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CXCR3-expressing metastasis-initiating cells induce and exploit a fibroblast niche in the lungs to fuel metastatic colonization

Maren Pein, Jacob Insua-Rodriguez, Jasmin Meier, Tsunaki Hongu, Lena Wiedmann, Marieke A.G. Essers, Hans-Peter Sinn, Saskia Spaich, Marc Sutterlin, Andreas Schneeweiss, Andreas Trumpp, Thordur Oskarsson
doi: https://doi.org/10.1101/546952
Maren Pein
DKFZ and HI-STEM gGmbH;
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Jacob Insua-Rodriguez
DKFZ and HI-STEM gGmbH;
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Jasmin Meier
DKFZ and HI-STEM gGmbH;
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Tsunaki Hongu
DKFZ and HI-STEM gGmbH;
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Lena Wiedmann
DKFZ and HI-STEM gGmbH;
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Marieke A.G. Essers
DKFZ and HI-STEM gGmbH;
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Hans-Peter Sinn
Institute of Pathology, University of Heidelberg;
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Saskia Spaich
University Medical Centre Mannheim;
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Marc Sutterlin
University Medical Centre Mannheim;
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Andreas Schneeweiss
National Center for Tumor Diseases, Heidelberg University Hospital
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Andreas Trumpp
DKFZ and HI-STEM gGmbH;
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Thordur Oskarsson
DKFZ and HI-STEM gGmbH;
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  • For correspondence: thordur.oskarsson@hi-stem.de
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Abstract

Metastatic colonization relies on interactions between disseminated cancer cells and the microenvironment in secondary organs. Here, we show that disseminated breast cancer cells evoke major phenotypic changes in lung fibroblasts to form a metastatic niche that supports malignant growth. Colonization of the lungs by cancer cells confers an inflammatory phenotype in associated fibroblasts, where IL-1α and IL-1β, secreted by breast cancer cells, induce CXCL9 and CXCL10 production in metastasis-associated fibroblasts via NF-κB signaling. These paracrine interactions fuel the growth of lung metastases. Notably, we find that the chemokine receptor CXCR3, that binds CXCL9/10, is specifically expressed in a small subset of breast cancer cells with stem/progenitor cell properties and high tumor-initiating ability when co-transplanted with fibroblasts. CXCR3-expressing cancer cells show high JNK signaling that drives IL-1α/β expression. Thus, CXCR3 marks a population of breast cancer cells that induces CXCL9/10 production in fibroblast, but can also respond to and benefit from these chemokines. Importantly, disruption of this intercellular JNK-IL-1-CXCL9/10-CXCR3 axis significantly reduces metastatic colonization in xenograft and syngeneic mouse models. These data mechanistically demonstrate an essential role for this molecular crosstalk between breast cancer cells and their fibroblast niche in the progression of metastasis.

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Posted February 11, 2019.
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CXCR3-expressing metastasis-initiating cells induce and exploit a fibroblast niche in the lungs to fuel metastatic colonization
Maren Pein, Jacob Insua-Rodriguez, Jasmin Meier, Tsunaki Hongu, Lena Wiedmann, Marieke A.G. Essers, Hans-Peter Sinn, Saskia Spaich, Marc Sutterlin, Andreas Schneeweiss, Andreas Trumpp, Thordur Oskarsson
bioRxiv 546952; doi: https://doi.org/10.1101/546952
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CXCR3-expressing metastasis-initiating cells induce and exploit a fibroblast niche in the lungs to fuel metastatic colonization
Maren Pein, Jacob Insua-Rodriguez, Jasmin Meier, Tsunaki Hongu, Lena Wiedmann, Marieke A.G. Essers, Hans-Peter Sinn, Saskia Spaich, Marc Sutterlin, Andreas Schneeweiss, Andreas Trumpp, Thordur Oskarsson
bioRxiv 546952; doi: https://doi.org/10.1101/546952

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