Single-Chromosomal Gains Can Function as Metastasis Suppressors and Promoters in Colon Cancer

Vasudevan, Anand; Baruah, Prasamit Saurav; Smith, John K.; Wang, Zihua; Sayles, Nicole M.; Andrews, Peter; Kendall, Jude; Leu, Justin; Chunduri, Narendra Kumar; Levy, Dan; Wigler, Michael; Storchová, Zuzana; Sheltzer, Jason M.

doi:10.1016/j.devcel.2020.01.034

Cited by 86 publications

(83 citation statements)

References 72 publications

(90 reference statements)

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“…Could other immune-response inducing pathways contribute to aneuploid cell recognition by NK cells? Chromosome mis-segregation has been linked to induction of an interferon response (Bakhoum et al 2018;Vasudevan et al 2020). We do observe up-regulation of the alpha and gamma interferon response in ArCK cells but not in aneuploid cycling cells.…”

Section: The Nf-κb Pathway Induces Immunogenicity Of Aneuploid Cellssupporting

confidence: 51%

Aneuploid cells activate NF-κB to promote their immune clearance by NK cells

Wang

Vigano'

Ben‐David

et al. 2020

Preprint

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SummaryThe immune system plays a major role in the protection against cancer. Identifying and characterizing the pathways mediating this immune surveillance is thus critical for understanding how cancer cells are recognized and eliminated. We previously found that untransformed cells that had undergone senescence due to highly abnormal karyotypes are eliminated by Natural Killer (NK) cells in vitro. Here we show that this is also true for aneuploid untransformed cells that had not lost their ability to proliferate. Their elimination by NK cells, like that of aneuploid senescent cells, is predominantly mediated by non-cell autonomous mechanisms. Our data further indicate that NF-κB signaling in aneuploid cells is central to eliciting this immune response. Inactivating NF-κB abolishes NK-cell mediated clearance in aneuploid cells in vitro. In cancer cell lines, NF-κB signaling correlates with degree of aneuploidy, raising the possibility that aneuploidy-induced immune recognition is partially retained in cancer.

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Section: The Nf-κb Pathway Induces Immunogenicity Of Aneuploid Cellssupporting

confidence: 51%

Aneuploid cells activate NF-κB to promote their immune clearance by NK cells

Wang

Vigano'

Ben‐David

et al. 2020

Preprint

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“…Treatment with 2µM AZ3146 caused a robust increase in the frequency of mitotic errors in cancer cell lines ( Figure S1) 10 . We have previously shown that mutations in the Mps1 kinase domain block the increase in errors caused by AZ3146, verifying that this represents an on-target effect of Mps1 inhibition 17 . We next devised a competition-based strategy to assess if CIN is capable of driving the acquisition of resistance to an anti-cancer therapy ( Figure 1A).…”

Section: Inhibition Of Mps1 Accelerates the Acquisition Of Resistancementioning

confidence: 61%

“…While CIN and the aneuploidies that result from CIN cause numerous cellular stresses, chromosomal errors are ubiquitous during tumorigenesis, and the level of aneuploidy tends to be highest in aggressive cancers associated with poor patient outcomes 2,6,7,17,32 . It remains unclear to what extent the aneuploidy that arises during tumorigenesis functions as a driver of cancer progression, and to what extent aneuploidy occurs simply as a byproduct of the loss of checkpoint control that often occurs in advanced malignancies.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, aneuploidy triggers a transcriptional program involving the upregulation of stress response genes and the down regulation of cell cycle genes, often leading to cell cycle arrest and senescence [11][12][13] . Nonetheless, in human tumors, high levels of aneuploidy are commonly associated with poor patient outcomes, suggesting that aneuploidy could contribute to certain aspects of tumor progression [14][15][16][17] .…”

Section: Introductionmentioning

confidence: 99%

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Chromosomal instability accelerates the evolution of resistance to anti-cancer therapies

Lukow

Sausville

Suri

et al. 2020

Preprint

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Aneuploidy is a ubiquitous feature of human tumors, but the acquisition of aneuploidy is typically detrimental to cellular fitness. To investigate how aneuploidy could contribute to tumor growth, we triggered periods of chromosomal instability (CIN) in human cells and then exposed them to a variety of different culture environments. While chromosomal instability was universally detrimental under normal growth conditions, we discovered that transient CIN reproducibly accelerated the ability of cells to adapt and thrive in the presence of anti-cancer therapeutic agents. Single-cell sequencing revealed that these drug-resistant populations recurrently developed specific whole-chromosome gains and losses. We independently derived one aneuploidy that was frequently recovered in cells exposed to paclitaxel, and we found that this chromosome loss event was sufficient to decrease paclitaxel sensitivity. Finally, we demonstrated that intrinsic levels of CIN correlate with poor responses to a variety of systemic therapies in a collection of patient-derived xenografts. In total, our results show that while chromosomal instability generally antagonizes cell fitness, it also provides phenotypic plasticity to cancer cells that can allow them to adapt to diverse stressful environments. Moreover, our findings suggest that aneuploidy may function as an under-explored cause of therapy failure in human tumors.

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“…Their relevance to genome instability and reversion from polyploidy to diploidy or aneuploidy have been described and may explain some aspects of tumorigenesis through dysregulation of various pathways [76], including EGFR/RAS/MAPK signaling [77]. Of note, it has been recently shown that whole-genome doubling buffers the impact of deleterious alterations [78] and that single-chromosomal gains can function as promoters and metastasis suppressors [79].…”

Section: Chromosomementioning

confidence: 99%

DNA FISH Diagnostic Assay on Cytological Samples of Thyroid Follicular Neoplasms

Vielh

Balogh

Suciu

et al. 2020

Cancers

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Although fine-needle aspiration cytology (FNAC) is helpful in determining whether thyroid nodules are benign or malignant, this distinction remains a cytological challenge in follicular neoplasms. Identification of genomic alterations in cytological specimens with direct and routine techniques would therefore have great clinical value. A series of 153 cases consisting of 72 and 81 histopathologically confirmed classic follicular adenomas (cFAs) and classic follicular thyroid carcinomas (cFTCs), respectively, was studied by means of different molecular techniques in three different cohorts of patients (pts). In the first cohort (training set) of 66 pts, three specific alterations characterized by array comparative genomic hybridization (aCGH) were exclusively found in half of cFTCs. These structural abnormalities corresponded to losses of 1p36.33-35.1 and 22q13.2-13.31, and gain of whole chromosome X. The second independent cohort (validation set) of 60 pts confirmed these data on touch preparations of frozen follicular neoplasms by triple DNA fluorescent in situ hybridization using selected commercially available probes. The third cohort, consisting of 27 archived cytological samples from an equal number of pts that had been obtained for preoperative FNAC and morphologically classified as and histologically verified to be follicular neoplasms, confirmed our previous findings and showed the feasibility of the DNA FISH (DNA fluorescent in situ hybridization) assay. All together, these data suggest that our triple DNA FISH diagnostic assay may detect 50% of cFTCs with a specificity higher than 98% and be useful as a low-cost adjunct to cytomorphology to help further classify follicular neoplasms on already routinely stained cytological specimens.

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Single-Chromosomal Gains Can Function as Metastasis Suppressors and Promoters in Colon Cancer

Abstract: Highlights d A trisomy increases metastatic behavior in colon cancer cells by inducing a partial EMT d Chromosomal instability activates cGAS/STING signaling but suppresses invasiveness d Whole-chromosome aneuploidies show strong correlations with prognosis across cancers

Cited by 86 publications

References 72 publications

Aneuploid cells activate NF-κB to promote their immune clearance by NK cells

Aneuploid cells activate NF-κB to promote their immune clearance by NK cells

Chromosomal instability accelerates the evolution of resistance to anti-cancer therapies

DNA FISH Diagnostic Assay on Cytological Samples of Thyroid Follicular Neoplasms

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