Uptake of tumor-derived microparticles induces metabolic reprogramming of macrophages in the early metastatic lung
Kelly Kersten,
Ran You,
Sophia Liang,
Kevin M. Tharp,
Joshua Pollack,
Valerie M. Weaver,
Matthew F. Krummel,
Mark B. Headley
Affiliations
Kelly Kersten
Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA; ImmunoX Initiative, University of California San Francisco, San Francisco, CA 94143, USA
Ran You
Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA; ImmunoX Initiative, University of California San Francisco, San Francisco, CA 94143, USA
Sophia Liang
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Kevin M. Tharp
Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco, San Francisco, CA 94143, USA
Joshua Pollack
ImmunoX Initiative, University of California San Francisco, San Francisco, CA 94143, USA; Foundery Innovations, San Francisco, CA 94080, USA
Valerie M. Weaver
Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco, San Francisco, CA 94143, USA
Matthew F. Krummel
Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA; ImmunoX Initiative, University of California San Francisco, San Francisco, CA 94143, USA; Foundery Innovations, San Francisco, CA 94080, USA
Mark B. Headley
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Immunology, University of Washington, Seattle, WA 98109, USA; Corresponding author
Summary: Pre-metastatic niche formation is a critical step during the metastatic spread of cancer. One way by which primary tumors prime host cells at future metastatic sites is through the shedding of tumor-derived microparticles as a consequence of vascular sheer flow. However, it remains unclear how the uptake of such particles by resident immune cells affects their phenotype and function. Here, we show that ingestion of tumor-derived microparticles by macrophages induces a rapid metabolic and phenotypic switch that is characterized by enhanced mitochondrial mass and function, increased oxidative phosphorylation, and upregulation of adhesion molecules, resulting in reduced motility in the early metastatic lung. This reprogramming event is dependent on signaling through the mTORC1, but not the mTORC2, pathway and is induced by uptake of tumor-derived microparticles. Together, these data support a mechanism by which uptake of tumor-derived microparticles induces reprogramming of macrophages to shape their fate and function in the early metastatic lung.
