3D neuronal monitoring platforms for electrochemical sensing of neurotransmitters / IL1RAP targeting as a new therapeutic strategy for advanced triple negative breast cancer: identification of response biomarkers and mechanisms of action

3D neuronal monitoring platforms for electrochemical sensing of neurotransmitters

As the world’s population is living longer, neurodegenerative and neurological diseases are becoming a global issue. At the base of several neurological diseases (e.g., Alzheimer’s disease, Parkinson’s disease) there are neurotransmitters dysfunctions. Thus, determination of neurotransmission dynamics is a compelling phenotype to judge drug-induced neuroprotection. This project aims to develop an electrochemical biosensor of 3D hybrid hydrogel based on extracellular matrix and functionalized carbon nanotubes (f-CNTs) that quantifies neurotransmitters concentration in 3D neuronal cell cultures.

As first step, this study presents a comprehensive investigation into the development of neuronal cultures with distinct neurotransmission phenotypes. Models were developed from induced pluripotent stem cells (iPSC) derived neurons resulting in mature dopaminergic, cholinergic, and glutamatergic neurons with observable morphological traits and functional properties. In parallel, an electrochemical sensor platform was designed using Indium-Tin-Oxide coated coverslips with f-CNTs serving as working electrode. The CNTs were functionalized with gold nanoclusters or cobalt phthalocyanine (CoPC) for dopamine and hydrogen peroxide detection, respectively. The CNT-Au sensor’s electrochemical performance was characterized by differential pulse voltammetry, demonstrating a noticeable limit of detection (LOD) of 150nM and a sensitivity of 3,98E-04 A cm-2 μM-1.

IL1RAP targeting as a new therapeutic strategy for advanced triple negative breast cancer: identification of response biomarkers and mechanisms of action

IL1RAP, the receptor accessory protein of IL-1 pathway, is overexpressed in triple negative breast cancer (TNBC). Its blockade may be a potential therapeutic strategy in this disease. In fact, nadunolimab, a specific anti-IL1RAP antibody, is being tested in the TRIFOUR clinical trial, in which we participate, in combination with chemotherapy in TNBC. The aim of our project is to decipher the mechanisms involved in the pro-tumoral role of IL1RAP and to demonstrate that its blockade in TNBC may be an effective therapy to inhibit tumor-promoting inflammation. We also want to identify biomarkers of response to IL1RAP blockade by using patients’ samples from the TRIFOUR trial.

Our first experiments show that IL-1 stimulates the expression of pro-inflammatory cytokines known to be associated with breast cancer progression. We have also discovered that OSM may induce IL-1 signaling as it promotes the expression of IL-1α, IL-1β, IL1R1 and IL1RAP in culture cells and tumor xenografts. Bioinformatic analyses suggest that IL1RAP expression correlates with the presence of CAFs in the tumor microenvironment in breast cancer. Our results suggest that IL-1 signaling have a central role in the crosstalk between tumor cells and the surrounding microenvironment.