The ERRα nuclear receptor as a modulator of interactions between cancer cells and immune cells

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Title: The ERRα nuclear receptor as a modulator of interactions between cancer cells and immune cells
Directors: Jean-Marc VANACKER & Bing DU
Discipline: Biology
Status: Incubating Project
Starting date: 2020

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Summary

High expression of the ERRα orphan nuclear receptor is globally associated with a poor prognosis in tumors including those of the breast. In cancer cells in vitro, ERRα promotes several parameters of cancer progression such as resistance to hypoxia, angiogenesis, cell migration and extracellular matrix invasion. Work from the French lab has also documented the molecular mechanisms through which ERRα regulates the latter processes and has identified a number of involved transcriptional coactivators and target. In vivo investigations have shown that ERRα promotes tumor growth as well as the establishment of metastasis from human cancer cells xenografted into immunodeficient mice. Altogether, these data allow to proposing ERRα as a promising target to counteract cancer progression. However, most of the above-mentioned data addressed the effects of ERRα in the cancer cells, i.e. in a cell-autonomous manner, and not within the frame of the complex relations that these cancer cells display with their immediate environment. Tumors are indeed heterogeneous as being composed of cancerous and non-cancerous cells that dynamically impact on each others’ features and activities to promote or limit cancer progression. For instance, under the influence of cancer cells, fibroblasts in the tumor microenvironment shift toward so-called cancer associated fibroblasts which in turn provide tumor-promoting cues to cancer cells. In an opposed manner, immune cells are recruited to the tumor to eliminate aberrant cells which will develop strategies to escape immunosurveillance.

We propose that ERRα not only acts as a cancer-cell-autonomous factor (i.e. modulating the properties of the cancer cells per se), but also impacts on cell-to-cell dialogs within a tumor. It is furthermore possible that ERRα regulates these dialogs through its activities in cancer cells and/or in cells of the local microenvironment. For example, the host lab has shown that ERRα regulates the expression and secretion of the matrix metalloprotease 1 (MMP1), leading to alterations of the surrounding extracellular matrix in 3D cultures. This phenomenon may lead to altered migration of both cancer and non-cancer cells within a tumor. As demonstrated by collaborative works of the host lab, ERRα also dampens the inflammatory process in macrophages and regulates their intrinsic migration capacities in vivo and ex vivo. As such it is possible that tumor immunosurveillance may be modulated by ERRα. The general purpose of the french lab is to study the effects of ERRα in these cell-to-cell interactions during tumor establishment. The current project is inserted into this general frame and will mainly focus on the relations between cancer cells and immune cells. Tools and results generated during the project will be used to develop other aspects of the team projects.

 

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