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

Sabat-Pospiech, Dorota, Fabian-Kolpanowicz, Kim, Kalirai, Helen ORCID: 0000-0002-4440-2576, Kipling, Natalie, Coupland, Sarah E ORCID: 0000-0002-1464-2069, Coulson, Judy M ORCID: 0000-0003-2191-2001 and Fielding, Andrew B
(2022) Aggressive uveal melanoma displays a high degree of centrosome amplification, opening the door to therapeutic intervention. JOURNAL OF PATHOLOGY CLINICAL RESEARCH, 8 (4). pp. 383-394.

Access the full-text of this item by clicking on the Open Access link.


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.

Item Type: Article
Uncontrolled Keywords: uveal melanoma, centrosome amplification, centrosome clustering, pericentriolar matrix, mitotic spindle, monosomy 3, primary, metastatic, proliferation
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 17 Jun 2022 14:44
Last Modified: 18 Jan 2023 20:57
DOI: 10.1002/cjp2.272
Open Access URL:
Related URLs: