The crosstalk among tumor microenvironment cells through extracellular vesicles favors the establishment of tumor niche

Abstract

Oral squamous cell carcinoma (OSCC) is the most incident malignant tumor in head and neck cancer, with 300,000 new cases and 145,000 deaths around the world per year, with 50% survival rate of advanced cases after five years of diagnosis. The molecular mechanisms involved in this tumor establishment are poorly characterized, and no molecular markers are currently available in clinical practice. In this context, the current FAPESP post-doctorate project (Process 2016/19337-3) has been studying the cargo proteins of different extracellular vesicles (EVs) from less and high aggressive oral cancer cells to understand their possible role in tumor microenvironment modulation, immune regulation, and progression. However, the tumor-stroma communication is not a unidirectional process, driven only by cancer cells, but also by resident cells, like cancer-associated fibroblasts (CAFs), macrophages, endothelial cells, stem cells, secreted factors and other components of the extracellular matrix (ECM), and all of them can alter and be altered by the microenvironment. Therefore, to complement the main project, we propose this BEPE project to advance the knowledge about the transference of bioactive molecules by EVs, using healthy and 'cancer affected' human induced pluripotent stem cells (hiPSCs) and organoids technology. This research strategy will enable the study of the oral tumor behavior, in a reductionist and integrative manner, using for that different analytical tools, such as LC-MS/MS (DDA and SRM), NGS and immunofluorescence target panel. The hiPSCs are known to conserve the genetic diversity of donors and can recapitulate tumorigenesis in vitro, thus serving as a model of cancer stem cell (CSC) and the differentiated cancer cell. Understanding the molecular mechanisms that are implicated in the crosstalk among tumor microenvironment cells can give new insights to the tumor establishment and progression and, in future, provide critical molecules that can improve the diagnosis, prognosis, staging, and treatment of OSCC. Finally, the long-term collaboration between UVA and CNPEM groups can provide scientific enhancing and technical learning for both sides.