CENTR-ALL · Clarifying role of the CENTROSOME in abnormal mitotic processes featuring the most common childhood malignancy: paediatric High Hyperdiploid Acute Lymphoblastic Leukaemia (HHDpALL)
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-01-24 → 2021-01-23
- EU contribution
- €171,461
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
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Results in brief
Clarifying role of the CENTROSOME in abnormal mitotic processes featuring the most commonchildhood malignancy: paediatric High Hyperdiploid Acute Lymphoblastic Leukaemia (HHDpALL)
Paediatric Acute Lymphoblastic Leukaemia (pALL) still accounts for most cancer-related deaths in children. Hyperdiploidy (HHD) is the most frequent subtype, having an elevated chromosome number compared to other patients. It is still not clear how this disease develops, but recently it was shown that chromosomal instability (CIN) plays a key role. The most common cause of CIN is centrosome amplification (CA). Centrosomes coordinate cell division and having access number of them (CA), can result in an unequal distribution of the chromosomes to the daughter cells and eventually cancer. If a cell has too many centrosomes, the cell division can get out of hand, which can result in cell death (Fig. 1). Preventing centrosome clustering (by which tumor cells keep CA under control) seems a promising therapeutic option for patients with CA. HHD-pALL is also known to often have mutations in RAS signalling genes, which, in turn, might effect centrosome development; the exact relation, however, is unclear. To reveal if CA plays a role in the development of HHD-pALL, we analyzed patient samples and investigated, in an experimental setting, the effect that the most frequently mutated RAS gene (KRAS) has on the development of these organelles. Centrosomes are mostly visualized by immunofluorescence (IF) microscopy, but precise evaluation is error-prone and not always straightforward. A diagnostic and high-throughput screening method would thus be of great help. To develop a fully automated fluorescence light microscopy application, determining the amount of cells with CA, we combined a deep neural network (DNN) classifier with an automated slide scanning system. Research was carried out primarily by Dr Gabor Pajor in a field-leading group (headed by Prof. Alwin Krämer) at the German Cancer Research Center (DKFZ, Germany) and in a cross-sector collaboration with a non-academic world leader in automated image analysis (MetaSystems, Germany).
Data: CORDIS, © European Union
Project objective
Paediatric Acute Lymphoblastic Leukaemia (pALL) still accounts for most cancer-related deaths in children. Although high hyperdiploidy (HHD) is the most frequent pattern, its pathomechanism remains poorly understood. Recently, Experienced Researcher (ER) et al showed that sequential chromosomal gains and chromosomal instability (CIN) are critical features in HHD-pALL evolvement. The most common cause of CIN is centrosome amplification (CA) and recent findings indicate that inhibiting centrosome clustering (mechanism by which tumour cells control CA to retain viability) is a promising therapeutic avenue. Opposed to most solid and hematologic malignancies, the role of CA in HHDpALL has not been clarified thus far. Primary goal of ER is to illuminate this issue, which is expected to result in new diagnostic- and screening methodologies, as well as novel therapeutics. ER will join a leading group in the field of ‘cancer associated centrosome abnormalities’ (headed by Professor Alwin Krämer), in one of Europe’s largest cancer research institutes (DKFZ, Germany), applying state-of the art technologies in genomics and functional cell biology. Centrosomes are mostly visualized by immunocytochemistry, but precise evaluation is error prone and featured with inter-personal/-laboratory variance. A diagnostic and high-throughput screening methodology thus is highly desirable. Accordingly, second aim is to develop a novel automated fluorescence light microscopy (aFLM) application for centrosome analysis, building on ER's previous experience, but in a cross-sector collaboration with a non-academic world leader in image analysis (MetaSystems, Germany). To gain ultrastructural information as well, ER will also align aFLM with scanning electron microscopy for the first time, in collaboration with the Schwab Group (EMBL, Germany) creating high-capacity correlative light electron microscopy (hcCLEM). Commercial potentials of above original developments will also be investigated.
Original text from CORDIS.
Participants
- DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG · HeidelbergCoordinatorGermany
Links
Data: CORDIS, © European Union