Centrosome amplification: a quantifiable cancer cell trait with prognostic value in solid malignancies

Mittal, Karuna; Kaur, Jaspreet; Jaczko, Meghan; Wei, Guanhao; Toss, Michael S.; Rakha, Emad A.; Janssen, Emiel A. M.; Søiland, Håvard; Küçük, Ömer; Reid, Michelle D.; Gupta, Meenakshi V.; Aneja, Ritu

doi:10.1007/s10555-020-09937-z

Cited by 28 publications

(24 citation statements)

References 181 publications

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“…CA is one of the hallmarks of cancer 1,2 and is associated with tumor aggressiveness and worse clinical outcome in many cancers, including breast, lung and prostate cancers 2 . Given the key roles of centrosomes in supporting bipolar spindle formation, CC is among the major coping mechanisms utilized by cancer cells with CA to prevent multipolar mitosis and cell death.…”

Section: Discussionmentioning

confidence: 99%

Targeting TACC3 represents a novel vulnerability in highly aggressive breast cancers with centrosome amplification

Saatçi

Akbulut

Çetįn

et al. 2022

Preprint

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Centrosome amplification (CA) is a hallmark of cancer that is strongly associated with highly aggressive disease and worse clinical outcome. However, there are no effective strategies targeting cancer cells with CA while sparing normal cells. Here, we identified Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3) to be overexpressed in tumors with CA, and its high expression is associated with dramatically worse clinical outcome. We demonstrated that TACC3 forms distinct functional interactions in mitotic and non-mitotic cancer cells with CA to facilitate centrosome clustering (CC) and transcriptional repression of tumor suppressors, respectively. We showed, for the first time, that TACC3 interacts with the Kinesin Family Member C1 (KIFC1) via its TACC domain in mitotic cells with CA and inhibition of TACC3 blocks this interaction, leading to apoptosis via multipolar spindle formation and activation of spindle assembly checkpoint (SAC)/CDK1/p-Bcl2 axis. In interphase, TACC3 interacts with the members of the nucleosome remodeling and deacetylase (NuRD) complex (HDAC2 and MBD2) in nucleus, and its inhibition causes p53-independent G1 arrest and apoptosis by blocking these interactions and activating the transcription of key tumor suppressors (e.g., p21, p16 and APAF1). Notably, inducing CA by chemical (cytochalasin D) or genomic (PLK4 overexpression or p53 loss) modulations renders cancer cells highly sensitive to TACC3 inhibition. Targeting TACC3 by small molecule inhibitors or guide RNAs strongly inhibits growth of organoids and breast cancer cell line- and patient-derived xenografts with CA. Altogether our results pave the way towards therapeutic targeting of TACC3 in highly aggressive cancers.

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Section: Discussionmentioning

confidence: 99%

Targeting TACC3 represents a novel vulnerability in highly aggressive breast cancers with centrosome amplification

Saatçi

Akbulut

Çetįn

et al. 2022

Preprint

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“…While the mechanisms through which aluminum affects chromosomes integrity and segregation await further investigation, centrosome amplification, aneuploidy and CIN are a common characteristic of human cancers. Centrosome amplification is an early event in tumorigenesis, has a strong correlation with CIN and is associated with disease progression and poor prognosis [56]. Aneuploidy, observed in 90% of solid human tumors, correlates with metastatic behavior, drug resistance and poor patient outcome [25,57,58].…”

Section: Discussionmentioning

confidence: 99%

Aluminum Enters Mammalian Cells and Destabilizes Chromosome Structure and Number

Tenan

Nicolle

Moralli

et al. 2021

IJMS

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Chromosome instability (CIN) consists of high rates of structural and numerical chromosome abnormalities and is a well-known hallmark of cancer. Aluminum is added to many industrial products of frequent use. Yet, it has no known physiological role and is a suspected human carcinogen. Here, we show that V79 cells, a well-established model for the evaluation of candidate chemical carcinogens in regulatory toxicology, when cultured in presence of aluminum—in the form of aluminum chloride (AlCl3) and at concentrations in the range of those measured in human tissues—incorporate the metal in a dose-dependent manner, predominantly accumulating it in the perinuclear region. Intracellular aluminum accumulation rapidly leads to a dose-dependent increase in DNA double strand breaks (DSB), in chromosome numerical abnormalities (aneuploidy) and to proliferation arrest in the G2/M phase of the cell cycle. During mitosis, V79 cells exposed to aluminum assemble abnormal multipolar mitotic spindles and appear to cluster supernumerary centrosomes, possibly explaining why they accumulate chromosome segregation errors and damage. We postulate that chronic aluminum absorption favors CIN in mammalian cells, thus promoting carcinogenesis.

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“…Centrosome amplification or its structural aberrations represent a hallmark of human cancers with direct consequences for chromosomal instability and can trigger cellular invasion [ 15 , 16 ]. Numerous studies have correlated the presence and the degree of centrosome amplification with indicators of poor prognoses, such as higher tumor grade and ability to recur and metastasize [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of Microtubule Nucleating Proteins in Cancer Cells

Dráberová

2021

Cancers

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In cells, microtubules typically nucleate from microtubule organizing centers, such as centrosomes. γ-Tubulin, which forms multiprotein complexes, is essential for nucleation. The γ-tubulin ring complex (γ-TuRC) is an efficient microtubule nucleator that requires additional centrosomal proteins for its activation and targeting. Evidence suggests that there is a dysfunction of centrosomal microtubule nucleation in cancer cells. Despite decades of molecular analysis of γ-TuRC and its interacting factors, the mechanisms of microtubule nucleation in normal and cancer cells remains obscure. Here, we review recent work on the high-resolution structure of γ-TuRC, which brings new insight into the mechanism of microtubule nucleation. We discuss the effects of γ-TuRC protein dysregulation on cancer cell behavior and new compounds targeting γ-tubulin. Drugs inhibiting γ-TuRC functions could represent an alternative to microtubule targeting agents in cancer chemotherapy.

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Centrosome amplification: a quantifiable cancer cell trait with prognostic value in solid malignancies

Cited by 28 publications

References 181 publications

Targeting TACC3 represents a novel vulnerability in highly aggressive breast cancers with centrosome amplification

Targeting TACC3 represents a novel vulnerability in highly aggressive breast cancers with centrosome amplification

Aluminum Enters Mammalian Cells and Destabilizes Chromosome Structure and Number

Dysregulation of Microtubule Nucleating Proteins in Cancer Cells

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