Activitat pleiotrópica de les vesícules extracel·lulars provinents de cèllules mare tumorals en càncer

Resumen

Triple Negative Breast Cancer (TNBC) and Head and Neck Squamous Cell Carcinoma (HNSCC) tumors usually show high grade of intratumor heterogeneity. Among tumor cell subpopulations, Cancer Stem Cells (CSC) emerge as critical cell population that play key roles in tumor initiation, progression, metastasis and tumor relapse after therapy. Indeed, cancer cell plasticity mediates the repopulation of CSC in tumors through de-differentiation processes of differentiated cancer cells (DCC) towards CSC phenotypes. Extracellular Vesicles (EVs) released by tumor cells are known to play a relevant role in the inter-cellular communication and cancer disease. However, the particular contribution of EVs secreted by either CSC or DDC (EVsCSC and EVsDCC) to tumor progression remains elusive. Here we isolated and characterized EVsCSC and EVsDCC subpopulations, released by TNBC models. Indeed, and given the immunosupressive nature of HNSCC tumors, we stablished an experimental approach to track the in vivo interactions between HNSCC EVsCSC, EVsDCC and immune cells subsets. Interestingly, this thesis showed that both tumor secreted EVsCSC and EVsDCC stablish an exclusive commu-nication crosstalk with CSC, DCC and stromal cells present in the tumor microenvironment. Re-markably, we exposed the unique role of TNBC derived EVsCSC and EVsDCC in guiding cancer cells plasticity and in mediating distant activation of stromal cells at future metastatic sites. Furthermore, we addressed that TNBC derived EVsCSC and EVsDCC exerted opposite roles in directing tumor cell plasticity. While EVsCSC promoted cancer cells differentiation towards DCC phenotypes, EVsDCC induced tumor cells transitions towards CSC-like states. This plasticity regulation seems to be a mechanism to maintain tumor CSC/DCC dynamic equilibrium in tumors. Interestingly, we demonstrated that EVsCSC and EVsDCC mediate cancer associated fibroblasts (CAFs) activation in two functional and unique ways. On one hand, EVsDCC activated cytokine se-cretory CAFs phenotype, triggering IL-6/IL-8 signaling and sustaining CSC phenotype maintenance. On the other hand, EVsCSC produced the in vitro and in vivo activation of myofibroblastic CAFs subpopulations displaying enhanced invasive potential. Moreover, EVsCSC were able to re-model endothelial cells to promote angiogenesis. Indeed, we showed that HNSCC EVsCSC preferably interact with MHC-II- M2 Macrophages and PD-1+T cells in the tumor immune microenvironment. Of note, both immune cell populations are highly involved in tumor immunosuppression. Lastly, we showed that exogenously administered EVsCSC prompted the formation of receptive lung metastatic niches supporting macrometastasis growth whilst EVsDCC induced the secretion of pro-stem signals in the niche.