Large Oncosomes Induce Pro‐Metastatic Stromal‐Myeloid Reprogramming
8 affiliations
- 1Department of Urology Cedars‐Sinai Health Sciences University Los Angeles California USA
- 2Department of Medicine Cedars‐Sinai Health Sciences University Los Angeles California USA
- 3Department of Biomedical Sciences Cedars‐Sinai Health Sciences University Los Angeles California USA
- 4Department of Orthopaedics Cedars‐Sinai Health Sciences University Los Angeles California USA
- 5Department of Molecular Medicine and Medical Biotechnology University of Naples Federico II Naples Italy
- 6Department of Radiation Oncology Cedars‐Sinai Health Sciences University Los Angeles California USA
- 7Department of Genetics University of Texas MD Anderson Cancer Center Houston Texas USA
- 8Department of Radiological, Oncological and Pathological Sciences Sapienza University of Rome Rome Italy
Abstract
Bone metastasis can be facilitated by systemic remodeling, yet the tumor‐derived signals that influence the bone marrow microenvironment remain incompletely understood. Large oncosomes (LOs) are atypically large (> 1 µm), tumor‐derived extracellular vesicles shed by amoeboid cancer cells. Here, we demonstrate that LOs function as systemic mediators of metastatic niche formation by activating innate immune sensing in bone marrow mesenchymal stem cells (BM‐MSCs). Systemic administration of LOs to immunocompetent tumor‐bearing mice did not affect primary tumor growth but increased metastatic burden. LOs induced a robust, dose‐dependent interferon‐driven inflammatory program, characterized by interferon‐stimulated genes and neutrophil chemokines. Mechanistically, this response was driven by LO‐associated nucleic acids activating convergent cytosolic DNA‐ and RNA‐sensing pathways in recipient stromal cells. LO‐conditioned BM‐MSCs promoted the accumulation and polarization of neutrophils toward an immunosuppressive, polymorphonuclear myeloid‐derived suppressor cell (PMN‐MDSC)‐like phenotype. In vivo, genetic suppression of LO shedding in tumor cells reduced PMN‐MDSC accumulation in the bone marrow, which was reversed by systemic LO administration. Together, these findings support a model in which LO‐associated signals reprogram the bone marrow microenvironment to support metastatic colonization, identifying a previously unrecognized mechanism linking tumor vesiculation to immune remodeling at distant sites.
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BibTeX
@article{silva2026large,
title = {{Large Oncosomes Induce Pro‐Metastatic Stromal‐Myeloid Reprogramming}},
author = {Taylon Felipe Silva and Virginia Marcia Concato‐Lopes and Fatima Bedier and Lauren Newman and Diana Kitka and Jamelle Brown and Blandine Victor and Minhyung Kim and Tatyana Vagner and Catherine Grasso and Dmitriy Sheyn and Sungyong You and Michael R. Freeman and Fayyaz S. Sutterwala and Helen S. Goodridge and Caroline Jefferies and Paola de Candia and Jlenia Guarnerio and Dolores Di Vizio},
journal = {Advanced Science},
year = {2026},
month = oct,
doi = {10.1002/advs.78406},
url = {https://doi.org/10.1002/advs.78406},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Large Oncosomes Induce Pro‐Metastatic Stromal‐Myeloid Reprogramming
AU - Taylon Felipe Silva
AU - Virginia Marcia Concato‐Lopes
AU - Fatima Bedier
AU - Lauren Newman
AU - Diana Kitka
AU - Jamelle Brown
AU - Blandine Victor
AU - Minhyung Kim
AU - Tatyana Vagner
AU - Catherine Grasso
AU - Dmitriy Sheyn
AU - Sungyong You
AU - Michael R. Freeman
AU - Fayyaz S. Sutterwala
AU - Helen S. Goodridge
AU - Caroline Jefferies
AU - Paola de Candia
AU - Jlenia Guarnerio
AU - Dolores Di Vizio
PY - 2026
DA - 2026/10/25
JO - Advanced Science
DO - 10.1002/advs.78406
UR - https://doi.org/10.1002/advs.78406
AB - Bone metastasis can be facilitated by systemic remodeling, yet the tumor‐derived signals that influence the bone marrow microenvironment remain incompletely understood. Large oncosomes (LOs) are atypically large (> 1 µm), tumor‐derived extracellular vesicles shed by amoeboid cancer cells. Here, we demonstrate that LOs function as systemic mediators of metastatic niche formation by activating innate immune sensing in bone marrow mesenchymal stem cells (BM‐MSCs). Systemic administration of LOs to immunocompetent tumor‐bearing mice did not affect primary tumor growth but increased metastatic burden. LOs induced a robust, dose‐dependent interferon‐driven inflammatory program, characterized by interferon‐stimulated genes and neutrophil chemokines. Mechanistically, this response was driven by LO‐associated nucleic acids activating convergent cytosolic DNA‐ and RNA‐sensing pathways in recipient stromal cells. LO‐conditioned BM‐MSCs promoted the accumulation and polarization of neutrophils toward an immunosuppressive, polymorphonuclear myeloid‐derived suppressor cell (PMN‐MDSC)‐like phenotype. In vivo, genetic suppression of LO shedding in tumor cells reduced PMN‐MDSC accumulation in the bone marrow, which was reversed by systemic LO administration. Together, these findings support a model in which LO‐associated signals reprogram the bone marrow microenvironment to support metastatic colonization, identifying a previously unrecognized mechanism linking tumor vesiculation to immune remodeling at distant sites.
SN - 2198-3844
ER -