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, Alexander; Lorber, Thomas; Bubendorf, Lukas; Vetter, Judith R.F. de; Zaman, Guido J.R.; Storchová, Zuzana; Nigg, Erich A.

doi:10.1091/mbc.e17-10-0577

Cited by 44 publications

(35 citation statements)

References 102 publications

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

Cited by 44 publications

References 102 publications

Tolerance of Chromosomal Instability in Cancer: Mechanisms and Therapeutic Opportunities

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

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