Bioengineering a Patient‐Derived Vascularized Lung Tumor‐on‐Chip Model to Decipher Immunomodulation by the Endothelium
The endothelium compartment is a key player in tumor initiation and progression, but most existing tumor-on-chip models lack clinical relevance. Here, a 3D vascularized tumor-on-chip (vToC) model, generated with patient-derived microvascular endothelial cells (ECs) that are freshly isolated from surgical lung cancer samples, is presented. The microvessel molecular identity, morphology, and functionality are assessed by transcriptomic, immunofluorescence, TNF-α stimulation, and permeability assays. Lung cancer cells, cancer-associated fibroblasts (CAFs), and CD8+ tumor-infiltrating lymphocytes are embedded into the surrounding collagen matrix to partially recapitulate the lung tumor microenvironment (TME). The proof-of-concept of feasibility to generate personalized immunocompetent vToC composed of primary fully autologous cell types is provided. This vToC model is used to investigate the interplay between ECs and other TME cellular components by transcriptomic analysis. Using a rationally designed panel of endothelial genes, it is found that the presence of cancer cells and CAFs in the endothelial environment decreases expression by ECs of VCAM-1 leukocyte adhesion protein, a crucial regulator of immune infiltration, and of many immunomodulatory chemokines, recapitulating endothelial cell anergy. This in vitro model will be a valuable clinically-relevant tool to study the tumor-CAF-immune-endothelium interplay.
Authors
- Stéphanie Descroix (ORCID: https://orcid.org/0000-0003-0027-352X)
- Martin Nurmik (ORCID: https://orcid.org/0000-0002-6350-0577)
- Giacomo Gropplero
- Fabrice Soncin (ORCID: https://orcid.org/0000-0001-6312-0673)
- Irina Veith (ORCID: https://orcid.org/0000-0002-4654-2265)
- Nicolas Poté (ORCID: https://orcid.org/0000-0001-7695-7317)
- Manh‐Louis Nguyen
- Fathia Mami‐Chouaib (ORCID: https://orcid.org/0000-0001-9685-6011)
- Ségolène Ladaigue (ORCID: https://orcid.org/0000-0003-2937-0091)
- Gérard Zalcman
- Maria Carla Parrini (ORCID: https://orcid.org/0000-0002-7082-9792)
- Nicolas Zimmermann
- Fatima Mechta‐Grigoriou (ORCID: https://orcid.org/0000-0002-3751-6989)
- Christine Lansche
- Arnaud Roussel (ORCID: https://orcid.org/0009-0003-1747-6312)
- Pierre Mordant (ORCID: https://orcid.org/0000-0001-5716-4848)
- Solenn Brosseau (ORCID: https://orcid.org/0000-0002-8103-1954)
Institutions
- Université Claude Bernard Lyon 1 (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Paris Cité (FR)
- Université Paris Sciences et Lettres (FR)
- Université Paris-Saclay (FR)
- Institut Gustave Roussy (FR)
- Laboratory for Integrated Micro-Mechatronic Systems (JP)
- Institut Pierre-Gilles de Gennes pour la Microfluidique (FR)
- Centre Oscar Lambret (FR)
- Hôpital Bichat-Claude-Bernard (FR)
- Physique des Cellules et Cancers (FR)
- The University of Tokyo (JP)
- Institut Curie (FR)
Publication Details
- Journal
- Advanced Healthcare Materials
- Published
- 2025-05-09
- DOI
- https://doi.org/10.1002/adhm.202403446
- Citations
- 4
- Primary Topic
- 3D Printing in Biomedical Research
- Type
- article
- Field-Weighted Citation Impact
- 2.70
Funders
- Infrastructures en Biologie Santé et Agronomie
- Equipex
- European Commission
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale
- Fondation ARC pour la Recherche sur le Cancer
- Fondation de France
- Institut National Du Cancer
- Direction Générale de l’offre de Soins
- HORIZON EUROPE Framework Programme