Chromosomal instability as a driver of cancer progression

Chen, Xuelan; Agustinus, Albert S.; Li, Jun; DiBona, Melody; Bakhoum, Samuel F.

doi:10.1038/s41576-024-00761-7

Cited by 2 publications

References 181 publications

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Origins ofde novochromosome rearrangements unveiled by coupled imaging and genomics

Cosenza,

Gaiatto,

Erarslan Uysal

et al. 2024

Preprint

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Chromosomal instability results in widespread structural and numerical chromosomal abnormalities (CAs) during cancer evolution1-3. While CAs have been linked to mitotic errors resulting in the emergence of nuclear atypias4-7, the underlying processes and basal rates of spontaneous CA formation in human cells remain under-explored. Here we introduce machine learning-assisted genomics-and-imaging convergence (MAGIC), an autonomously operated platform that integrates automated live-cell imaging of micronucleated cells, machine learning in real-time, and single-cell genomics to investigate de novo CA formation at scale. Applying MAGIC to near-diploid, non-transformed cell lines, we track CA events over successive cell cycles, highlighting the common role of dicentric chromosomes as an initiating event. We determine the baseline CA rate, which approximately doubles in TP53-deficient cells, and show that chromosome losses arise more rapidly than gains. The targeted induction of DNA double-strand breaks along chromosomes triggers distinct CA processes, revealing stable isochromosomes, amplification and coordinated segregation of isoacentric segments in multiples of two, and complex CA outcomes, depending on the break location. Our data contrast de novo CA spectra from somatic mutational landscapes after selection occurred. The large-scale experimentation enabled by MAGIC provides insights into de novo CA formation, paving the way to unravel fundamental determinants of chromosome instability.

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Origins ofde novochromosome rearrangements unveiled by coupled imaging and genomics

Cosenza,

Gaiatto,

Erarslan Uysal

et al. 2024

Preprint

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Chromosomal instability as an architect of the cancer stemness landscape

Baba,

Zakeri,

Desgrosellier

2024

Front. Cell Dev. Biol.

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Despite a critical role for tumor-initiating cancer stem cells (CSCs) in breast cancer progression, major questions remain about the properties and signaling pathways essential for their function. Recent discoveries highlighting mechanisms of CSC-resistance to the stress caused by chromosomal instability (CIN) may provide valuable new insight into the underlying forces driving stemness properties. While stress tolerance is a well-known attribute of CSCs, CIN-induced stress is distinctive since levels appear to increase during tumor initiation and metastasis. These dynamic changes in CIN levels may serve as a barrier constraining the effects of non-CSCs and shaping the stemness landscape during the early stages of disease progression. In contrast to most other stresses, CIN can also paradoxically activate pro-tumorigenic antiviral signaling. Though seemingly contradictory, this may indicate that mechanisms of CIN tolerance and pro-tumorigenic inflammatory signaling closely collaborate to define the CSC state. Together, these unique features may form the basis for a critical relationship between CIN and stemness properties.

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Chromosomal instability as a driver of cancer progression

Cited by 2 publications

References 181 publications

Origins ofde novochromosome rearrangements unveiled by coupled imaging and genomics

Origins ofde novochromosome rearrangements unveiled by coupled imaging and genomics

Chromosomal instability as an architect of the cancer stemness landscape

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