Cellular heterogeneity and Rho GTPase signalling in neuroblastoma tumours
Instituto de Biomedicina de Sevilla – IbiS / Universidad de Sevilla
The acquisition of invasive and metastatic capabilities by cancer cells is revealed as one of the principal hallmarks in cancer, dictating its aggressiveness and deadliness. Few genetic mutations specifically associated with metastasis have been identified so far, indicating that epigenetic and transcriptional reversible changes are probably the main drivers of metastasis. Tumor cells with the necessary phenotypic plasticity are therefore the ideal candidates to become metastasis initiating cells and decisively contribute to the aggressiveness of the tumor. Undifferentiated tumor cells with stem-like properties, often referred as cancer stem cells or tumor propagating cells, fulfil this requirement.
Neuroblastoma (NB) is a developmental cancer arising during the formation of the sympathetic nervous system from the neural crest. It is characterized by a high heterogeneity, including an aggressive version refractory to therapy and with frequent deadly metastasis in a proportion of patients. Single cell transcriptomics studies also identify a great cellular heterogeneity, with at least 3 types of tumor cell populations with divergent expression profiles and phenotypes: a compromised adrenergic proliferative cell population (ADRN), a mesenchymal cell population (MES) and an undifferentiated neural crest stem cell-like population (NBCSC) with potential initiating and propagating tumor cell capabilities.
Our focus is to establish the contribution of NBCSC to disease progression and metastasis, exploring the reversible signaling pathways mediating the acquisition of invasive and metastatic capabilities. To this aim, we have devised methods to obtained cell cultures enriched in undifferentiated neural crest stem-like cells from NB samples. We have performed image-based cellular phenotyping to explore the adhesive, migratory and invasive properties of these cells compared to the ADRN population. We describe that NBCSC possess a differentiated cytoskeletal architecture which confers particular migratory properties.
Moreover, our research point towards an important role for RhoGTPase signaling in NB progression. In particular, Cdc42 signaling seems to intervene in the balance between differentiation and stemness in NB cells, suggesting specific signaling events controlling NBCSC identity and plasticity.