Aggressive uveal melanoma displays a high degree of centrosome amplification, opening the door to therapeutic intervention

Abstract

Uveal melanoma (UM) is the most common intraocular cancer in adults. Whilst treatment of primary UM (PUM) is often successful, around 50% of patients develop metastatic disease with poor outcomes, linked to chromosome 3 loss (monosomy 3, M3). Advances in understanding UM cell biology may indicate new therapeutic options. We report that UM exhibits centrosome abnormalities, which in other cancers are associated with increased invasiveness and worse prognosis, but also represent a potential Achilles' heel for cancer‐specific therapeutics. Analysis of 75 PUM patient samples revealed both higher centrosome numbers and an increase in centrosomes with enlarged pericentriolar matrix (PCM) compared to surrounding normal tissue, both indicative of centrosome amplification. The PCM phenotype was significantly associated with M3 (t‐test, p < 0.01). Centrosomes naturally enlarge as cells approach mitosis; however, whilst UM with higher mitotic scores had enlarged PCM regardless of genetic status, the PCM phenotype remained significantly associated with M3 in UM with low mitotic scores (ANOVA, p = 0.021) suggesting that this is independent of proliferation. Phenotypic analysis of patient‐derived cultures and established UM lines revealed comparable levels of centrosome amplification in PUM cells to archetypal triple‐negative breast cancer cell lines, whilst metastatic UM (MUM) cell lines had even higher levels. Importantly, many UM cells also exhibit centrosome clustering, a common strategy employed by other cancer cells with centrosome amplification to survive cell division. As UM samples with M3 display centrosome abnormalities indicative of amplification, this phenotype may contribute to the development of MUM, suggesting that centrosome de‐clustering drugs may provide a novel therapeutic approach.

Identification of KIFC1 as a putative vulnerability in lung cancers with centrosome amplification

“…Liu et al . also reported that KIFC1 was overexpressed in NSCLC compared to non-malignant lung tissues and that high expression was associated with worse prognosis, which is consistent with findings from other LC studies[35–37, 59, 60] and reports in other malignancies[34, 36, 61–65]. Our analyses of multiple LC cohorts confirmed associations of KIFC1 with clinical factors including survival and stage as well as CA20.…”

Causes, consequences and clinical significance of aneuploidy across melanoma subtypes

“…Of note, loss of 9p21 – where CDKN2A/B reside - is prevalent in melanoma and has recently been associated with primary resistance to ICI treatment ( 99 ). Finally, a recent study ( 82 ) utilizing a cohort of 75 primary uveal melanomas showed amplified centrosome numbers as well as an increase in centrosomes with enlarged pericentriolar matrix (PCM) relative to the surrounding normal tissue, with PCM phenotype significantly associated with monosomy of chromosome 3. Uveal melanomas with monosomy of chromosome 3 have increased aneuploidy compared to those with disomy of the same chromosome, in agreement with a scenario of increased centrosomal abnormalities in the former group ( 82 ).…”

“…Finally, a recent study (82) utilizing a cohort of 75 primary uveal melanomas showed amplified centrosome numbers as well as an increase in centrosomes with enlarged pericentriolar matrix (PCM) relative to the surrounding normal tissue, with PCM phenotype significantly associated with monosomy of chromosome 3. Uveal melanomas with monosomy of chromosome 3 have increased aneuploidy compared to those with disomy of the same chromosome, in agreement with a scenario of increased centrosomal abnormalities in the former group (82). The authors argue that prior observations that melanomas with monosomy of chromosome 3 have increased aneuploidy compared to melanomas with disomy of this chromosome ( 66) is consistent with increased centrosomal abnormalities in the former melanoma group.…”

“… Cell cycle defects that can lead to aneuploidy in melanoma. Defects include centrosomal amplification ( 29 , 81 , 82 ), replication stress ( 28 ), G2 decatenation failure ( 83 – 85 ) and SAC dysregulation ( 26 ). ( 27 , 86 ).…”

A centrosome-related gene signature for predicting the overall survival of uveal melanoma

“…More recently, CA has been reported for the first time in UVM. Sabat-Pośpiech et al confirmed that CA existed in UVM primary tumors and cell lines ( 13 ). Moreover, a study showed that chromosome monosomy 3 (M3) and BAP1 mutant UVM had a higher level of CA, which was related to worse prognosis ( 13 ); however, this is the only study available on the role of CA in UVM and the mechanism needs further detailed study.…”