Aneuploidy-Driven Genome Instability Triggers Resistance to Chemotherapy

Ippolito, Marica Rosaria; Martis, Valentino; Hong, Christy; Wardenaar, René; Zerbib, Johanna; Spierings, Diana C.J.; Ben‐David, Uri; Foijer, Floris; Santaguida, Stefano

doi:10.2139/ssrn.3732358

Cited by 4 publications

(6 citation statements)

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“…approaches, which included single-cell cloning and growth in soft-agar. While these findings are in line with WGD being more permissive to aneuploidy in general, this does not mean that specific karyotypes would not get selected for under different selection pressures (Rutledge et al 2016;Ippolito et al 2020;Lukow et al 2020). Further studies are necessary in order to systematically map the interactions between WGD and specific aneuploidies across a variety of selection pressures.…”

Section: Discussionmentioning

confidence: 89%

Whole-genome duplication shapes the aneuploidy landscape of human cancers

Prasad

Bloomfield

Levi

et al. 2021

Preprint

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Aneuploidy – a hallmark of cancer – has tissue-specific recurrence patterns suggesting it plays a driving role in cancer initiation and progression. However, the contribution of aneuploidy to tumorigenesis depends on the cellular and genomic context in which it arises. Whole-genome duplication (WGD) is a common macro-evolutionary event that occurs in >25% of human tumors during the early stages of tumorigenesis. Although tumors that have undergone WGD are reported to be more permissive to aneuploidy than tumors that have not, it remains unknown whether WGD affects aneuploidy recurrence patterns in human cancers. Here we analyzed clinical tumor samples from 449 WGD- tumors and 157 WGD+ tumors across 22 tumor types. We found distinct recurrence patterns of aneuploidy in WGD- and WGD+ tumors. The relative prevalence of recurrent aneuploidies decreased in WGD+ tumors, in line with increased aneuploidy tolerance. Moreover, the genetic interactions between chromosome arms differed between WGD- and WGD+ tumors, giving rise to distinct co-occurrence and mutual exclusivity aneuploidy patterns. The proportion of whole-chromosome aneuploidy vs. arm-level aneuploidy was significantly higher in WGD+ tumors, indicating distinct dominant mechanisms for aneuploidy formation in WGD- and WGD+ tumors. Human cancer cell lines successfully reproduced these WGD/aneuploidy interactions, confirming the relevance of studying this phenomenon in culture. Lastly, we induced WGD in human colon cancer cell lines, and followed aneuploidy formation in the isogenic WGD+/WGD-cells under standard or selective conditions. These experiments validated key findings from the clinical tumor analysis, and revealed a causal link between WGD and altered aneuploidy landscapes. We conclude that WGD shapes the aneuploidy landscape of human tumors, and propose that the interaction between WGD and aneuploidy is a major contributor to tumor evolution.

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Section: Discussionmentioning

confidence: 89%

Whole-genome duplication shapes the aneuploidy landscape of human cancers

Prasad

Bloomfield

Levi

et al. 2021

Preprint

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“…Mps1/TTK inhibition triggers genomic instability and results in cancer cell apoptosis. Aneuploid cancer cells show resistance to multiple chemotherapeutic regimens, induce tumor heterogeneity, and improve the tumors' adaptation to harsh conditions ( 28 , 29 ). In particular, highly aneuploid cancer cells are more sensitive to the energy and proteotoxic stress induced by AMPK agonists than normal cells ( 20 , 30 , 31 ).…”

Section: Discussionmentioning

confidence: 99%

Energy‑stress‑mediated activation of AMPK sensitizes MPS1 kinase inhibition in triple‑negative breast cancer

Lim,

Kim,

Song

et al. 2024

Oncol Rep

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“…In a mouse model, low-to-moderate levels of CIN were found to promote tumorigenesis, while high levels of CIN suppressed tumor progression [ 163 ]. As a result of these observations, it has been proposed that exacerbating CIN beyond a tolerable level may be a viable therapeutic strategy [ 190 ], but such an approach should be considered with caution [ 191 , 192 ].…”

Section: Aneuploidy and Polyploidy Can Both Promote And Buffer Karyotypic Heterogeneitymentioning

confidence: 99%

“…This suggests that most CAAs associated with drug responses likely depend on the interaction of multiple genes across the affected genomic region and/or other interchromosomal genetic interactions. Following the induction of CIN, recurrent aneuploidies were observed in non-small cell lung cancer cells that developed resistance to the topoisomerase I inhibitor Topotecan [ 192 ]. The drug-resistant phenotype in this case was not driven by chromosomal alterations affecting the expression of the drug target.…”

Section: The Role Of Aneuploidy and Polyploidy In Tumor Niche Constructionmentioning

confidence: 99%

“…The drug-resistant phenotype in this case was not driven by chromosomal alterations affecting the expression of the drug target. Instead, chromosome 6p gain caused the overexpression of resident genes MAPK13 and MAPK14 that encode for p38 kinase subunits, which led to the selective upregulation of a drug efflux pump on chromosome 4q [ 192 ]. Direct gain of 4q may not have been favorable in this context because it harbors numerous tumor suppressor genes, indicating that genetic interactions between specific aneuploidies and other chromosomes influence karyotype evolution (as reported in yeast [ 301 ]).…”

Section: The Role Of Aneuploidy and Polyploidy In Tumor Niche Constructionmentioning

confidence: 99%

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Karyotype Aberrations in Action: The Evolution of Cancer Genomes and the Tumor Microenvironment

Baudoin

Bloomfield

2021

Genes

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Cancer is a disease of cellular evolution. For this cellular evolution to take place, a population of cells must contain functional heterogeneity and an assessment of this heterogeneity in the form of natural selection. Cancer cells from advanced malignancies are genomically and functionally very different compared to the healthy cells from which they evolved. Genomic alterations include aneuploidy (numerical and structural changes in chromosome content) and polyploidy (e.g., whole genome doubling), which can have considerable effects on cell physiology and phenotype. Likewise, conditions in the tumor microenvironment are spatially heterogeneous and vastly different than in healthy tissues, resulting in a number of environmental niches that play important roles in driving the evolution of tumor cells. While a number of studies have documented abnormal conditions of the tumor microenvironment and the cellular consequences of aneuploidy and polyploidy, a thorough overview of the interplay between karyotypically abnormal cells and the tissue and tumor microenvironments is not available. Here, we examine the evidence for how this interaction may unfold during tumor evolution. We describe a bidirectional interplay in which aneuploid and polyploid cells alter and shape the microenvironment in which they and their progeny reside; in turn, this microenvironment modulates the rate of genesis for new karyotype aberrations and selects for cells that are most fit under a given condition. We conclude by discussing the importance of this interaction for tumor evolution and the possibility of leveraging our understanding of this interplay for cancer therapy.

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Aneuploidy-Driven Genome Instability Triggers Resistance to Chemotherapy

Cited by 4 publications

References 0 publications

Whole-genome duplication shapes the aneuploidy landscape of human cancers

Whole-genome duplication shapes the aneuploidy landscape of human cancers

Energy‑stress‑mediated activation of AMPK sensitizes MPS1 kinase inhibition in triple‑negative breast cancer

Karyotype Aberrations in Action: The Evolution of Cancer Genomes and the Tumor Microenvironment

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