Descrizione del progetto
Studiare i meccanismi di tolleranza all’aneuploidia
La biologia degli embrioni consentirebbe di riconoscere molte caratteristiche dello sviluppo tumorale, tra cui la proliferazione, la migrazione, l’angiogenesi, la soppressione immunitaria e la tolleranza dell’instabilità genomica. Gli errori di segregazione cromosomica conducono all’aneuploidia, all’eterogeneità tumorale, alla resistenza alla terapia e alla crescita metastatica nel caso del cancro. Tuttavia, durante lo sviluppo, l’aneuploidia è dannosa e la porzione di cellule aneuploidi negli embrioni si esaurisce con il progredire della differenziazione. Finanziato dal programma di azioni Marie Skłodowska-Curie, il progetto OncoFetal_Ploidy si propone di studiare la tolleranza all’aneuploidia nell’embriogenesi e nel cancro. OncoFetal_Ploidy esaminerà la risposta delle cellule all’induzione dell’aneuploidia nei gastruloidi delle cellule staminali embrionali umane, negli organoidi del cancro del colon-retto e negli organoidi normali del colon, stabilendo i modelli condivisi tra le cellule cancerogene e le cellule staminali embrionali.
Obiettivo
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.
Campo scientifico
Not validated
Not validated
Parole chiave
Programma(i)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Meccanismo di finanziamento
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinatore
1066 CX Amsterdam
Paesi Bassi