OncoFetal_Ploidy · Understanding aneuploidy tolerance in cancer by studying early embryogenesis
Horizon Europe — Marie Skłodowska-Curie Actions
- Duration
- 2022-07-01 → 2024-11-30
- EU contribution
- €190,374
- Participants
- 2
- Scheme
- HORIZON-TMA-MSCA-PF-EF
Lines connect the coordinator with its partners.
Results in brief
Understanding aneuploidy tolerance in cancer by studying early embryogenesis
What is Aneuploidy? Every human cell contains DNA that is packed into 46 chromosomes. Imagine these 46 chromosomes as instruction manuals in a library that help the cell operate its functions. Within the human body cells divide everyday. During cell divisions, errors can occur, and daughter cells can end up with extra or missing chromosomes - a condition called aneuploidy. If chromosomes are like instruction manuals for the cells, missing a copy of a manual means losing crucial information, while an extra copy creates confusion about which version to use. Therefore, one might assume aneuploidy is always detrimental to the cell, however, it turns out it depends on a context. What makes some cells tolerant to aneuploidy? In the body cells can have different levels of specializations. “Specialized” cells perform specific tasks, for example red blood cells carry oxygen, muscle cells contract, nerve cells carry electrical impulses. “Unspecialized” cells haven’t been assigned a role yet—they can turn into different types of cells depending on what your body needs. Do those different types of cell specializations influence tolerance of aneuploidy? If yes, what are the mechanisms? Why study aneuploidy? Aneuploid cancer cells tend to be more resistant to the treatment, more prone to spread to other parts of the body, and aneuploid cancers tend to be associated with poorer prognosis for the patient. Understanding what allows cancer cells to tolerate a high degree of aneuploidy would allow us to understand the disease better, take actions to target those mechanisms, ultimately making the disease more manageable.
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS · AmsterdamCoordinatorNetherlands
- CALIFORNIA INSTITUTE OF TECHNOLOGYCORP · PasadenaUnited States
Links
- View on CORDIS
- DOI: 10.3030/101068843
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e506a9c918&appId=PPGMS
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e51ca2f004&appId=PPGMS
Data: CORDIS, © European Union