Contribution of the tissue microenvironment to OSCC progression: role of CAFs, TAMs and fibronectin / a5b1 integrin signaling

• Grant number: 20/10664-7
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2021
• End date: December 31, 2023
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Carlos Rossa Junior
• Grantee: Carlos Rossa Junior
• Host Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

In the past two decades, interest in the tumor microenvironment (TME) has surged due to the increased acknowledgment of the impact of non-neoplastic cells and extracellular matrix on the initiation, progression, treatment response and therapeutic resistance of solid tumors. Recently, research in tumor immunology yielded novel therapeutic approaches incorporated into the clinical management. These approaches are derived from promising results of in vitro and pre-clinical studies; however, they have shown limited clinical efficacy. This limited clinical translation may be associated with the complexity and heterogeneity of the TME, particularly of the interaction with a tridimensional microenvironment and the reciprocal influences of the therapy on different cells and biological processes relevant for tumor biology. Macrophages (TAMs) are the most abundant immune cells in the TME of oral squamous cell carcinomas (OSCC) and are strongly associated with worse prognosis and poor response to treatment. Fibroblasts are the most abundant non-neoplastic cells in the tumor stroma and also assume a distinct phenotype (CAFs), which is strongly related to tumor aggressiveness and inversely related with prognosis. Considering that composition of ECM has a critical role for tumor progression, we will also assess the influence of fibronectin (a major constituent of ECM and associated with increased aggressiveness and poor prognosis of OSCC), via its major receptor a5b1 integrin on the phenotypes of CAFs, TAMs and on their interactions and modulation of tumor cell invasion. The fact that TAMs and CAFs are co-localized in the tumor stroma suggests the potential relevance of the reciprocal interactions between these cell types, neoplastic cells and fibronectin for tumor progression. There is scarce evidence of the combined influence of these neoplastic cells/TME interactions on tumor progression, which may be specific to the type of cancer, organs/tissues affected and histological subtypes. In this proposal, we use in vitro studies in tridimensional co-cultures to characterize the reciprocal modulation and influence of fibronectin/a5b1 integrin on the phenotypes of CAFs and TAMs; and in vivo sequential approaches to investigate the potential of pharmacological modulation of these TME components on tumor growth, invasion and metastasis. The general hypothesis is that interactions between neoplastic cells and these components of the TME (TAMs, CAFs and fibronectin via a5b1 integrin) determine their phenotypes and modulate tumor cell invasion and response to treatment. The information derived from these studies can apply particularly to desmoplastic tumors with abundance of CAFs and high infiltration of TAMs, which are more aggressive, present poor prognosis and are less responsive to treatment. (AU)