Adhesion forces between macrophages and cancer cells promote early tumor development
Abstract
Biochemical mechanisms of macrophage-driven tumor promotion are well documented, but the contribution of physical forces to early tumor development remains poorly understood. Here, we combine experimental analyses with physical modeling to investigate these forces in Kras G12D p53 −/− (KP) lung tumor spheroids grown in 3D. Real-time microscopy showed that tissue-resident macrophages, but not monocytes, promote early tumor growth. Using quantitative measurements, we built a physical model that recapitulates cancer cell proliferation dynamics and macrophage–tumor interactions. KP tumor cells grown alone formed a single aggregate that contracted over time due to nutrient limitation, whereas macrophages induced the formation of multiple aggregates that grew, fused, and expanded nutrient access, thereby increasing proliferation. Similar macrophage-driven growth was observed when alveolar or bone-marrow–derived macrophages were cocultured with KP or pancreatic carcinoma cells. The model predicted a redistribution of macrophages toward the periphery of aggregates, a pattern confirmed in vitro and previously observed in vivo. It also identified adhesion forces between tumor cells and macrophages as a key driver of spheroid nucleation and growth. Among candidate integrins, CD11c was highly expressed by alveolar macrophages; CD11c blockade reduced adhesion forces, prevented macrophage-driven spheroid nucleation, and impaired tumor growth. Bone-marrow-derived macrophages required simultaneous CD11b and CD11c blockade for similar effects. Finally, CD11c inhibition in RAG-Knock Out (KO) mice reduced tumor survival probability and slowed the growth of ear-implanted tumors, indicating that CD11c-dependent interactions support tumor establishment beyond the lung. Together, these findings uncover a critical physical mechanism through which macrophages promote early tumor progression.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (18)
Jovan Nikolic
Institut Curie, Paris Sciences & Lettres University, Institut National de la Santé et de la recherche Médicale U932, Immunity and Cancer
Joseph Ackermann
Laboratoire de Physique de l’Ecole normale supérieure, Ecole Normale Supérieure, Université Paris Sciences et Lettres, Centre National de la Recherche Scientifique, Sorbonne Université, Université Paris Cité
Ines Marin
Genentech, Department of Immunology and Ophthalmology
Sarah Taheraly
Institut Curie, Paris Sciences & Lettres University, Institut National de la Santé et de la recherche Médicale U932, Immunity and Cancer
Morgane Mabire
Institut Curie, Paris Sciences & Lettres University, Institut National de la Santé et de la recherche Médicale U932, Immunity and Cancer
François-Xavier Gobert
Institut Curie, Paris Sciences & Lettres University, Institut National de la Santé et de la recherche Médicale U932, Immunity and Cancer
Mathieu Maurin
Institut Curie, Paris Sciences & Lettres University, Institut National de la Santé et de la recherche Médicale U932, Immunity and Cancer
Apolline de Testas de Folmont
Institut Curie, Paris Sciences & Lettres University, Institut National de la Santé et de la recherche Médicale U932, Immunity and Cancer
Ouardia Aït-Mohamed
Institut Curie, Paris Sciences & Lettres University, Institut National de la Santé et de la recherche Médicale U932, Immunity and Cancer
Edison Gerena
Sorbonne Université, Centre National de la Recherche Scientifique UMR7222, Institut des Systèmes Intelligents et de Robotique
Sophie Goyard
Institut Pasteur, Université de Paris Cité, Institut National de la Santé et de la recherche Médicale-U1224, Cell Biology of Lymphocytes
Jérémy Mesple
Institut Curie, Paris Sciences & Lettres University, Institut National de la Santé et de la recherche Médicale U932, Immunity and Cancer
Hélène Salmon
Institut Curie, Paris, France.
Thierry Rose
Institut Pasteur, Université de Paris Cité, Institut National de la Santé et de la recherche Médicale-U1224, Cell Biology of Lymphocytes
Christine Moussion
Genentech, South San Francisco, CA, USA.
Martine Ben Amar
Laboratoire de Physique de l’Ecole normale supérieure, Ecole Normale Supérieure, Université Paris Sciences et Lettres, Centre National de la Recherche Scientifique, Sorbonne Université, Université Paris Cité
Jean-François Joanny
Institut Curie Physics of Cells and Cancer/Collège de France Chair Soft Matter and Biophysics
Philippe Benaroch
Institut Curie, Paris Sciences & Lettres University, Institut National de la Santé et de la recherche Médicale U932, Immunity and Cancer