Metastasis-initiating cells induce and exploit a fibroblast niche to fuel malignant colonization of the lungs

Maren Pein, Jacob Insua-Rodríguez, Tsunaki Hongu, Angela Riedel, Jasmin Meier, Lena Wiedmann, Kristin Decker, Marieke A. G. Essers, Hans-Peter Sinn, Saskia Spaich, Marc Sütterlin, Andreas Schneeweiss, Andreas Trumpp and Thordur Oskarsson ()
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Maren Pein: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Jacob Insua-Rodríguez: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Tsunaki Hongu: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Angela Riedel: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Jasmin Meier: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Lena Wiedmann: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Kristin Decker: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Marieke A. G. Essers: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Hans-Peter Sinn: University of Heidelberg
Saskia Spaich: University Medical Centre Mannheim, Heidelberg University
Marc Sütterlin: University Medical Centre Mannheim, Heidelberg University
Andreas Schneeweiss: Heidelberg University Hospital, German Cancer Research Center
Andreas Trumpp: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Thordur Oskarsson: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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 phenotypic changes in lung fibroblasts, forming a supportive metastatic niche. Colonization of the lungs confers an inflammatory phenotype in metastasis-associated fibroblasts. Specifically, IL-1α and IL-1β secreted by breast cancer cells induce CXCL9 and CXCL10 production in lung fibroblasts via NF-κB signaling, fueling 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, which exhibits tumor-initiating ability when co-transplanted with fibroblasts and has high JNK signaling that drives IL-1α/β expression. Importantly, disruption of the intercellular JNK-IL-1-CXCL9/10-CXCR3 axis reduces metastatic colonization in xenograft and syngeneic mouse models. These data mechanistically demonstrate an essential role for the molecular crosstalk between breast cancer cells and their fibroblast niche in the progression of metastasis.

Date: 2020
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DOI: 10.1038/s41467-020-15188-x

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