Project Portugal 2030

Summary

The identification of novel therapeutic options to fight OS stands at a scientific and clinical impasse for the last decades, hampered by the limited understanding of OS pathophysiology(1). A deeper understanding of OS mechanisms leading to its progression and to the metastatic process constitutes an urgent clinical need. Our team has recently conducted a comprehensive review of the current state of the art in biologically relevant 3D in vitro models of OS(1). We explored how the representativity of these models in mimicking native tissue can pose challenges in fully comprehending the disease. The lack of in vitro and in vivo models that enable the study of the complexity of OS tumor microenvironment (TME) in a biomimetic and fully human scenario, has hindered our understanding of how the dynamics of the TME influence the progression of the disease. Overcoming this gap in the current state of the art, we have recently developed an advanced model of OS that takes into consideration the multiple players of the tumor TME: the cancer, the stromal and the immune cells. This model was shown to resembles the native tumor in its extracellular matrix (ECM) composition, and its immunosuppressive phenotype (Supporting data in attachment). DUMBO delves into the complex crosstalk between OS cells, macrophages, stromal cells, and the metabolic landscape, to further unveil the molecular intricacies that govern these interactions, and lead to metastasis. To attain such goals, DUMBO will focus on 4 specific objectives: SO1: to address the role of the TME on the metabolic profile of OS tumors SO2: to unravel potential role of metabolism on OS immunity and its impact on OS progression and metastasis SO4: to shed light on novel therapeutic avenues for disrupting the metabolic symbiosis that fuels OS progression SO4: to formulate a nanotechnology approach capable of targeting the TME lipid metabolism, altering the immune landscape within the tumor, thereby inhibiting tumor progression and metastasis. Through a comprehensive exploration of these intertwined elements, this work aspires to contribute to the evolving understanding of OS biology and offer insights that will pave the way for the development of innovative therapeutic strategies.