic instability through chromothripsis.

    “While MN have been proposed to activate as tumor suppressor pathways, MN also play a critical pathogenic role in the evolution of cancer genomes and metastasis by driving genomic instability through chromothripsis (Bakhoum et al., 2018; Umbreit et al., 2020; Ye et al., 2019; Zhang et al., 2015).”

    From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Bakhoum et al., 2018

  • STING-dependent activation of noncanonical NF-κB signaling due to ruptured MN promotes metastasis.

    “Moreover, STING-dependent activation of noncanonical NF-κB signaling, due to ruptured MN, promotes metastasis (Bakhoum et al., 2018).”

    From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Bakhoum et al., 2018

  • In breast and lung cancers, suppressing chromosomal instability and associated cytoDNA reduces metastasis.

    “For example, in breast and lung cancers, suppression of chromosomal instability and associated cytoDNA decreases metastasis (Bakhoum et al., 2018).”

    From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Bakhoum et al., 2018

  • Differences have been observed in the expression of essential genes in the cGAS-STING signaling mechanism between normal and malignant tissues, along with MB21D1-encoding cGAS, TMEM-173-encoding STING, TBK-1 and IRF-3.

    “Researchers have observed differences in the expression of essential genes in the cGAS‐STING signaling mechanism between normal and malignant tissues, along with MB21D1‐encoding cGAS, transmembrane protein 173 (TMEM‐173)‐encoding STING, TANK‐binding kinase 1 (TBK‐1) and interferon regulatory factor 3 (IRF‐3).”

    From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [253]

  • The four genes MB21D1, TMEM173, TBK1 and IRF3 were significantly elevated in almost all cancer models, suggesting that cGAS-STING signal transduction might be stimulated in all cancer types.

    “Comprehensive research and recent evidence proved that these four genes were significantly elevated in almost all cancer models, suggesting that cGAS‐STING signal transduction might be stimulated in all cancer types [252, 253].”

    From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [253]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Noncanonical NF-κB protein ratios differ between the text and figure caption

    Minor

    The text describes ratios of p52 and phosphorylated p100 to total p100. The Extended Data Figure 8 caption instead names phosphorylated p52-to-p100 and p100-to-total p100 ratios.

  • PCR indexing step is described as both 10 and 14 cycles

    Minor

    The methods give two different cycle counts for the same sample-index PCR amplification.

2 of 2

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Authors
Bakhoum, S. F., Ngo, B., Laughney, A. M., Cavallo, J.-A., Murphy, C. J., Ly, P., Shah, P., Sriram, R. K., Watkins, T. B. K., Taunk, N. K., Duran, M., Pauli, C., Shaw, C., Chadalavada, K., Rajasekhar, V. K., Genovese, G., Venkatesan, S., Birkbak, N. J., McGranahan, N., Lundquist, M., LaPlant, Q., Healey, J. H., Elemento, O., Chung, C. H., Lee, N. Y., Imielenski, M., Nanjangud, G., Pe’er, D., Cleveland, D. W., Powell, S. N., Lammerding, J., Swanton, C., & Cantley, L. C.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • Weill Cornell Medicine (US)
  • University of California San Diego (US)
  • Cornell University (US)
  • The Francis Crick Institute (GB)
  • University of Zurich (CH)
  • Broad Institute (US)
  • University College London (GB)
  • Moffitt Cancer Center (US)
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2018-01-17
Volume
553
Issue
7689
Pages
467-472
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature25432
PMC
PMC5785464
OpenAlex
W2783667606
Cited by
1,638
References
59
Citations by year
2026: 174 · 2025: 210 · 2024: 223 · 2023: 225 · 2022: 190 · 2021: 203 · 2020: 149 · 2019: 100 · 2018: 77 · 2017: 1 · 2012: 1
FWCI
49.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
  • Europe PMC (PubMed Central) (submittedVersion)
  • PubMed Central (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
  • Zurich Open Repository and Archive (University of Zurich)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Keywords
chromosomal instability, metastasis, cytosolic DNA sensing, cGAS-STING pathway, micronuclei, chromosome segregation errors, NF-κB signaling, innate immunity
MeSH terms
STING Protein, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Animals, Brain Neoplasms

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-19.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-19.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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