| Summary: | The development of an organism is highly influenced by the proliferation of progenitor cells. Progenitor cells are multipotent stem cells, with the ability to self-renew and generate more differentiated daughter cells, giving rise to the cellular diversity in animals. However, it is important that stem cells tightly regulate their proliferation, fate and lifespan, since a dysregulation in these processes can lead to excess self-renewal and formation of tumors. The current view in the field dictates that tumors are composed of heterogenous cell populations with cancer stem cells at the base of this hierarchical organization. It is though that cancer stem cells are no longer responsive to regulatory mechanisms that would tightly balance normal stem cell proliferation, differentiation and lifespan. Most of these signals are derived from their niche, the specific microenvironment around stem cells that protects, nurtures and balances stem cell properties. It is usually thought that cancer stem cells have the capacity to take advantage of their own niche to support overproliferation, like normal malignant neoplasms. Altogether, understanding how this type of malignant cells are regulated and depend on their own microenvironment is very important for the design of future therapies. To understand how cancer stem cells regulate their proliferation, Drosophila has emerged as great model, in particular Drosophila neural stem cells, the neuroblasts (NBs). Neurogenesis in flies begins with the generation of NBs in embryo stages that continue to proliferate until they reach early pupal stages and disappear. NBs have the capacity to divide asymmetrically by differentially segregating cell fate determinants, allowing their self-renewal and the generation of a more committed daughter cell, in this case neurons or glia. However, defects in NB asymmetric division, caused by mutations in cell fate determinants, like Brain tumor (Brat), lead to uncontrolled proliferation and subsequent tumor formation. While wild-type NBs should exit proliferation during pupal stages, brat-/- tumor-like NBs are able to divide indefinitely and survive until adulthood. Furthermore, these tumors can form metastasis and continue to proliferate after serial transplantations into adult hosts. Interestingly, tumor-like NBs lose the capacity to form tumors once they are isolated in vitro. This suggests that the tumor niche and microenvironment could be involved in sustaining tumorigenesis in vivo. Therefore, in this study, I demonstrate that the tumor microenvironment could be fuelling tumor-like NBs with essential metabolites and nutrients to allow tumor growth. The rationale behind this, lies on the fact wild-type NBs’ fate and proliferation potential highly depend on metabolism. Here, I analyse the metabolic dependency of tumors from their microenvironment and show that Brat depleted tumor-like NBs are able to upregulate many plasma membrane metabolic transporters to increase external nutrient uptake. Subsequently, I demonstrate that blocking some of these transporters can lead to a reduction in tumor growth, indicative that external nutrients/metabolites are essential for tumor-like NB proliferation.
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