Subclonal cooperation drives metastasis by modulating local and systemic immune microenvironments
Autor: | Maša Alečković, Minsuk Kwak, Andriy Marusyk, Muhammad B. Ekram, Tyler Laszewski, Franziska Michor, Natalie L. Kingston, Kimiyo N. Yamamoto, Nikhil Wagle, Rong Fan, Adrienne M. Luoma, Kornelia Polyak, Yuanbo Qin, Nicholas W. Harper, Carlos R. Gil Del Alcazar, Simona Cristea, Michalina Janiszewska, Kai W. Wucherpfennig, Zafira Castaño, Katherine Murphy, Sandra S. McAllister, Ofir Cohen, Shaokun Shu, Doris P. Tabassum |
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Rok vydání: | 2019 |
Předmět: |
Lung Neoplasms
Stromal cell Carcinogenesis Neutrophils Population Cell Breast Neoplasms Biology Article Metastasis 03 medical and health sciences 0302 clinical medicine Immune system Tumor Microenvironment medicine Animals Humans Neoplasm Metastasis education Lung 030304 developmental biology 0303 health sciences education.field_of_study Tumor microenvironment Mesenchymal stem cell Mesenchymal Stem Cells Cell Biology medicine.disease 3. Good health Cell biology medicine.anatomical_structure 030220 oncology & carcinogenesis Monoclonal Disease Progression |
Zdroj: | Nature cell biology |
ISSN: | 1476-4679 1465-7392 |
Popis: | Most human tumours are heterogeneous, composed of cellular clones with different properties present at variable frequencies. Highly heterogeneous tumours have poor clinical outcomes, yet the underlying mechanism remains poorly understood. Here, we show that minor subclones of breast cancer cells expressing IL11 and FIGF (VEGFD) cooperate to promote metastatic progression and generate polyclonal metastases composed of driver and neutral subclones. Expression profiling of the epithelial and stromal compartments of monoclonal and polyclonal primary and metastatic lesions revealed that this cooperation is indirect, mediated through the local and systemic microenvironments. We identified neutrophils as a leukocyte population stimulated by the IL11-expressing minor subclone and showed that the depletion of neutrophils prevents metastatic outgrowth. Single-cell RNA-seq of CD45+ cell populations from primary tumours, blood and lungs demonstrated that IL11 acts on bone-marrow-derived mesenchymal stromal cells, which induce pro-tumorigenic and pro-metastatic neutrophils. Our results indicate key roles for non-cell-autonomous drivers and minor subclones in metastasis. |
Databáze: | OpenAIRE |
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