Gene copy-number changes and chromosomal instability induced by aneuploidy confer resistance to chemotherapy

Ippolito, Marica Rosaria; Martis, Valentino; Martin, Sara L.; Tijhuis, Andréa E.; Hong, Christy; Wardenaar, René; Dumont, Marie; Zerbib, Johanna; Spierings, Diana C.J.; Fachinetti, Daniele; Ben‐David, Uri; Foijer, Floris; Santaguida, Stefano

doi:10.1016/j.devcel.2021.07.006

Cited by 130 publications

(123 citation statements)

References 69 publications

(111 reference statements)

Supporting

Mentioning

111

Contrasting

Order By: Relevance

“…Increased EGFR gene copy number both promotes proliferation [40] and, by virtue of having more EGFR gene templates for replication-acquired mutation, increases the apparent mutability of individual cells [57]. These findings are consistent with previous studies showing selective pressure for cancer cells to sustain nCIN and demonstrating that high levels of nCIN can drive the generation and selection of drug-resistant clones [6,7,58,59].…”

Section: Whole Chromosome Segregation Errors Enable Tumor Evolution A...supporting

confidence: 89%

“…Clonal mutations that enable resistance to targeted or chemotherapeutic approaches pose a clinical challenge and remain a major cause of death in many cancer types [54]. Clinically and experimentally, the degree of intra-tumor genomic heterogeneity, and underlying defects in mitotic cell division have been functionally linked to tumor evolution, drug resistance, and metastasis [3, 4, 6, 7, 55, 56]. In the context of NSCLC, identification of driver mutations in EGFR and the initial clinical success of TKI treatment has been hampered by rapid and prevalent acquisition of drug resistance [38].…”

Section: Discussionmentioning

confidence: 99%

“…Whole chromosome instability, or numerical CIN (nCIN), is generated by underlying defects in mitosis [1,2]. The aneuploidy that results from mitotic segregation errors promotes intra-tumor heterogeneity and is a driving force in cancer that contributes to tumor evolution and drug resistance [1][2][3][4][5][6][7]. Chromosome segregation is exquisitely sensitive to the regulation of dynamic microtubule attachments and defects that either increase or decrease the stability of microtubule attachments can corrupt mitotic fidelity and contribute to nCIN [8,9].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Suppression of chromosome instability limits acquired drug resistance

Manning¹,

Hermance²,

Crowley³

et al. 2020

Preprint

View full text Add to dashboard Cite

Chromosome instability, or CIN, defined as a high frequency of whole chromosome gains and losses, is prevalent in many solid tumors. CIN has been shown to promote intra-tumor heterogeneity and correspond with tumor aggressiveness, drug resistance and tumor relapse. However, whether CIN promotes the acquisition of genomic changes responsible for drug resistance remain unclear. Here we assess the role of CIN in the acquisition of drug resistance in non small cell lung cancer. We show that impairment of centromeric cohesion underlies the generation of whole chromosome segregation errors and CIN in non small cell lung cancer cells. Further, we demonstrate that centromere-specific enhancement of chromosome cohesion strongly suppresses CIN and reduces intra-tumor heterogeneity. We demonstrate that suppression of CIN has no impact on NSCLC cell proliferation in vitro nor in tumor initiation in mouse xenograft models. However, suppression of CIN alters the timing and molecular mechanism that drive acquired drug resistance. These findings suggest mechanisms to suppress CIN may serve as effective co-therapies to limit tumor evolution and sustain drug response.

show abstract

Section: Whole Chromosome Segregation Errors Enable Tumor Evolution A...supporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Suppression of chromosome instability limits acquired drug resistance

Manning¹,

Hermance²,

Crowley³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…In this review, we have discussed how chromosome segregation errors induce DNA damage and how this exacerbates genome instability in the resulting aneuploid cells, a condition that has recently been shown to confer proliferative advantages under specific conditions ( Ippolito et al, 2021 ; Lukow et al, 2021 ; Salgueiro et al, 2020 ) ( Figure 1 ). It has to be noted that the vast majority of studies conducted so far have employed an heterogenous population of aneuploid cells, comprising both chromosome gains and losses as well as cycling and arrested cells.…”

Section: Discussionmentioning

confidence: 99%

“…This seems to be particularly relevant to cancer cells, which are found to be very often aneuploid (Vasudevan et al, 2021). In fact, recent work has shown that abnormal chromosome number in the context of cancer can promote resistance to chemotherapy (Salgueiro et al, 2020;Ippolito et al, 2021;Lukow et al, 2021), in line with the observation that highly aneuploid tumors correlate with poorer patient outcomes (Davoli et al, 2017;Vasudevan et al, 2020). In details, chromosome missegregation events cause increased karyotypic heterogeneity that can be utilized by cancer cells to find the correct karyotypic landscape and thus survive under selective pressures such as chemotherapy.…”

Section: Consequences Of Genomic Instability On Aneuploid Cell Fitnessmentioning

confidence: 99%

The Dynamic Instability of the Aneuploid Genome

Garribba

Santaguida

2022

Front. Cell Dev. Biol.

Self Cite

View full text Add to dashboard Cite

Proper partitioning of replicated sister chromatids at each mitosis is crucial for maintaining cell homeostasis. Errors in this process lead to aneuploidy, a condition in which daughter cells harbor genome imbalances. Importantly, aneuploid cells often experience DNA damage, which in turn could drive genome instability. This might be the product of DNA damage accumulation in micronuclei and/or a consequence of aneuploidy-induced replication stress in S-phase. Although high levels of genome instability are associated with cell cycle arrest, they can also confer a proliferative advantage in some circumstances and fuel tumor growth. Here, we review the main consequences of chromosome segregation errors on genome stability, with a special focus on the bidirectional relationship between aneuploidy and DNA damage. Also, we discuss recent findings showing how increased genome instability can provide a proliferation improvement under specific conditions, including chemotherapeutic treatments.

show abstract

Tetraploidy‐linked sensitization to CENP‐E inhibition in human cells

et al. 2023

View full text Add to dashboard Cite

Tetraploidy is a hallmark of cancer cells, and tetraploidy‐selective cell growth suppression is a potential strategy for targeted cancer therapy. However, how tetraploid cells differ from normal diploids in their sensitivity to anti‐proliferative treatments remains largely unknown. In this study, we found that tetraploid cells are significantly more susceptible to inhibitors of a mitotic kinesin (CENP‐E) than are diploids. Treatment with a CENP‐E inhibitor preferentially diminished the tetraploid cell population in a diploid–tetraploid co‐culture at optimum conditions. Live imaging revealed that a tetraploidy‐linked increase in unsolvable chromosome misalignment caused substantially longer mitotic delay in tetraploids than in diploids upon moderate CENP‐E inhibition. This time gap of mitotic arrest resulted in cohesion fatigue and subsequent cell death, specifically in tetraploids, leading to tetraploidy‐selective cell growth suppression. In contrast, the microtubule‐stabilizing compound paclitaxel caused tetraploidy‐selective suppression through the aggravation of spindle multipolarization. We also found that treatment with a CENP‐E inhibitor had superior generality to paclitaxel in its tetraploidy selectivity across a broader spectrum of cell lines. Our results highlight the unique properties of CENP‐E inhibitors in tetraploidy‐selective suppression and their potential use in the development of tetraploidy‐targeting interventions in cancer.

show abstract

Gene copy-number changes and chromosomal instability induced by aneuploidy confer resistance to chemotherapy

Cited by 130 publications

References 69 publications

Suppression of chromosome instability limits acquired drug resistance

Suppression of chromosome instability limits acquired drug resistance

The Dynamic Instability of the Aneuploid Genome

Tetraploidy‐linked sensitization to CENP‐E inhibition in human cells

Contact Info

Product

Resources

About