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

• Grant number: 17/24287-8
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: April 15, 2018
• End date: April 08, 2019
• Field of knowledge: Biological Sciences - Physiology
• Principal Investigator: Pedro Augusto Carlos Magno Fernandes
• Grantee: Gabriela Sarti Kinker
• Supervisor: Itay Tirosh
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: 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. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

HARA, TOSHIRO; CHANOCH-MYERS, RONY; MATHEWSON, NATHAN D.; MYSKIW, CHAD; ATTA, LYLA; BUSSEMA, LILLIAN; EICHHORN, STEPHEN W.; GREENWALD, ALISSA C.; KINKER, GABRIELA S.; RODMAN, CHRISTOPHER; et al. Interactions between cancer cells and immune cells drive transitions to mesenchymal-like states in glioblastoma. CANCER CELL, v. 39, n. 6, p. 779+, JUN 14 2021. (14/27287-0, 17/24287-8)

KINKER, GABRIELA S.; GREENWALD, ALISSA C.; TAL, ROTEM; ORLOVA, ZHANNA; CUOCO, MICHAEL S.; MCFARLAND, JAMES M.; WARREN, ALLISON; RODMAN, CHRISTOPHER; ROTH, JENNIFER A.; BENDER, SAMANTHA A.; et al. Pan-cancer single-cell RNA-seq identifies recurring programs of cellular heterogeneity. Nature Genetics, v. 52, n. 11, p. 1208+, NOV 2020. (17/24287-8, 14/27287-0)

KINKER, G. S.; OSTROWSKI, L. H.; RIBEIRO, P. A. C.; CHANOCH, R.; MUXEL, S. M.; TIROSH, I.; SPADONI, G.; RIVARA, S.; MARTINS, V. R.; SANTOS, T. G.; et al. MT1 and MT2 melatonin receptors play opposite roles in brain cancer progression. JOURNAL OF MOLECULAR MEDICINE-JMM, v. 99, n. 2, JAN 2021. (14/23830-1, 14/27287-0, 13/13691-1, 17/24287-8, 14/50943-1, 15/23348-8)