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Understanding aneuploidy tolerance in cancer by studying early embryogenesis

Project description

Studying the mechanisms of aneuploidy tolerance

Many characteristics of cancer development could be recognised in the biology of embryos, including proliferation, migration, angiogenesis, immune suppression, and the tolerance of genome instability. Chromosome segregation errors result in aneuploidy, tumour heterogeneity, therapy resistance and metastatic growth in the case of cancer. However, during development, aneuploidy is detrimental and the proportion of aneuploid cells in embryos is depleted as the differentiation progresses. Funded by the Marie Skłodowska-Curie Actions programme, the OncoFetal_Ploidy project aims to study aneuploidy tolerance in embryogenesis and cancer. OncoFetal_Ploidy will examine cells' response to aneuploidy induction in human embryonic stem cell gastruloids, colorectal cancer organoids and normal colon organoids, establishing the patterns shared between cancer cells and embryonic stem cells.

Objective

Can we study complex cancer biology by using a more predictable and structured model of embryogenesis? Many of the hallmarks of cancer biology are shared with the biology of embryos: sustained proliferation, migratory behavior, angiogenesis, immune system suppression, and in my opinion the most fascinating: the tolerance of genome instability.

Chromosome segregation errors and resulting aneuploidy are an important source of intratumor heterogeneity, therapy resistance, and metastasis in cancer. On the other hand, aneuploidy is detrimental during development. However, despite the detrimental effects of aneuploidy, most human pre-implantation embryos are mosaics of euploid and aneuploid cells, and the proportion of aneuploid cells is progressively depleted from embryos as the cell differentiation progresses from the blastocyst stage onwards. Therefore, could it be the undifferentiated state or de-differentiation of cells that might play a role in aneuploidy tolerance? Here I plan to study and compare aneuploidy tolerance during embryogenesis and in cancer, and investigate if differentiation and de-differentiation of cells play a role in this phenomenon.

In the suggested experiments I will examine cells' response to chromosome segregation errors in human embryonic stem cell gastruloids (hESC), colorectal cancer organoids (CC), and normal colon organoids (NC) after aneuploidy induction with Msp1 inhibitor (+/- CENP-E inhibitors). Specifically, I will assess the cell proliferation rate, cell cycle progression and apoptosis with live-cell imaging, as well as transcriptional profiles using single-cell RNA-seq. Next, I will assess the same phenotypes after the addition of different growth factors that change the differentiation state of the cells.

Ultimately, I would like to find the patterns shared between cancer cells and embryonic stem cells, which could be exploited for novel cancer therapies that would not be detrimental to somatic cells.

Coordinator

STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS
Net EU contribution
€ 187 624,32
Address
PLESMANLAAN 121
1066 CX Amsterdam
Netherlands

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Region
West-Nederland Noord-Holland Groot-Amsterdam
Activity type
Research Organisations
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Total cost
No data

Partners (1)