Quantitative proteomic and phosphoproteomic comparison of human colon cancer DLD-1 cells differing in ploidy and chromosome stability

Viganó, Cristina; Schubert, Conrad von; Ahrné, Erik; Schmidt, Albrecht; Lorber, Thomas; Bubendorf, Lukas; Vetter, Judith R.F. de; Zaman, Guido J.R.; Storchova, Zuzana; Nigg, Erich A.

doi:10.1091/mbc.e17-10-0577

Cited by 37 publications

(151 citation statements)

References 102 publications

(151 reference statements)

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“…2). Similarly, recent analysis of aneuploid cancer cells has shown that these cells modulate their phospho-proteome and the microRNAome to adapt their physiology to the adverse effects of aneuploidy (65,66). Although evidence of proteome homeostasis as an aneuploidy maintenance mechanism has been gained from in vitro systems, studies in breast cancer supports the notion that attenuation of the effect of chromosome imbalances on protein levels also occurs in human tumors (67).…”

Section: Correcting the Consequences Of Cin: Dosage Compensation And mentioning

confidence: 99%

Tolerance of Chromosomal Instability in Cancer: Mechanisms and Therapeutic Opportunities

Grönroos

López-García

2018

Cancer Research

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Chromosomal instability (CIN) is the result of ongoing changes in the number (aneuploidy) and structure of chromosomes. CIN is induced by chromosome missegregation in mitosis and leads to karyotypic diversity within the cancer cell population, thereby adding to intratumor heterogeneity. Regardless of the overall pro-oncogenic function of CIN, its onset is typically detrimental for cell fitness and thus tumors must develop CIN-tolerance mechanisms in order to propagate. There is overwhelming genetic and functional evidence linking mutations in the tumor suppressor TP53 with CIN-tolerance. However, the pathways leading to p53 activation following chromosome missegregation remain controversial. Recently,

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“…However, the identity of these gene(s) is at present unknown. Chromosome-specific and drug-specific interactions may complement the multi-drug resistance phenotype that has been observed in near-tetraploid cells that have undergone whole-genome duplications [40][41][42] . However, Mps1i treatment did not accelerate evolution in every context tested.…”

Section: Discussionmentioning

confidence: 99%

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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“…More specifically, (re)activation of the immune system can become a new therapeutic strategy to treat aneuploid tumours since aneuploid cells might be recognized by the innate immune system (table 1) [102]. Aneuploid cells with complex karyotypes trigger an upregulation of pro-inflammatory factors [32,102] and are cleared by natural killer cells in a co-culture setting [102].…”

Section: Activating the Immune System To Target Aneuploidymentioning

confidence: 99%

Exploiting aneuploidy-imposed stresses and coping mechanisms to battle cancer

2020

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Aneuploidy, an irregular number of chromosomes in cells, is a hallmark feature of cancer. Aneuploidy results from chromosomal instability (CIN) and occurs in almost 90% of all tumours. While many cancers display an ongoing CIN phenotype, cells can also be aneuploid without displaying CIN. CIN drives tumour evolution as ongoing chromosomal missegregation will yield a progeny of cells with variable aneuploid karyotypes. The resulting aneuploidy is initially toxic to cells because it leads to proteotoxic and metabolic stress, cell cycle arrest, cell death, immune cell activation and further genomic instability. In order to overcome these aneuploidy-imposed stresses and adopt a malignant fate, aneuploid cancer cells must develop aneuploidy-tolerating mechanisms to cope with CIN. Aneuploidy-coping mechanisms can thus be considered as promising therapeutic targets. However, before such therapies can make it into the clinic, we first need to better understand the molecular mechanisms that are activated upon aneuploidization and the coping mechanisms that are selected for in aneuploid cancer cells. In this review, we discuss the key biological responses to aneuploidization, some of the recently uncovered aneuploidy-coping mechanisms and some strategies to exploit these in cancer therapy.

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“…There are several benefits of CIN for tumours: it varies them over time [54], contributing significantly to their chance of becoming metastatic [55] and resistant to chemotherapy [56,57]. Extensive transcriptional [5] and proteomic analyses [58,59] in human and yeast models have shown that CIN cells are significantly different to stable diploids. These effects of chromosomal instability are relatively uncontroversial; less clear is whether CIN makes tumours vulnerable to immune attack.…”

Section: The Effect Of Aneuploidy On Tumorigenesismentioning

confidence: 99%

Co-Operation between Aneuploidy and Metabolic Changes in Driving Tumorigenesis

Newman

Gregory

2019

IJMS

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Alterations from the normal set of chromosomes are extremely common as cells progress toward tumourigenesis. Similarly, we expect to see disruption of normal cellular metabolism, particularly in the use of glucose. In this review, we discuss the connections between these two processes: how chromosomal aberrations lead to metabolic disruption, and vice versa. Both processes typically result in the production of elevated levels of reactive oxygen species, so we particularly focus on their role in mediating oncogenic changes.

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“…Despite these results, cGAS/STING signaling undoubtedly has a profound effect on multiple cancer-related phenotypes. Additionally, STING is encoded on chromosome 5, and multiple inflammatory genes are upregulated in trisomic cell lines Viganó et al 2018), leading us to investigate whether cGAS/STING contributed to the metastatic behavior of the HCT116 Ts5 cells. To accomplish this, we stably expressed a dCAS9-KRAB CRISPRi vector in two independent Ts5 clones, which allowed us to trigger the specific down-regulation of a gene of interest (Horlbeck et al 2016).…”

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confidence: 99%

Single chromosome gains can function as metastasis suppressors and metastasis promoters in colon cancer

Vasudevan

Baruah

Smith

et al. 2019

Preprint

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Most human tumors display chromosome-scale copy number alterations, and high levels of aneuploidy are frequently associated with advanced disease and poor patient prognosis. To examine the relationship between aneuploidy and cancer progression, we generated and analyzed a series of congenic human cell lines that harbor single extra chromosomes. We find that different aneuploidies can have distinct effects on invasive behavior: across 13 different cell lines, 12 trisomies suppressed invasiveness or were largely neutral, while a single trisomy increased metastatic behavior by triggering a partial epithelial-mesenchymal transition. In contrast, chromosomal instability, which can lead to the development of aneuploidy, uniformly suppressed cellular invasion. By analyzing genomic copy number and survival data from 10,133 cancer patients, we demonstrate that specific aneuploidies are associated with distinct clinical outcomes, and the acquisition of certain aneuploidies is in fact linked with a favorable prognosis.Thus, aneuploidy is not a uniform driver of malignancy, and different chromosome copy number changes can uniquely influence tumor progression. At the same time, the gain of a single chromosome is capable of inducing a profound cell state transition, underscoring how genomic plasticity can engender phenotypic plasticity and lead to the acquisition of enhanced metastatic properties.

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Quantitative proteomic and phosphoproteomic comparison of human colon cancer DLD-1 cells differing in ploidy and chromosome stability

Cited by 37 publications

References 102 publications

Tolerance of Chromosomal Instability in Cancer: Mechanisms and Therapeutic Opportunities

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

Exploiting aneuploidy-imposed stresses and coping mechanisms to battle cancer

Co-Operation between Aneuploidy and Metabolic Changes in Driving Tumorigenesis

Single chromosome gains can function as metastasis suppressors and metastasis promoters in colon cancer

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