1. Piracy of intracellular Signaling and Trafficking for Life-and-Death Decisions
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The CARMA-BCL10-MALT1 (CBM) complex is a gateway to lymphocyte activation and unlimited growth of some cancer cells. The CBM complex conveys NF-κB signal transduction and unleashes the protease activity of MALT1. By cleaving a limited set of substrates, MALT1 shapes the immune response, the mTOR signaling, and the homeostasis of lysosomes. What is the molecular basis for MALT1-mediated control of lysosomes? How exactly is the CBM complex regulated? What is the landscape of the functions controlled by the CBM partners? Finally, is intracellular organelle equipoise a checkpoint for life-and-death decisions?
2. Balance between extracellular and intracellular Vesicle Trafficking in Life-and-Death Decisions
The term “Extracellular Vesicles” (EVs) is a moniker for a variety of small, heterogeneous, membrane vesicles (30-1000 nm), released by cells into surrounding biofluids. EVs deliver expelled materials from their cell of origin to recipient cells, notably in the tumor microenvironment. While it is known that a class of EVs is generated through the endocytic pathway, the balance and importance of routing between extra- and intra-cellular vesicle cargo have not been extensively investigated. What are the mechanisms of EV production by tumor cells, and how are they connected with intracellular trafficking? What is the impact of external cues, such as therapeutic and cell death assaults, on EV production and composition? How, in turn, do EVs modulate tumor cell survival, expansion, and response to treatments
3. Intertwined Dialogue between Endothelium and tumor Cells
Glioblastoma Stem-like Cells (GSCs) have been found in the vicinity of brain endothelial cells, suggesting that functional and reciprocal interactions take place in the tumor vascular niche. In this scenario, the endothelium not only supplies oxygen and necessary nutrients but also seeds a protective microenvironment for tumor growth. Conversely, tumor-derived cues, by the mean of soluble factors, adhesive marks, and/or extracellular vesicles may convey messages to the surrounding endothelial compartment that might culminate in vascular dysfunctions, such as endothelial permeability and/or remodeling. What are the cellular mechanisms, including adhesion and signaling, by which endothelial cell shapes tumor cell fate? Vice Versa, how do external cues emanating from tumor cells educate their endothelial habitat?
Overall, our team combines cell biology and biochemistry approaches to identify new control points for tumor communication and thus characterize potentially relevant targets
for the development of clinical treatments and diagnostic tools.