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The role of tumor microenvironment elements in malignant cell plasticity and heterogeneity

Grant number: 17/24287-8
Support type:Scholarships abroad - Research Internship - Doctorate (Direct)
Effective date (Start): April 15, 2018
Effective date (End): April 08, 2019
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:Pedro Augusto Carlos Magno Fernandes
Grantee:Gabriela Sarti Kinker
Supervisor abroad: Itay Tirosh
Home Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Local de pesquisa : Weizmann Institute of Science, Israel  
Associated to the scholarship:14/27287-0 - Characterization of the melatonergic system of human gliomas and its implication on tumor aggressiveness and invasiveness, BP.DD

Abstract

Cellular plasticity and heterogeneity are fundamental features of human tumors and arise as a consequence of genetic and epigenetic mechanisms, as well as environmental signals. Such diversity is considered an important source of treatment failure, as subpopulations of drug-resistant cells may underlie tumor recurrence and metastasis. In the tumor ecosystem, malignant and stromal cells communicate through cell-to-cell interactions or soluble factors. Cytokines such as IL6, IL8 and TGF-beta, for example, have been shown to modulate tumor cell proliferation, survival, invasion and metastasis. Additionally, we have recently demonstrated that glioma cells can produce melatonin, an indolamine known for being released by the pineal gland during the night. We showed that glioma-synthesized melatonin can exert autocrine anti-proliferative effects by activating its G-protein coupled receptor MT1. With that in mind, combining the gene expression levels of melatonin synthesis and metabolism enzymes, we developed a two-gene predictive model of the content of melatonin in the tumor microenvironment, the ASMT:CYP1B1 index. Interestingly, a low index value, indicative of decreased melatonin, is associated with poor prognosis in gliomas and other 8 types of solid tumors. It is now clear that soluble factor produced within the tumor microenvironment can shape the malignant behavior. However, the role of such non-heritable mechanisms in intra-tumor heterogeneity is still largely unknown. As such, using droplet-based single-cell RNA-seq (scRNA-seq) and a multiplexing strategy, we will investigate the role of melatonin (and analogous), cytokines, macrophage/fibroblast-conditioned media and hypoxia in modulating the heterogeneity and plasticity of ~20 human cell lines from different types of tumors (glioma, melanoma, head and neck carcinoma and colon adenocarcinoma). Ultimately, this work can lay the groundwork for the proposition of microenvironment-based target therapies, while using the scRNA-seq resolution to identify gene expression signatures with the potential to predict treatment response.