Dados do Resumo

Título

Functional and Epigenetic Characterization of an Immune-Mediated Dormancy Model of Melanoma

Introdução

Tumor recurrence, which can occur many years after therapeutic intervention, represents the main challenge in clinical oncology. Clinically, this period between the "cure" of the primary tumor and its local or distal metastatic relapse is known as the "dormancy state." This means the disease is present in the body but remains asymptomatic and undetectable. Tumor dormancy can be divided into mass dormancy or cellular dormancy. Cellular dormancy is a temporary and reversible stage of mitotic arrest, where the cell is trapped in the G0 phase of mitotic division through the activation of quiescence mechanisms. When dormancy is tumor-related, it is assumed to be a balance between cancer cell proliferation and their decline due to cell death. This balance can be achieved and maintained by two different processes: angiogenic dormancy or immune-mediated dormancy. The first is caused by the absence of new blood vessel formation, and the second is due to the interaction between the neoplastic cells and the immune system. This process has been linked to therapeutic resistance and a high metastatic potential of malignant neoplasias.

Objetivo

Given the importance of this process for cancer development and progression, this project aims to functionally and epigenetically characterize a murine model of immune-mediated tumor dormancy in cutaneous melanoma, a highly aggressive cancer

Métodos

We use a metastatic melanoma cell line (4C11+) obtained through a linear progression model in melanocytes and a model of inflammation-induced tumorigenesis - both developed by our research group. In this model, a sub-tumorigenic dose of melanoma cells (immune-mediated dormancy), when co-injected with apoptotic (but not necrotic) cells, can generate fast-growing tumors in C57BL/6 mice

Resultados

Our study shows that the sub-tumorigenic dose of viable cells only generates tumors in immunosuppressed (NSG) mice (100% of animals), indicating that in immunocompetent animals, the primary defense system - T and B lymphocytes, and NK cells - appears to contain it. Additionally, considering the role of epigenetic modulation in cellular malignant transformation, our study indicates that the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine limits the tumorigenesis process in this model. Thereby, RNA sequencing (RNAseq) was performed to identify genes differentially expressed in tumors awaked by acute inflammation from animals treated and non-treated with the demethylating agent. The most differentially expressed non coding genes in tumors from treated versus non-treated animals were selected for further in vitro studies that are still being conducted.

Conclusões

The present work shows the development of dormancy model and its awekening triggerd by an acute inflammatory process in mice C57Bl/6. We demostrate that alterations in the methylation patter during the process of tumorigenesis afect tumor progression, by slowing this process in this in vivo model, which indicates that some genetic components of immune system might be being attenuated by DNA methylation and contributing with a worse tumorigenesis in mice. Gettered this results reiterate the importance of epigenetic modulations in cancer progression, offering insights of critical molecular pathways related to immunomediated dormancy-breakout of melanoma.

Financiador do resumo

FAPESP, CAPES, CNPq

Palavras Chave

epigenetics; Melanoma; Immunology;