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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-Rodríguez, Jasmin Meier, Tsunaki Hongu, Lena Wiedmann, Marieke A.G. Essers, Hans-Peter Sinn, Saskia Spaich, Marc Sütterlin, Andreas Schneeweiss, Andreas Trumpp, Thordur Oskarsson
doi: https://doi.org/10.1101/546952
Maren Pein
1Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
2Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
3Faculty of Biosciences, University of Heidelberg, Germany
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Jacob Insua-Rodríguez
1Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
2Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
3Faculty of Biosciences, University of Heidelberg, Germany
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Jasmin Meier
1Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
2Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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Tsunaki Hongu
1Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
2Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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Lena Wiedmann
1Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
2Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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Marieke A.G. Essers
1Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
4Division of Stress-induced Activation of Hematopoietic Stem Cells, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
7National Center for Tumor Diseases, Heidelberg University Hospital, German Cancer Research Center, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany
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Hans-Peter Sinn
5Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
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Saskia Spaich
6Department of Obstetrics and Gynaecology, University Medical Centre Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
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Marc Sütterlin
6Department of Obstetrics and Gynaecology, University Medical Centre Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
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Andreas Schneeweiss
7National Center for Tumor Diseases, Heidelberg University Hospital, German Cancer Research Center, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany
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Andreas Trumpp
1Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
2Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
8DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany
9German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
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Thordur Oskarsson
1Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
2Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
9German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
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  • For correspondence: t.oskarsson@dkfz.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-Rodríguez, Jasmin Meier, Tsunaki Hongu, Lena Wiedmann, Marieke A.G. Essers, Hans-Peter Sinn, Saskia Spaich, Marc Sütterlin, 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-Rodríguez, Jasmin Meier, Tsunaki Hongu, Lena Wiedmann, Marieke A.G. Essers, Hans-Peter Sinn, Saskia Spaich, Marc Sütterlin, Andreas Schneeweiss, Andreas Trumpp, Thordur Oskarsson
bioRxiv 546952; doi: https://doi.org/10.1101/546952

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