Tumor Microenvironment (early diagnosis)

Tumor Microenvironment (early diagnosis)

The tumor microenvironment (TME) is a highly dynamic ecosystem where cancer cells interact with stromal, immune, and neuronal components. Understanding these interactions is essential for developing novel therapeutic strategies. The NEUROCAN project focuses on elucidating the role of the sympathetic and parasympathetic nervous systems in the TME and their contribution to metastatic behavior. By integrating advanced single-cell and spatial multi-omics technologies (COSMIX), NEUROCAN aims to characterize nerve-tumor crosstalk and identify novel molecular targets involved in tumor progression.

NEUROCAN investigates how nervous system signaling influences tumor heterogeneity, angiogenesis, and immune modulation. The project focuses on two major research directions: (1) identifying ion channel-mediated nerve-tumor interactions and their signaling pathways, and (2) exploring the role of tumor-derived extracellular vesicles (EVs) in neuritogenesis and cancer progression.

Key Research Axes

Ion Channels and Nerve-Tumor Crosstalk

Neuro-cancer interactions significantly impact tumor growth and metastasis. Ion channels play a crucial role in this dialogue, regulating cancer cell migration, proliferation, and angiogenesis. NEUROCAN seeks to identify the channelosome, i.e., the specific ion channel signatures within neuro-cancer niches.

Challenges Addressed

  • Determining how nerve-derived signals regulate ion channels in tumor cells.
  • Identifying the protein partners of hydrophobic ion channels using innovative proteomics approaches.
  • Investigating the role of ORAI3 in tumor angiogenesis and metastasis.

Key Developments

  • Mechanistic studies on the activation of ORAI3 by muscarinic receptors, leading to epithelial-mesenchymal transition (EMT).
  • In vivo validation in xenograft mouse models, demonstrating that ORAI3 overexpression enhances blood vessel formation through VEGF, angiogenin, and amphiregulin secretion.
  • Generation of an ORAI3 lox/lox mouse model, allowing selective deletion of ORAI3 in breast epithelial cells to study its role in tumor progression.
  • BioID-based proteomic analysis to identify ORAI3-interacting proteins and decipher its molecular network.
  • Spatial and single-cell omics integration (tumor slices, 3D microenvironment models) to map ORAI3 expression in tumor and nerve-infiltrated regions.

Extracellular Vesicles (EVs) and Cancer-Nerve Communication

Extracellular vesicles (EVs) mediate intercellular communication by transferring bioactive molecules such as proteins, lipids, and nucleic acids. Tumor-derived EVs influence the local nerve microenvironment, modulating neuritogenesis and cancer progression

Challenges Addressed

  • Defining how EV subpopulations vary across breast cancer molecular subtypes.
  • Investigating the impact of EV surface proteins (surfaceome) on selective neuron targeting.
  • Exploring adrenergic and non-adrenergic signaling pathways in EV-mediated neuritogenesis.

Key Developments

  • Functional characterization of tumor-derived EVs from different breast cancer cell lines (MCF-7, MDA-MB-231, T47D).
  • Neuritogenesis assays showing distinct EV effects: MCF-7 EVs act independently of adrenergic pathways, while MDA-MB-231 and T47D EVs induce neuritogenesis via β-adrenergic receptors.
  • Surfaceome analysis of EV subpopulations, identifying key proteins responsible for selective neuron targeting.
  • In vitro inhibition assays using neutralizing antibodies against EV surface markers to disrupt cancer-nerve communication.
  • Integration of COSMIX tools to track EV uptake and functional effects in nerve cells.