Modelling pediatric tumor initiation with human stem cells

Cancers that occur in young children often start due to mutations during cell development. Development is a highly complex process: unspecialized progenitor cells, stem cells, take on different functional roles in the organism and become, for example, neurons, skin cells, blood cells, or other cell types in the body. The specialization process is regulated so that functional cells are produced at the right time and in the correct number during healthy development. When mutations in key genes occur during this specialization, development can be disrupted, leading to the formation of the first cancer cells. In such cases, cells cannot be produced in the correct number, and development is stalled at the progenitor stage, with cells continuing to multiply uncontrollably. This process eventually leads to the formation of tumors in young children. Although we know the mutations associated with childhood cancer, we still do not fully understand how these mutations disrupt the developmental process. At the same time, we are aware of examples where cells with the mutation do not develop cancer and that some pediatric tumors can resolve on their own. Therefore, we can assume that some cells are capable of resisting mutations and the tumor initiation process. In this project, we aim to find out how cells achieve resistance to cancer formation and what makes some other cells susceptible to cancer initiation. To answer these questions, we propose a combination of state-of-the-art techniques. Our main research tools are human mini-organs that replicate the developmental process. We can produce these mini-organs from cells engineered in such a way that we can activate cancer- associated mutations when needed. We will guide the cells through the developmental process within the mini-organs, activate mutations at different stages, and observe the changes caused by mutations in the first hours to understand how the cells are transformed into the first cancer cells. We will identify the resistant and susceptible cellular stages and characterize the cellular components that define them. To fully characterize the cellular stages, we will use single-cell genomics methods and functional tests to read the active genes of individual cells and identify which ones are most important for mutation susceptibility and resistance. This approach will allow us, for the first time, to look into the time window from when cells acquire mutations to the emergence of the first cancer cells with unprecedented resolution. We will gain a new understanding of how pediatric cancer starts. By learning these mechanisms, we may eventually be able to therapeutically intervene in this process at its early stages.

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